bluuebunny/crossref_metadata_2025 huggingface dataset:
Perioperative FLOT (fluorouracil, leucovorin, oxaliplatin and docetaxel) versus EOX/EOF (epirubicin, oxaliplatin and capecitabine or fluorouracil) for locally advanced, resectable gastric or gastro-oesophageal junction (GOJ) adenocarcinoma: A regional center experience.
Authors: Wong Emily , Tan Alvin Boon Tee
Published: May 2020

e16556

Background: The FLOT4-AIO trial demonstrated a survival benefit in patients with resectable gastric or GOJ adenocarcinoma who received FLOT compared to ECX/ECF (epirubicin, cisplatin, capecitabine or fluorouracil) chemotherapy, but there has been no direct comparison made between FLOT and EOX/EOF regimens in randomised trials to date. Methods: Patients with locally advanced, resectable gastric or GOJ adenocarcinoma treated between December 2012 to December 2019 with FLOT or EOX/EOF in the Midland region were identified. FLOT patients received four preoperative and four postoperative 2-week cycles of 50 mg/m2 docetaxel, 85 mg/m2 oxaliplatin, 200 mg/m2 leucovorin and 2600 mg/m2 fluorouracil as 24-h infusion on day 1. The EOX/EOF patients received three preoperative and three postoperative 3-week cycles of 50 mg/m2 epirubicin, 130 mg/m2 oxaliplatin on day 1 plus either 200 mg/m2 fluorouracil as continuous intravenous infusion or 1250 mg/m2 capecitabine orally on days 1 to 21. We compared the pathological response and tolerability of these regimens. Results: 38 patients received FLOT and 36 patients received EOX/EOF chemotherapy. The median age was 60 and 63.5 respectively. R0 resection was achieved in 31 out of 35 FLOT patients (89%), and 32 out of 35 EOX/EOF patients (91%) who proceeded with surgical resection following pre-operative chemotherapy. AJCC tumour regression score 0-1 was seen in 14 (37%) FLOT patients and 12 (33%) EOX/EOF patients. 30 (79%) FLOT patients and 29 (80%) EOX/EOF patients completed their planned preoperative courses. In the postoperative phase, 20 (56%) FLOT patients and 9 (25%) EOX/EOF patients completed their planned course. Dose reductions occurred in 27% of FLOT patients and 15% of EOX/EOF patients. Grade 3/4 adverse events occurred in 30% of FLOT cycles, and 19% of EOX/EOF cycles administered. Conclusions: Perioperative FLOT and EOX/EOF chemotherapy had similar pathological response, with higher completion of postoperative chemotherapy with FLOT regime.
Cytokine status in the omentum and peritoneum in metastatic gastric cancer.
Authors: Zlatnik Elena Yu. , Kit Oleg I. , Sagakyants Aleksandr B. , Zolotareva Ekaterina I. , Shulgina Oksana G. , Novikova Inna A. , Samoylenko Nikolay S. , Soldatkina Natalya V. , Gevorkyan Yuriy A. , Dzhenkova Elena A. , Kharagezov Dmitry A. , Dashkov Andrey V. , Kolesnikov Vladimir E. , Poluektov Sergey I. , Kaymakchi Dmitry O. , Dontsov Vladimir A. , Shaposhnikov Alexander V. , Petrov Dmitry S. , Fomenko Yuriy A.
Published: May 2020

e16557

Background: Gastric cancer (GC) is one of the most common malignant tumors and the second most common cause of cancer deaths in Russia. Many researchers note the ambiguous role of cytokines in the pathogenesis of tumor processes. The purpose of the study was to determine characteristics of the cytokine status in the omentum and peritoneum of patients with metastatic GC. Methods: The main group (Mgr) included 23 patients with T2-4N0-3M1 GC with metastases to the peritoneum and greater omentum, the mean age 58.9±9.7 years. The comparison group (Cgr) included 20 non-cancer patients, the mean age 55.9±9.7 years. Tissues of the omentum (OT) and peritoneum (PT) were obtained from all patients during cytoreductive and diagnostic surgeries. Ex tempore tissues were disintegrated using BD Medimachine (USA) with 0.9% NaCl; the cell suspension was centrifuged, and the supernatant was collected and aliquoted. Levels of cytokines IL-1β, IL-2, IL-6, IL-8, IL-18, TNF-α, IL-10 (Vektor-Best, Russia) and IL-1RA (eBioscience, Austria) were determined by ELISA. The results were expressed as the specific content per 1 g of protein evaluated by the biuret method (pg/mL/g of protein). Statisical analysis of the results was performed with the Statistica 10 program (StatSoft Inc., USA). Significance of differences was evaluated using the Mann-Whitney and Wilkinson tests; differences were considered significant at p < 0.05. Results: In Cgr, levels of IL-6, IL-8, IL-18 and IL-1β in OT were 4.1±1.1, 3.4±0.7, 21.2±5.5 and 10.8±2.1, while in Mgr – 55.3±24.4, 32.5±13.8, 144.9±48.4 and 21.01±5.4 pg/mL/g of protein, i.e. 13.7, 9.5, 6.9 and 1.9 times (p≤0.05) higher than in Cgr, respectively. The specific content of IL-1RA in OT was 12.6 times higher, p≤0.05 (215.7±69.8 vs. 2723.1±730.1), and the IL-10 concentration did not differ significantly. In PT of Cgr, levels of IL-8, IL-18 and IL-6 were 9.8±7.3, 35.2±21.7, 7.5±3.7, and in Mgr – 250.7±21.4, 322.9±16.9, 61.1±27.6 pg/mL/g, i.e. 25.7, 9.2 and 8.2 times (p≤0.05) higher than in Cgr. IL-1RA in PT of Mgr was 24.4 times higher than in Cgr, p≤0.05 (7656.2±3160.3 vs. 357.69±180.86). Conclusions: A certain microenvironment is formed in OT and PT affected by metastases, with specific features in the ratio and concentrations of various cytokines, which undoubtedly contribute to the formation of a secondary tumor.
Pembrolizumab vs paclitaxel as second-line treatment for Asian patients with PD-L1–positive advanced gastric or gastroesophageal cancer (GC) in the phase III KEYNOTE-063 trial.
Authors: Chung Hyun Cheol , Kang Yoon-Koo , Chen Zhendong , Bai Yuxian , Wan Ishak Wan Zamaniah , Shim Byoung Yong , Park Youngiee , Koo Dong-Hoe , LU Jin Wei , Xu Jianming , Bhagia Pooja , Kuang Shu , Shih Chie-Schin , Qin Shukui
Published: May 2020

