bluuebunny/crossref_metadata_2025_split huggingface dataset:
The influence of major hepatectomy on gemcitabine-based chemotherapy for advanced biliary tract cancer: An exploratory subset analysis of JCOG1113.
Authors: Okuno Tatsuya , Morizane Chigusa , Okusaka Takuji , Mizusawa Junki , Kataoka Tomoko , Ikeda Masafumi , Ozaka Masato , Sugimori Kazuya , Todaka Akiko , Shimizu Satoshi , Mizuno Nobumasa , Sekimoto Mitsugu , Sano Keiji , Tobimatsu Kazutoshi , Katanuma Akio , Gotoh Kunihito , Yamaguchi Hironori , Ishii Hiroshi , Ueno Makoto , Furuse Junji 
Published: January 2022

419 Background: JCOG1113 (UMIN000001685) is a randomized phase III trial in patients (pts) with advanced biliary tract cancers (BTCs) that shows the non-inferiority of gemcitabine plus S-1 (GS) to gemcitabine plus cisplatin (GC) regarding overall survival (OS). Previous reports suggest that a history of major hepatectomy (MH) may affect dose intensity and adverse event (AE) frequency and reduce treatment efficacy in chemotherapy due to impairment of liver function and drug metabolism. We thus investigated whether a history of MH affects the frequency of AEs and treatment efficacy in recurrent BTC pts in JCOG1113. Methods: Among the 354 pts enrolled in JCOG1113, 76 recurrent pts with recurrence after surgery were included in this analysis. We compared the frequency of AEs, progression-free survival (PFS), and OS of GC vs. GS in pts treated with MH vs. non-major hepatectomy (NMH). Results: Of the 76 pts, 17 on GC and 13 on GS were included in the MH group, while 20 on GC and 26 on GS were included in the NMH group. The primary sites were only intrahepatic cholangiocarcinoma and hilar cholangiocarcinoma in the MH group, and there were no differences between the groups regarding sex, performance status, biliary drainage, or site of recurrence. The hazard ratio (HR) of GS to GC for PFS was 0.74 (95% CI 0.35–1.56) in the MH group and 0.97 (95% CI 0.52–1.82) in the NMH group. The hazard ratio (HR) of GS to GC for OS was 0.99 (95% CI 0.418–2.36) in the MH group and 1.17 (95% CI 0.59–2.33) in the NMH group. The median PFS and OS for GS in the MH group were 12.2 months and 21.5 months. These were longer than the 6.8 months and 15.1 months in the original results for GS in JCOG1113. Regarding AEs, Grade 3-4 AEs, specifically neutrophil count decreased (73.1%/92.3%), platelet count decreased (3.9%/15.4%), and rash (7.7%/15.4%), were more common in MH pts than NMH pts on GS. On GC, AEs in the MH and NMH pts did not show any consistent trends. The relative dose intensities (RDIs) of gemcitabine (70.7%/62.5%) and S-1 (70.4%/54.5%) were lower in MH pts than NMH pts on GS. The RDIs of gemcitabine (67.4%/63.0%) and cisplatin (73.6%/65.0%) were slightly lower in MH pts than NMH pts on GC. Conclusions: For pts with a history of MH, some AEs increased, and the RDIs were lower, especially that of S-1 for GS. On the other hand, the HR for PFS suggests that GS may be more effective than GC in MH pts.
Clinical results of dynamic tumor-tracking stereotactic body radiotherapy with real-time monitoring for liver tumors using a gimbal-mounted linac: A multi-institutional phase II study.