e16586

Background: Approximately 75% of GC cases occur in Asian persons. Pembrolizumab has shown antitumor activity in global studies of GC. KEYNOTE-063 (NCT03019588) is a randomized, open-label, phase 3 trial in Asian patients with advanced PD-L1–positive (combined positive score [CPS] ≥1) GC that progressed after platinum + fluoropyrimidine chemotherapy. After the KEYNOTE-063 study began, results of the global KEYNOTE-061 study (NCT02370498) showed that pembrolizumab did not prolong overall survival (OS) vs paclitaxel in patients previously treated for advanced GC (median OS, 9.1 months vs 8.3 months; hazard ratio [HR], 0.82; 95% CI, 0.66-1.03; 1-sided P= 0.0421 [significance threshold for OS was 1-sided P= 0.0135]). Methods: Eligible patients were randomly assigned in a 1:1 ratio to receive pembrolizumab 200 mg Q3W for up to 35 cycles (~2 years) or standard-dose paclitaxel. The primary efficacy end points were OS and progression-free survival (PFS). Planned enrollment was ~360 patients. Results: Because pembrolizumab did not significantly prolong OS in KEYNOTE-061, enrollment in KEYNOTE-063 was discontinued after 94 patients were enrolled (47 patients in each treatment group). In these Asian patients, median OS was 8.4 months in the pembrolizumab group and 7.7 months in the paclitaxel group; median PFS was 1.9 months and 4.0 months, respectively (Table). Objective response rate (ORR) and median duration of response (DOR) are shown in the Table. Drug-related adverse events (AEs) occurred in 59.6% of patients receiving pembrolizumab and in 95.5% of patients receiving paclitaxel (Table). Conclusions: In this small sample of Asian patients with PD-L1–positive advanced GC, definitive conclusions are limited; however, second-line pembrolizumab monotherapy seems to be well tolerated in this patient population. Because this study was terminated early, there was insufficient power for comparisons between groups; therefore, these data should be viewed with caution. Clinical trial information: NCT03019588 . [Table: see text]
Transarterial infusion chemotherapy (TAI) combined with Sintilimab in locally advanced, potentially resectable hepatocellular carcinoma (HCC).
Authors: Xu Li , Zhang Yaojun , Wang Xiaohui , Shi Mude , Wang Juncheng , Tang Yuhao , Fu Yizhen , Zhou Zhongguo , Chen Minshan
Published: May 2020

e16593

Background: Our previous studies showed that TAI with modified FOLFOX increased tumor response and resection rate compared with conventional TACE in advanced HCC. PD-1/PD-L1 inhibitors have been demonstrated promising value in HCC. This study aims to evaluate the efficacy and safety of FOLFOX-TAI combined with Sintilimab (a PD-1 inhibitor) in locally advanced, potentially resectable HCC. Methods: This prospective, nonrandomized controlled phase II study is recruiting 40 pts with locally advanced, potentially resectable HCC (localized to semi-liver with invasion to branch of the portal vein). Pts in the combined group receive repeated 3-week cycles of Sintilimab 200mg IV Day1 and TAI with FOLFOX Day2 (Oxaliplatin 130 mg/m2, Leucovorin 400 mg/m2, 5-FU 400 mg/m2 and 5-FU 2400 mg/m2, next 46 hours). Pts in the control group only received TAI. Tumor assessment with RECIST 1.1 was performed every 2 cycles. The pts gained visible tumor shrinkage and opportunity for resection received surgical hepatectomy. Pts with stable disease (SD) or unconfirmed progression disease (PD) will receive repeated cycles until confirmed PD or intolerable toxicity, with max cycles of 8 for TAI and 16 for Sintilimab. The primary endpoint is progression or postoperative relapse free survival (PFS). Secondary endpoints include ORR, DCR, resection rate, OS, and safety. Results: As of Jan 10, 2020, 33 eligible pts were enrolled. All treatment related AEs were grade 1 or 2, including transaminase and bilirubin increase, nausea, hypoalbuminemia, rash, leucopenia, thrombopenia, and weight loss. No irAE and treatment related SAE was observed. Conclusions: TAI combined with Sintilimab attributed to high surgical conversion rate and good safety profile for locally advanced, potentially resectable HCC. Clinical trial information: NCT03869034 .
Does an association exist between liver fibrosis and non-HCC cancers.
Authors: Banskota Shristi Upadhyay , Farooq Muhammad Zain , Agrawal Rohit , Vohra Ishaan , Ba Aqeel Sheeba Habeeb , Lingamaneni Prasanth , Sherazi Syed Ali Amir , Moturi Krishna Rekha , Wang Yuchen
Published: May 2020

e16594

Background: The association between liver fibrosis and hepatocellular cancer (HCC) is well established, however there is limitation of data on liver fibrosis and non-HCC cancers. The aim of this study was to explore the link between the degree of liver fibrosis and other cancers. Methods: We searched the electronic medical records of Stroger Hospital who underwent liver elastography from January 1st, 2014 to December 31st, 2018 and had cancer. We extracted variables: demographics, cancer histology and metastatic status and then stratified patient into categories based the fibrosis stage. Results: Our analysis identified 103 patients with non-advanced fibrosis (F0-F2) and 74 with advanced fibrosis (F3-F4). HCC was seen in 33.3% of the patients with advanced fibrosis while genitourinary (GU) was the second most common cancer. Adenocarcinoma comprised 21% of these cancers and around 46% were metastatic. Of the 104 patients with non-advanced fibrosis, HCC was seen in 3.77% while gastrointestinal (GI) and GU cancers were seen in 24.27% and 12.62% respectively. Adenocarcinoma was most common (40%) in this group as well (Table). Conclusions: Our study not only reiterates the fact that the degree of liver fibrosis is proportional to the presence of HCC, but it also reports the association of liver fibrosis with several non-HCC cancers. The meaning of these associations is unclear, but it provides an area of further research to explore if causality exists. [Table: see text]
Survival of older patients with advanced biliary tract cancers by disease site.
Authors: Bobiak Sarah , Lubeck Deborah P. , Duryea Jennifer , Danese Mark D.
Published: May 2020

e16598

Background: Biliary tract cancers (BTC) arise from the epithelial lining of the biliary tree and include intrahepatic and extrahepatic cholangiocarcinoma, gallbladder cancer, and sometimes cancer of the ampulla of Vater. Although this is a closely related group of diseases, comparisons of risk factors, treatment, and mortality by disease site are limited. Methods: This retrospective cohort study used Surveillance, Epidemiology, and End Results (SEER) cancer registry data linked with Medicare claims. Patients aged ≥66 years with a pathologically confirmed diagnosis of advanced (stage III or IV) BTC from 2010 to 2015 were included and followed up through 2016. Patients with any SEER-reported cancer in the prior 2 years were excluded. Any outpatient systemic treatment during follow-up was identified using Medicare claims. Patients were followed up until death, end of follow-up, subsequent primary cancer, or switch to managed care. The Kaplan-Meier estimator was used to estimate unadjusted median survival. A Cox proportional hazards model was used to identify factors associated with survival. Results: There were 2,891 patients in the cohort (Table). Factors significantly associated with worse survival included older age, presence of mobility limitations, living in an area with > 30% of the people below poverty, higher comorbidity burden, and stage IV BTC (vs stage III). Factors significantly associated with better survival included history of cancer, intrahepatic BTC (vs extrahepatic), or ampulla of Vater BTC (vs extrahepatic). Conclusions: Survival in BTC is poor and many patients do not receive outpatient systemic therapy. Patients with gallbladder and extrahepatic BTC had worse median survival and were less likely to receive systemic therapy than those with intrahepatic or ampulla of Vater BTC. Fewer ampulla of Vater patients present with Stage IV disease which could be a contributing factor to the significantly longer survival. Prior work has demonstrated an association between history of some types of cancer and survival; additional research is needed to better understand this finding. [Table: see text]
A phase Ib/II, open-label study of tivozanib in combination with durvalumab in subjects with untreated advanced hepatocellular carcinoma.
Authors: Iyer Renuka V. , Li Daneng , Dayyani Farshid , Needle Michael N. , Abrams Thomas Adam
Published: May 2020

e16599

Background: VEGFR TKIs and checkpoint inhibitors are current standards of care in HCC as single agents, however treatment options are limited, and significant unmet need remains. A recent ph3 study combining bevacizumab (VEGF-A Mab) with a PDL1 inhibitor have shown promising improvements in OS demonstrating that a combination of VEGF and PDL1 inhibition can improve patient outcomes over single agent treatment. Tivozanib (T, a potent and selective VEGFR 1, 2 & 3 TKI) and durvlaumab (D, a PD-L1 antibody) have both demonstrated single agent activity in HCC and have been combined safely with other therapies to enhance patient outcomes in other tumor types. It is hypothesized that more complete inhibition of the VEGF pathway by tivozanib compared to bevacizumab combined with PDL1 inhibition may further enhance patient outcomes. The ph1 portion of this study combines T with D to establish the recommended phase 2 dose (RP2D) and provide preliminary safety and efficacy data. Methods: Major eligibility criteria are adults with documented advanced HCC, Child-Pugh Class A, ECOG 0 or 1, creatinine clearance > 40 ml/min. Major exclusion criteria are co-infection with HBV and either HDV or HCV and significant organ dysfunction. Six patients with untreated advanced HCC will be treated with the combination of T 1 mg orally for 21 days followed by 7 days off treatment and D 1500 mg intravenously every 28 days. A DLT is generally defined as the occurrence of any Grade ≥3 immune or non-immune AE in Cycle 1 that is at least possibly related to the investigational regimen other than any grade of vitiligo or alopecia or Grade 3 controllable hypertension. If two or more patients have a DLT then the dose of tivozanib will be reduced to 1 mg every other day without interruption for the second cohort. In the Phase 2 portion of the study an additional 30 patients will be treated at the RP2D. The primary objective is to establish the RP2D and the safety and tolerability for this combination in patients with advanced HCC. Secondary objectives are to assess the objective response rate, progression free survival, and overall survival in this population. Patients will be treated until progression of disease, unacceptable side effects, or death. Outcome measures will be adverse events per CTCAE v.5 and cross-sectional imaging performed every 8 weeks. Results: Phase 1 safety and efficacy findings for this novel combination will be reported at the meeting. Conclusions: Phase 1 safety and efficacy findings for this novel combination will be reported at the meeting. Clinical trial information: NCT03970616 .
Does time to treatment initiation affect survival in patients with gallbladder cancer?
Authors: Islam KM , Odhiambo Lorriane Achieng , Ansa Benjamin , Copur Mehmet Sitki
Published: May 2020