Authors: Iizuka Yusuke , Hiraoka Masahiro , Kokubo Masaki , Sakamoto Takashi , Karasawa Katsuyuki , Murofushi Keiko , Nakamura Mitsuhiro , Matsuo Yukinori , Morita Satoshi , Inokuchi Haruo , Mizowaki Takashi 
Published: January 2022

441 Background: Dynamic tumor-tracking (DTT) stereotactic body radiotherapy (SBRT) with real-time monitoring for liver tumors using a gimbal-mounted linac can decrease the normal liver dose and planning target volume (PTV) without sacrificing the target dose. We hypothesized that this method would yield excellent tumor control comparable to that by the conventional SBRT. We conducted a multi-institutional prospective phase II study to evaluate the safety and efficacy of DTT-SBRT for liver tumors (UMIN-CTR, UMIN000017886). Methods: The main eligibility criteria were as follows: (1) < 4 liver tumors; (2) technical difficulties with percutaneous ablation therapies, inoperable lesions, or patient refusal to undergo surgery; (3) Eastern Cooperative Oncology Group performance status of 0–2; (4) Child-Pugh score of ≤8; and (5) respiratory motion of ≥10 mm. The primary endpoint was the local control rate (LC) at 2 years (expected endpoint: > 90%), and the secondary endpoints were overall survival rate (OS), progression-free survival rate (PFS), and treatment-related toxicity. We performed DTT-SBRT with 40 Gy in 5 fractions prescribed to the PTV D95, and a maximum dose of 55−58 Gy using 7–9 static non-coplanar ports of the 6-MV beam was applied. The Kaplan-Meier analysis was performed to estimate the OS and LC. Treatment-related toxicity was scored according to the Common Terminology Criteria for Adverse Events v.4.0. Results: Forty-eight patients (48 tumors) were registered from four institutes and successfully treated between September 2015 and March 2019. Their median age was 74 years (range, 52–97). Thirty-nine tumors were hepatocellular carcinomas, and nine were metastatic liver tumors. The median tumor size was 5.8 ml (range, 0.7–64.1). At the time of data cutoff on March 31, 2021, the median follow-up period was 36.5 months (range, 3.0–62.4). The 2-year LC was 98.0%. Two-year OS and PFS were 88.8% and 55.1%, respectively. Recurrences were observed in 33 patients (68.5%). One patient (0.2%) had local recurrence, 30 (62.5%) developed new hepatic lesions outside of the irradiation field, and 9 (18.8%) had distant metastases. Grade 3 adverse events were observed in seven patients, including elevation of liver or biliary enzyme levels and hematopoietic adverse events. No treatment-related toxicity of grade 4 or higher was observed. Conclusions: Employing DTT-SBRT to treat liver tumors resulted in excellent LC with acceptable incidence of adverse events. This method will be a promising alternative therapy for patients who cannot receive surgery or percutaneous ablation therapy. To the best of our knowledge, this is the first phase II trial evaluating DTT-SBRT for liver tumors. Clinical trial information: UMIN000017886.
Downstaging radiotherapy and surgical transformation for initially unresectable or borderline resectable hepatocellular carcinoma: A phase II study.
Authors: Su Ting-Shi , Gong Wen-Feng , Zhao Chang , Liang Shi-Xiong , Li Le-Qun , Xiang Bang-De 
Published: January 2022

442 Background: Downstaging radiotherapy provide patients with initially unresectable or borderline resectable hepatocellular carcinoma (HCC) a chance to receive conversion curative resection. This study intended to prospectively evaluate the efficacy and toxicities of downstaging radiotherapy for HCC with macroscopic vascular invasion. Methods: From March 2018 to May 2020, 30 HCC patients with macroscopic vascular invasion were prospectively treated with transcatheter arterial chemoembolization combined with radiotherapy (n = 24) or radiotherapy alone (n = 6). The primary study endpoint was overall survival (OS). The secondary study endpoints were progression free survival (PFS), downstaging success rate, and surgical conversion rate. Adverse events were assessed. Results: The follow-up time of the entire cohort was 24 months. The median OS of the entire cohort was 22.0 months, 12-, and 24- months OS was 60.0% and 47.8%, respectively. The median PFS was 13.0 months, 12-, and 24-months PFS was 53.3% and 27.0%, respectively. During downstaging window phase within 3-6 months, 22 patients were evaluated as downstaging success by clinical imaging. Among them, 9 patients underwent R0 radical hepatectomy and 13 patients refused surgical treatment, yielding a downstaging success rate of 73.3% (22/30 patients) and a surgical conversion rate of 30.0% (9/30 patients). Of the patients who underwent surgery, 4 patients (44.4%) experienced ≥ grade 4 postoperative complications, including 2 (22.2%) with gastrointestinal bleeding and 2 (22.2%) with bile leakage. Conclusions: For unresectable or borderline resectable HCCs complicated with macroscopic vascular invasion, high-dose radiotherapy-based treatment provided favorable downstaging efficacy, surgical conversion rate, and survival outcomes. Clinical trial information: ChiCTR1800015350.