e16600

Background: Gallbladder cancer (GBC) is the most aggressive malignancy of the biliary tract. Though rare, most diagnoses are made in advanced stages, which significantly impacts survival outcomes. In the U.S., only 20% of GBC cases are diagnosed early. In addition to late diagnosis, time to treatment initiation (TTI) after diagnosis may contribute to poor prognosis in GBC patients. The role TTI plays on survival is not well understood in patients with GBC. This study aimed to determine the effect of time to treatment initiation on overall survival and by stage. Methods: Data on 26,952 GBC patients from 2004 to 2012 were obtained from the National Cancer Database (NCDB). The primary outcome was overall survival in months. TTI was defined as the number of days between diagnosis and treatment initiation (surgery, chemotherapy, radiation). The Kaplan-Meier method was used to calculate survival estimates and Cox proportional hazards regression model to evaluate the effects of TTI (continuous variable) stratified by stage. Results: The overall median survival was 8.6 months (I.Q.R. = 2.6-23.9). The effect of TTI on survival (unadjusted Hazard Ration (UHR) 1.0 (p = < 0.0001)) was significant, but not after adjusting for other variables, (adjusted Hazard Ratio (AHR) 1.0 (p = 0.1506)). The trend was different across cancer stages. TTI showed a negative effect on survival in stages III (AHR: 1.00, p = 0.0083) and IV (AHR: 0.99, p < .0001). Other factors associated with lower survival are advanced stage, male, older age, comorbidity, community cancer facility, and whether a patient visited more than one facility for treatment. Conclusions: In general, time to treatment initiation did not affect survival but advanced stage lowered survival significantly. More attention should be given to patients who decide to seek second opinion at or those given treatment referrals to other facilities as the adjustments may contribute to delays in treatment initiation.
Hepatic artery infusion chemotherapy combined with apatinib and toripalimab in advanced hepatocellular carcinoma: Real-world data from a single center.
Authors: Gu Yang-Kui , Zhang Tian-Qi , Huang Zi-Lin , Geng Zhi-Jun , Chen Chen , Li Fu-Gui , Xu Li , Sun Jian , Li Jibin , Huang Zhi-Mei , Shen Lujun
Published: May 2020

e16602

Background: Outcomes remain poor for patients with advanced hepatocellular carcinoma (HCC). Hepatic arterial infusion chemotherapy (HAIC), antiangiogenic agents, and immune checkpoint inhibitors (ICIs) are available monotherapy options. Considering different anti-malignancy mechanisms, combining these three modalities may improve outcomes. We aimed to assess the efficacy and safety in a small cohort treated with HAIC combined with Apatinib and ICI (Toripalimab) for advanced HCC patients. Methods: We performed a retrospective study included patients with advanced HCC treated in the Sun Yat-sen University Cancer Center. Patients received 6 treatment cycles of 21 days, with HAIC given over an initial period of 50 hours (oxaliplatin 85 mg/m2, then folinic acid 400 mg/m2, then fluorouracil 2500 mg/m2). Patients also received apatinib (250 mg daily, starting day 8 of cycle 1), toripalimab (240 mg on day 4 of each cycle, starting with cycle 2), both continuing after the HAIC cycles until disease progression. Disease control was assessed using the RECIST 1.1 and mRECIST criteria. Safety was assessed using the CTCAE 5.0. Blood biomarkers (AFP and PIVKA-II) were log transferred and compared at baseline and last follow-up. Results: From April to August 2019, 6 patients (5 males, 51.7±11.6 years) were included. All patients finished 6 cycles of HAIC. After a median follow-up of 7.0 (range, 3.9-8.3) months, all patients remained objective response (6 PR by RECIST; 3 CR and 3 PR by mRECIST). Median time to response was 1.3 (range, 0.7-2.0) months. Blood logAFP (baseline: 3.2±1.6, last follow-up: 1.3±1.4; p = 0.029) and logPIVKA-II (baseline: 4.4±0.6, last follow-up: 2.0±1.4; p = 0.006) levels were significantly decreased after treatment. The most common adverse events (AEs) included hypertension, palmar-plantar erythrodysesthesia syndrome, and anorexia, observed in all patients. Four patients had Grade 3 AEs (myelosuppression in 2; palmar-plantar erythrodysesthesia, hypothyroidism, anorexia, hyperbilirubinemia and hypokalemia in 1). No Grade 4/5 AEs occurred. Conclusions: In patients with advanced HCC, treatment with strategically timed triple combination therapy of HAIC, apatinib, and toripalimab shows promising clinical benefit and safety. [Table: see text]
Treatment outcome and prognostic indicators in 26 cases of fibrolamellar hepatocellular carcinoma under interferon based therapy.
Authors: Mohamed Yehia I. , Qayyum Aliya , Hassan Manal , Xiao Lianchun , Duda Dan G. , Hatia Rikita , Lee Sunyoung S. , Wolff Robert A. , Morris Jeffrey , Altameemi Lina , Yao James C. , Amin Hesham M. , Kaseb Ahmed Omar
Published: May 2020

e16626

Background: Fibrolamellar hepatocellular carcinoma (FLHCC) is a variant of HCC that comprises ∼1%–9% of all HCCs, with about 200 annual cases reported globally, most often affects younger patients (10–35 years of age) with no underlying liver disease. There is no current standard of care therapy for unresectable FLHCC. We report an analysis of the treatment outcomes, and prognostic indicators of 26 cases. Methods: We retrospectively collected clinicopathologic and treatment outcome data from 26 FLHCC patients who received interferon alfa-2b (IFN) based therapy. Median overall survival (OS) and PFS were calculated using Kaplan-Meier curves, and survival rates were compared by the log-rank test. Results: 21 patient underwent treatment with continuous infusion (CI) 5-Fluorouracil (FU) at 200 mg/m2/day for 7 days on, 7 days off plus IFN at 4 million units/m2, subQ every other day for 7 days on, 7 days off, 1 patient FU+IFN+bevacizumab and 4 patients had PIAF (cisPlatin+IFN+Adriamycin+FU). Median age was 24 years (15-44), 13 males and 13 females, 8 of the 26 patients died, the median overall survival was 33.9 months (95% CI, 20.9, NA), estimated 3-year survival was 20.2% (95% CI: 4.1%, 98.5%), median follow up time was 13.4 months (95% CI: 9.79, NA) and median progression-free survival was 11.7 months (95% CI: 5.09, NA). The estimated 1-year survival was 47.9% (95% CI: 29.9%, 76.8%). Finally, FU+IFN combination was the most frequently used systemic therapy. 3/26 pts underwent surgical resection following neoadjuvant treatment with interferon based therapy; Interferon based therapy for the 26 patients had limited side effects, with only 3 of the 26 patients discontinued treatment due to grade 3-4 adverse event in the form of mucositis, severe fatigue and/or hematologic toxicity. Conclusions: Our analyses indicate that CI FU + IFN could be an effective treatment for FLHCC, and may have a neoadjuvant role in this disease with 3/26 were resectable following neoadjuvant treatment with interferon based therapy. This regimen can be well tolerated. Unfortunately, nonsurgical options for patients with FLC remain limited with no approved local or systemic therapies. Therefore, future research is needed to identify better multimodality therapies.
Long-term outcome analysis of Y90 radioembolization in hepatocellular carcinoma.
Authors: Alder Laura , Nguyen Matthew , Qu James , Lee Hannah , Thacker Leroy R. , Dougherty Sean , Poklepovic Andrew Stewart
Published: May 2020

e16633

Background: Yttrium-90 (Y90) radioembolization is a catheter-based therapy utilized in the treatment of hepatic tumors such as hepatocellular carcinoma (HCC). Multiple trials have evaluated the efficacy of Y90 in HCC; few have assessed long term hepatic function. These studies reported PFS ranging from 7.9 to 18 months (m), and median OS of 17.2 to 18 m for Child-Pugh (CP) Class A and 6.0 to 7.7 m for CP Class B. This study aimed to evaluate a clinical real-world experience of Y90 therapeutic effectiveness and long-term impact on hepatic function. Methods: A single-center retrospective chart review was performed for patients with a CP score of A or B who received Y90 for primary HCC between 2008 and 2016. Model for end stage liver disease (MELD) and CP scores were calculated for the day of treatment and at 1, 3, 6, 12, and 24 m post procedure. OS and PFS were characterized using a Kaplan-Meier survival analysis and a multivariate model. Results: 134 patients were included. Mean age was 60 years old, ranging from 44-90. Underlying liver disease included HCV – 66%, ETOH cirrhosis – 23%, NAFLD – 19%, HBV – 5%. CP Class A patients (79%) had a median OS of 16.59 m (95% CI: 8.90 to 23.10m) from date of Y90 treatment compared to a median of 7.90 m (95% CI: 4.60 to 15.64 m) for CP Class B. CP Class A patients had a median PFS of 3.45 m (95% CI: 2.99 to 5.55 m) from date of Y90 treatment compared to a median of 3.71 m (95% CI: 2.07 to 8.28 m) for CP Class B patients. These differences were not statistically significant. Median OS from date of diagnosis for the entire study population was 29.37 m (95% CI: 23.00 to 38.77 m). MELD scores were statistically significantly higher at 1, 3, 6 and 12 m post-treatment than on Day 0, with significant recovery at 24 vs 3 m. Older age, higher T stage, higher MELD and CP scores, and patients with a history of portal vein thrombosis (PVT) had significantly lower OS. PFS was significantly shorter in those with advanced stage at diagnosis and higher CP score. Conclusions: While our study supports the literature for OS in Y90 patients, we found a shorter PFS in this population. This may reflect the utilization of RECIST in clinical trials vs clinical radiology practice in determining progression. Over time, the most significant factors associated with OS were age, MELD and CP scores and PVT. For PFS, CP score and stage at diagnosis were significant. The increasing MELD and CP scores over time reflect a possible mix of radio embolization‐induced liver disease and progression of HCC. The downtrend at 24 m is likely due to durable survivors with significant benefit from therapy and no long-term complications from Y90.
A phase Ib/II study of olutasidenib in patients with relapsed/refractory IDH1 mutant solid tumors: Safety and efficacy as single agent.
Authors: Jones Robin Lewis , Macarulla Teresa , Charlson John A. , Van Tine Brian Andrew , Goyal Lipika , Italiano Antoine , Massard Christophe , Rosenthal Mark , De La Fuente Macarena Ines , Roxburgh Patricia , Kundranda Madappa N. , Blay Jean-Yves , Yoo Changhoon , Lipford Kate , Forsyth Sanjeev , Guichard Sylvie Mireille , Mikhailov Yelena , Thomson Blythe , Kelly Patrick Francis , Duffaud Florence
Published: May 2020

e16643

Background: Isocitrate dehydrogenase 1 mutations (mIDH1) are present in a variety of solid tumors resulting in production and accumulation of (R)-2-hydroxyglutarate causing DNA hypermethylation and promoting tumorigenesis. Olutasidenib is an oral, potent and selective inhibitor of mutated IDH1 protein. We report preliminary results from the ongoing, first-in-human, Phase 1, open-label, single-arm study of olutasidenib in non-CNS solid tumors. Methods: Patients with advanced relapsed/refractory (R/R) mIDH1 solid tumors received olutasidenib 150 mg BID, orally. Following a dose confirmation cohort (Phase 1b), patients with intrahepatic cholangiocarcinoma (IHCC), chondrosarcoma (CS), or unspecified mIDH1 solid tumors (Other) were enrolled in a Phase 2 efficacy evaluation (NCT: 03684811). Results: As of 31-Oct-2019, 44 patients with relapsed or refractory mIDH1 solid tumors were treated with olutasidenib. Diagnosis included: IHCC (n = 26), CS (n = 13), and Other (n = 5). The median age was 58 years (range: 29-81) and 43% were male. Median number of prior treatments was 2 (1-10). mIDH1 status was locally determined (IHC, NGS or PCR): R132C (61%), R132G (7%), R132S (7%), R132H (2%), R132L (2%), Others (2%) & unspecified (18%). Fourteen patients discontinued treatment (disease progression [n = 6; 3 IHCC, 2 CS, 1 Other], AE [n = 4; 3 IHCC, 1 CS], PI decision [n = 3; IHCC] & withdraw consent [n = 1; IHCC]). Treatment emergent adverse events (all grades, regardless of attribution) that occurred in > 15% of pts were: nausea (43%), fatigue (25%), decreased appetite (22%), AST increase (18%), ALT increase (16%), and constipation (16%). No protocol-defined DLTs occurred. Best responses by tumor type are shown in the table. Conclusions: Single agent olutasidenib at 150 mg BID demonstrates acceptable safety and tolerability with preliminary clinical activity in patients with R/R mIDH1 solid tumors. Updated safety and clinical activity, as well as exploratory evaluations of PK/PD will be provided. Clinical trial information: 03684811 . [Table: see text]
Clinical characteristics and outcomes of patients with advanced hepatocellular carcinoma treated with immunotherapy: A “real world” retrospective study.
Authors: Chergui Adel , Gadde Eswar , Acuna-Villaorduna Ana , Kabarriti Rafi , Goel Sanjay , Kaubisch Andreas
Published: May 2020