Pembrolizumab (PEM) plus granulocyte macrophage colony stimulating factor (GM-CSF) in advanced biliary cancers (ABC): Final outcomes of a phase 2 trial.
Authors: Kelley Robin Kate , Bracci Paige M. , Keenan Bridget , Behr Spencer , Ibrahim Faaiz , Pollak Marin , Gordan John , Ko Andrew H. , Van Loon Katherine , Atreya Chloe Evelyn , Cinar Pelin , Venook Alan P. , Fong Lawrence 
Published: January 2022

444 Background: Immune checkpoint inhibitors (ICI) have limited activity as monotherapy in unselected patients with ABC; the objective response rate (ORR) of PEM was 5.8% in the multicenter phase 2 KEYNOTE-158 trial. GM-CSF modulates immune cells including monocytes and the innate immune response and has demonstrated safety and prolonged survival (OS) in combination with ipilimumab in melanoma. This phase 2 trial was designed to evaluate the efficacy and safety of PEM in combination with GM-CSF in ABC. Methods: Single-center, phase 2 trial with Simon’s 2-stage design and expansion cohort (EC) (NCT02703714). Key eligibility: ABC with progression/intolerance on ≥ 1 standard therapy, no prior ICI, bilirubin ≤1.5xULN. Treatment: PEM 200 mg IV Q21 days plus 2 cycles of GM-CSF 250 µg SC D1-14 Q21 days in cycles 2 and 3 (Stage 1 and EC) or in cycles 1 and 2 (Stage 2). Primary endpoint was objective response rate (ORR) by RECIST 1.1, H0 5% vs. H1 20%. Key secondary endpoints were safety, progression-free survival (PFS), OS, PD-L1 expression. Exploratory endpoints included relationship between efficacy outcomes and anatomic subsite, risk factors, and tumor genotype. Results: Overall, 42 patients enrolled between 5/2016-12/2019: n = 9 in Stage 1, n = 18 in Stage 2, and n = 15 in EC. Overall: median age 61; female 67%; intrahepatic (ICC) 67%, extrahepatic (ECC) 26%, gallbladder (GBC) 7%; stage IV 90%; hepatitis B/C virus positive (HBV/HCV+) 24%; microsatellite instability (MSI-H)/stable (MSS)/unknown n = 1/35/6. Immune-related (ir)AE occurred in 69%, grade 3/4 treatment-related (tr)AE in 10%, all-cause serious (S)AE in 36%, and trSAE in 7%. ORR was 12% (95% CI: 4, 26), with median PFS of 63 days (95% CI: 55, 125), PFS at 6 months in 27% (95% CI: 14, 43), and median OS 3of 93 days (95% CI: 243, 573). There was no significant difference in ORR, PFS, or OS by anatomic subsite or tumor PD-L1 expression; HBV/HCV+ showed trends toward higher ORR (30% vs 6%, p = 0.08) and longer median PFS (276 vs 63 days, p = 0.06) and OS (1033 vs 323 days, p = 0.052). Conclusions: The combination of PEM plus GM-CSF was safe and well-tolerated with higher ORR than expected for PEM monotherapy in a predominantly MSS ABC population but did not meet target ORR threshold for efficacy. ORR and median PFS and OS were highest in patients with underlying HBV or HCV infection. Immune profiling of on-treatment biopsies and peripheral blood are ongoing to ascertain influence of both PEM and GM-CSF on circulating and tumor immune microenvironment. Clinical trial information: NCT02703714.
Updated results of the phase II ALTER-H003 trial: Anlotinib plus toripalimab as a first-line treatment for patients with unresectable hepatocellular carcinoma.