e16644

Background: Advanced hepatocellular carcinoma (HCC) is an aggressive malignancy with dismal prognosis. Newer agents, including immunotherapy (IO), have been granted accelerated approval for patients previously treated or unable to tolerate sorafenib. However, information outside clinical trials is scarce. This study aims to describe clinical characteristics and outcomes of HCC patients treated with IO. Methods: HCC patients treated with IO were identified using the institutional software, Clinical Looking Glass. Data regarding demographics, clinical and treatment characteristics were collected by chart review. Neutrophil/lymphocyte ratio (NLR) and AFP were collected at IO treatment initiation and considered low if below 4 and 400, respectively. Progression-free survival (PFS) was defined as time from treatment initiation to progression of disease or death, and overall-survival (OS) as time from IO initiation to death from any cause. Disease characteristics were analyzed using descriptive statistics, PFS and OS were plotted using Kaplan-Meier curves. Results: 52 patients with a median age of 64.5 years and male predominance (38, 73.1%) were identified. There were 24 (54.5%) Hispanics, 9 (20.5%) Non-Hispanic Blacks, 7 (15.9%) Non-Hispanic White and 4 (9.1%) Asians. Cirrhosis present in 41 (83.7%), median MELD of 8 (IQ: 7-10). 37 (77.1%) patients had ECOG 0-1. Hepatitis B and C and B infection were encountered in 12 (24.5%) and 22 (44%) patients, respectively. Intravascular invasion present in 16 (34.8%) and extrahepatic metastases in 7 (14.9%). Local treatment was provided to 29 (59.2%) and radiation to 14 (28.6%). First line treatment (tx1) was Sorafenib in 29 (55.8%) and Nivolumab in 21 (40.4%). Nivolumab was second line treatment or beyond (tx2) in 31 (59.6%). Median PFS was 6.2 (3.1-10.6) months and it did not differ between tx1 and tx2 (8 vs 5.9 months, p = 0.90). Median OS was 13.2 months; there was a tendency towards higher survival rates in patients that were treated in tx2 (11.8 vs 14.3 months, 0 = 0.59) and in patients with low NLR (14.8 vs 9.2 months, p = 0.14). Median OS was higher in patients with low AFP at IO treatment initiation (15.7 vs. 9.2 months, p = 0.03). Conclusions: In this multiethnic cohort, the “real world” experience of the benefit of IO in HCC is encouraging, with a median OS exceeding one year. NLR showed potential as a possible biomarker. Expanded data may elucidate the differences if any, between use of IO as front vs. second line therapy, in PFS and OS.
Clinical effect of sequential therapy of LEN combination with anti-PD1 antibody in uHCC patients who progressed on LEN treatment: A real-world data in China.
Authors: Chen Yi , Zhang Lan , Ge Ningling , Wang Yanhong , Ren Zhenggang
Published: May 2020

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Background: Lenvatinib (LEN) has been used in clinical practice because of its high response rate since administrated in China. However, no recommendation is available as second-line agents after LEN treatment. The combination therapy of anti-programmed death-1(PD1) antibodies with LEN have demonstrated promising clinical efficacy in advanced HCC. Some patients were used this combination treatment after progressed on LEN in real world settings in China. Preclinical studies also showed the immune-moderate effects of LEN. This study was retrospectively analyzed the efficacy and safety of 26 unresectable HCC patients treated with LEN and anti-PD1 antibody after progressed on LEN. Methods: Unresectable HCC (uHCC) patients who treated with the combination of LEN with anti-PD1 antibody after progressed on LEN were enrolled. Patients who combine other loco-treatment and systemic therapy during the LEN combination with PD-1 antibody treatment period were excluded. The efficacy of LEN and anti-PD1 antibody was evaluated by mRECIST criteria after 2 cycles of combination treatment. AE data were recorded during the combination treatment period. Results: From October 2018 to October 2019, 26 patients were finally enrolled. As of January 10, 2020, median follow-up was 6.7±3.19 months. Median age was 56.15±11.9 years old, 80.77% (21/26) was Child-pugh(CP) A while 19.23% (5/26) was CPB7 and 88.5% (23/26) was BCLC stage C. Before combination therapy, 11 patients (42.31%) used LEN only and the other 15 patients (57.69%) were experienced sorafenib/chemotherapy before LEN. Drugs of PD1 antibodies were Keytruda and Toripalimab. The median duration of combination treatment was 6.7±3.15months. The ORR was 26.9% in total 26 cases. 2 cases of them were complete response, and the disease control rate (DCR) was 88.5% (23/26). The most common adverse events (AEs) of combination treatment were hypertension (42.31%), diarrhea (38.46%), hypothyroidism (38.46%) and anorexia (34.62%). Grade 3 or higher AEs occurred in 6 (23.08%) patients. Conclusions: This was the first real-world data of sequential therapy of LEN combination with anti-PD1 followed LEN in uHCC patients. For advanced patients who have progressed after LEN treatment, the results were promising, showing high DCR and well tolerated. 2 cases even achieve complete response. Sequential therapy may be an option for these patients. The efficacy of combination treatment needs random clinical trial to be further studied.
Impact of race and socioeconomic factors on outcome in hepatocellular carcinoma.
Authors: Muzaffar Mahvish , Naqash Abdul Rafeh
Published: May 2020

e16657

Background: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer related deaths and sixth leading cause of cancer globally. In USA the incidence of HCC has gradually increased over years.We sought to investigate impact of race and socioeconomic factors on the outcome of HCC in USA. Methods: The SEER database (version 8.3.6) was reviewed for patients with Hepatocellular carcinoma diagnosed between 1990-2016. Cases identified on autopsy or reported only on a death certificate were excluded. Variables included were, age, race, gender, stage, insurance, Pacific Coast Purchased/Referred Care Delivery Areas (PRCDA). Cox proportional hazard regression model was employed to test the association between survival and variables. Results: We identified a total of 87,047 cases of HCC that met the inclusion criteria from SEER database. Mean age was 63.15 yrs.( 63.22-63.07),67% were white,13% black, and others 20%.The Male: Female ratio was 3:1 and 59% of patients belonged to Pacific Coast PRCDA compared to 29% to East PRCDA.43% had localized stage,25% regional, 14% distant and 18% unknown.58% patient had some insurance and 42% were uninsured or unknown status. Patients diagnosed between 1990-2003 had median survival for white (4mos), blacks(3mos), others (7 mos.) (p < .0001) and for the time period 2004-2016, median survival was better,white(13 mos), blacks(10 mons), others(20mos) (p < .001). Conclusions: Outcome for HCC have improved over last two decades, but race and socioeconomic factors continue to impact outcome. Interventions addressing the racial and socioeconomic disparity can result in meaningful improvement in survival. [Table: see text]
Development and validation of a novel ten-gene prognostic signature for hepatocellular carcinoma.
Authors: Zhou Taicheng , Cai Zhihua , Ma Ning , Xie Wenzhuan , Gao Chan , Huang Mengli , Bai Yuezong , Ni Yangpeng , Tang Yunqiang
Published: May 2020

e16665

Background: Hepatocellular carcinoma (HCC) remains a major challenge for public health worldwide and long-term outcomes remained dismal despite availability of curative treatment. We aimed to construct a multi-gene model for prognosis prediction to inform clinical management of HCC. Methods: RNA-seq data of paired tumor and normal tissue samples of HCC patients from the TCGA and GEO database were used to identify differentially expressed genes (DEGs). DEGs shared by both cohorts along with patients’ survival data of the TCGA cohort were further analyzed using univariate Cox regression and LASSO Cox regression to build a prognostic 10-gene signature, followed by validation of the signature via ICGC cohort and identification of independent prognostic predictors. A nomogram for prognosis prediction was built and Gene Set Enrichment Analysis (GSEA) was performed to further understand the underlying molecular mechanisms. Results: Of 571 patients (70.93% men and 29.07% women; median age [IQR], 65 [56-72] years), a signature of 10 genes was constructed using the training cohort. In the testing and validation cohorts, the signature significantly stratified patients into low- vs high-risk groups in terms of overall survival across and within subpopulations with stage I/II and III/IV disease and remained as an independent prognostic factor in multivariate analyses (hazard ratio range, 0.13 [95% CI, 0.07-0.24; P < 0 .001] to 0.38 [95% CI, 0.2-0.71; P < 0.001]) after adjusting for clinicopathological factors. Prognosis was significantly worse in the high-risk group than in the low-risk group across cohorts (P < 0.001 for all). The 10-gene signature achieved a higher accuracy (C-index, 0.84; AUCs for 1-, 3- and 5-year OS, 0.84, 0.81 and 0.85, respectively) than 8 previously reported multigene signatures (C-index range, 0.67 to 0.73; AUCs range, 0.68 to 0.79, 0.68 to 0.80 and 0.67 to 0.78, respectively) for estimation of survival in comparable cohorts. A nomogram incorporating tumor stage and signature-based risk group showed better predictive performance for 1- and 3- year survival than for 5 year survival. Moreover, GSEA revealed that the pathways related to cell cycle regulation were more prominently enriched in the high-risk group while the low-risk group had higher enrichment of metabolic process. Conclusions: Taken together, we established a robust 10-gene signature and a nomogram to predict overall survival of HCC patients, which may help recognize high-risk patients potentially benefiting from more aggressive treatment.
Mutational landscape and tumor mutation burden (TMB) feature of biliary cancer.
Authors: Yi Bin , Liu Lianke , Song Jinghai , Huang Yingying , Zhang Min , Chen Rongrong , Xia Xuefeng , Jiang Xiaoqing
Published: May 2020

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Background: Biliary cancer are relatively rare, highly aggressive and have poor prognoses. Most biliary cancers are diagnosed in the advanced and metastatic stages. Chemotherapy is the main treatment of advanced biliary cancer. We focus on gene mutation and tumor mutation burden (TMB) of biliary cancer. Methods: We retrospectively reviewed one hundred and fifty-six cases of biliary cancer. One hundred and fifty-six tumor tissues and 35 plasma samples were subjected to next-generation sequencing (NGS), which enables simultaneously assess snv, indel, rearrangements and cnv variations at least 59 genes (range 59-1021 genes). Results: Fifty-eight patients were intrahepatic cholangiocarcinoma (IHCC), 50 were extrahepatic cholangiocarcinoma (EHCC) and 48 were gall bladder cancer (GBC). From tissue samples, the commonly mutated genes were different in three groups. TP53 was the most frequently mutated gene among the three groups (IHCC 43%, EHCC 58%, GBC 79%). KRAS (33%), TERT (16%), LRP1B (16%), IDH1/2 (10%) were usual in IHCC. KRAS (28%), SMAD4 (20%), STK11 (18%), ARID1A (12%) were usual in EHCC. And ERBB2 (19%), LRP1B (17%), TERT (15%), MLL3 (15%) were usual in GBC. TP53, LRP1B and MLL3 had a higher frequency in GBC than cholangiocarcinoma (p < 0.05), and KRAS was more common in cholangiocarcinoma than GBC (p < 0.05). 72.4% IHCC, 76.0% EHCC and 60.4% GBC had gene mutation associated with target therapies, which involved in multiple signal pathway, such as IDH1/2, FGFR, ERBB1/2/3, MET, PIK3CA, PTEN, BRCA, etc. Thirty-five patients had paired tissue and plasma samples, 21 stage Ⅲ/Ⅳ, 11 stage Ⅱ and 3 unknown. The concordance between tissue and plasma was 53% in all patients and was higher in stage Ⅲ/Ⅳ than stage Ⅱ (p < 0.05). One hundred and thirty-three tissue samples assessed TMB, the mean TMB was highest in the GBC group, followed by EHCC and IHCC (7.1 vs 5.5 vs 3.9 muts/Mb, p < 0.05). The proportion of TMB-H (defined 9.0 muts/Mb as cutoff value) was higher in GBC than IHCC and EHCC. Conclusions: IHCC, EHCC, and GBC have distinctive mutational landscapes and TMB features. It maybe guide different target therapy and immunotherapy strategies in the clinic. ctDNA has promising potential in biliary cancer.
High serum sPD-1 and sPD-L1 levels 1 predict outcome in hepatocellular carcinoma patients treated with radiotherapy.
Authors: Du Shisuo , Chen Genwen , Chen Yixing , Yang Ping , Hu Yong , Zhao Qianqian , Zeng Zhao-Chong
Published: May 2020

e16672

Background: Accumulating data have shown that soluble (s)PD-1 and sPD-L1 are potential biomarkers for the curative efficacy of chemotherapy in several cancers. However, these markers have not been well established for outcomes in hepatocellular carcinoma (HCC) radiotherapy (RT). Therefore, this study aims to assess sPD-1/sPD-L1 levels before and after RT and their relationship to clinical characteristics and prognoses. Methods: Pre-treatment serum sPD-L1 and sPD-1 levels were measured with an enzyme-linked immunosorbent assay (ELISA) in 281 patients with HCC treated with RT. The association between serum sPD-L1 and sPD-1 levels and prognosis was assessed using survival analysis. Formalin-fixed paraffin-embedded samples were obtained from 40 patients with HCC who underwent surgery. The expression of PD-L1 was evaluated by immunohistochemical analysis. Results: Using multivariate analyses; sPD-L1 and sPD-1 levels were significant independent predictors of disease-free and overall survival. Patients with maximum tumor diameters ≥5 cm and Barcelona clinic liver cancer (BCLC) staging B and C had significantly higher median sPD-1/sPD-L1 serum concentrations compared to patients with smaller tumor sizes and earlier stages. There was a positive correlation (r = 0.377, p < 0.001) between sPD-L1 and sPD-1 levels. High pretreatment sPD-1/sPD-L1 levels were associated with poor prognoses, and increased sPD-1/sPD-L1 levels were associated with disease progression after RT. In post-irradiated tumor tissue, PD-L1 expression was significantly higher than matched, non-irradiated tissue. In addition, higher PD-L1 expression was correlated with decreased cytotoxic T-cell infiltration and poor survival. Therefore, sPD-1/sPD-L1 could be used as noninvasive biomarkers for evaluating HCC malignancy before RT and in predicting the response to RT in HCC patients. Conclusions: High pretreatment serum sPD-L1 and sPD-1 were associated with poor prognoses, and increased serum sPD-L1 levels were associated with the disease progression of HCC patients treated with RT. PD-L1/ PD-1 pathway may be explored as therapeutic targets and potential predictive biomarkers for HCC treated with RT.
Comparing clinicopathologic feature and treatment outcome of patients who underwent surgical resection or liver transplant for nonalcoholic fatty liver disease (NAFLD)-related and non-NAFLD related hepatocellular carcinoma (HCC).
Authors: Chaudhary Surendra Pal , Goyal Lipika , Chase Matthew L , Zhu Andrew X. , Hashemi Nikroo , Reyes Stephanie , Corey Kathleen E , Misdraji Joseph , Clark Jeffrey William
Published: May 2020

e16675

Background: NAFLD associated HCC is rapidly increasing in frequency worldwide. In this study, we evaluated potential differences in clinical characteristics and outcomes of patients who underwent surgery or liver transplant for NAFLD-associated HCC compared to HCC from other etiologies. Methods: Demographic, clinicopathological features and outcomes of patients with HCC who underwent liver resection or liver transplant at Massachusetts General Hospital and Brigham and Women’s Hospital were collected (January 2004 - April 2018). Of 713 patients screened, 481were eligible: 260 underwent resection [NAFLD (n = 61), viral (n = 150), cryptogenic (CC) (n = 49)]. 221 underwent transplant [(NAFLD (n = 14), viral (n = 201), CC (n = 6)]. Results: In the Resected cohort, NAFLD patients presented with median age of (71.5 years) compared with Viral (63.4) and Cryptogenic (68.4). NAFLD patients had significantly higher Body Mass Index (BMI) > 28.8 39(66%) p = < 0.001, while patients with cryptogenic HCC presented with large tumor size (>5cm) 37(75%) p = 0.001. In multivariate analysis, tumor size 5cm (HR1.78,p = 0.002), R1 or R2 resection (HR 2.48, p = < 0.001and 2.8,p = 0.007), low platelet count (HR 2.8,p = 0.002) and diabetes (HR 1.5,p = 0.025) were poor prognostic factors in resection cohort. Median overall survival (OS) was not significantly different between NAFLD, Cryptogenic and Viral (47.2, 69.7 and 69.0 months, p = 0.18) etiologies, respectively. In the Transplant cohort, NAFLD patients had a median age of 65.5 and cryptogenic, viral (61.3 and 58.5 years) respectively. NAFLD and Cryptogenic HCC patients compared with viral HCC patients had low AFP median 3.7, 3.9 and 7.5 ng/mL(p = 0.012) respectively. In multivariate analysis patients with perineural invasion (HR 20.7,p = 0.009), disease recurrence (HR 2.5,p = 0.001) and high AFP (HR 2.1,p = 0.001) were at higher risk of death among transplant patients. No significant difference in median OS was seen between NAFLD, cryptogenic and viral (69.1,92.3 and 88.0 months, p = 0.38). Conclusions: NAFLD patients had higher BMI and had a lower AFP than viral and CC. NAFLD had similar median OS following resection and transplant when compared to those with Viral and CC.