Authors: Lin Haifeng , Ma Jie , Zhuo Manyun , Zhang Chengsheng , Luo Jingru , Zhuang Xiaohong , Zeng Zhiming , Yang Lihua 
Published: January 2022

446 Background: The combination therapies of anti-angiogenic with anti-PD-1/L1 agents have shown superior efficacy over sorafenib in the first-line treatment for uHCC. Anlotinib, a multi-targeted tyrosine kinase inhibitor that targets VEGF receptors 1/2/3, FGF receptors 1-4, PDGF receptors α and β, and c-kit, is approved for treatment of several malignancies in China. Toripalimab is a humanized lgG4 mAb against PD-1. Preliminary results demonstrated good efficacy and tolerable safety of the combined regimen. Here we updated the results with more enrolled patients and longer follow-up duration. Methods: This single arm, multicenter, phase II trial of ALTER-H003 was planned to enroll 30 pts without prior systemic treatment to receive anlotinib (12 mg, p.o., qd, d1-14, q3w) and toripalimab (240 mg, iv, d1, q3w) until disease progression or unacceptable toxicity. Primary endpoint was ORR according to mRECIST and irRECIST. Secondary endpoints included PFS, OS, DCR, DoR and safety. Results: By the cutoff date of September 18, 2021, 31 pts were enrolled and treatment duration ranged from 0.23+ to 14.65+ months. Among 26 evaluable pts, the confirmed ORR and DCR according to mRECIST was 34.6% (95% Cl 17.2%-55.7%) and 92.3% (95% Cl 17.2%-55.7%), respectively. The DoRs ranged from 1.38 month to 9.69 month. The preliminary median PFS was 10.2m (95% Cl 6.1-14.3) and the median OS have not reached yet. 28 of 31 pts (90.3%) occurred treatment-related adverse events (TRAEs). Grade 3-5 TRAEs were recorded in 14 pts (45.2%). Immune-Related TRAEs (irTRAEs) occurred in 21 pts (67.7%), while 5 patients (16.1%) had grade 3-5 irTRAEs. The most common grade 3 TRAEs included hypertension (n = 3, 9.7%), hand-foot skin reaction (n = 2, 6.5%), arthralgia (n = 2, 6.5%), total bilirubin increased(n = 2, 6.5%) and fatigue (n = 2, 6.5%). The grade 3 irTRAEs were total bilirubin increased (n = 2, 6.5%), AST increased (n = 1, 3.2%), fever (n = 1, 3.2%), arthralgia (n = 1, 3.2%) and fatigue (n = 1, 3.2%). No grade 4 TRAEs occurred.1 patient had an irTRAE that led to death (immune-related pneumonitis). Conclusions: This combination therapy of anlotinib plus toripalimab in the first-line treatment for uHCC yielded satisfactory anti-tumor efficacy and manageable toxicity. The study is still ongoing and detailed data will be presented. Clinical trial information: ChiCTR1900028295.
The therapeutic strategy for choosing lenvatinib in systemic therapy for unresectable hepatocellular carcinoma.
Authors: Tsuchiya Kaoru , Kurosaki Masayuki , Yasui Yutaka , Kaneko Shun , Kirino Sakura , Inada Kento , Tanaka Yuki , Ishido Shun , Yamashita Koji , Nobusawa Tsubasa , Hayakawa Yuka , Matsumoto Hiroaki , Kakegawa Tatsuya , Higuchi Mayu , Takaura Kenta , Tanaka Shohei , Maeyashiki Chiaki , Tamaki Nobuharu , Nakanishi Hiroyuki , Izumi Namiki 
Published: January 2022

447 Background: In systemic therapy for unresectable HCC, atezolizumab plus bevacizumab is recommended as first-line, and there are no established strategies after the immunotherapy. Lenvatinib (LEN) showed a high radiological response rate both in clinical trials and real-world practice, while it was reported that age and ALBI grade 2 were associated with the discontinuation of LEN. The aim of this study is to investigate the best candidates for LEN therapy by using clinical variables. Methods: A total of 104 patients who received LEN at our institution between Apr 2018 and Feb 2021 was enrolled. The risk factors associated with overall survival (OS) and progression-free survival (PFS) were analyzed by a Cox proportional hazard model. Results: The median observation period was 12.8 months, and the median duration of LEN was 4.5 months. The median age was 74 years, and 90 patients were Child-Pugh A. BCLC stage B patients were 43%, and median AFP was 172 ng/mL. The median OS and PFS were 17.9 and 6.2 months. In this study, 72 patients received LEN as the first line. In a multivariate analysis of first-line patients, ECOG PS≥1, modified ALBI 2b or 3, AFP≥400 ng/mL, the existence of major vascular invasion (MVI), and neutrophil to lymphocyte ratio (NLR)≥2.8 were significant risk factors associated with OS and PFS. The median OS in patients with 0-1 risk factor (n = 33) was significantly longer than the patients with 2-5 risk factors (n = 39) (22.3 vs. 16.7 months, p <.0001). The median PFS in patients with no risk factor (n = 10) was 13.8 months, while the median PFS was 4.8 months in the patients with ≥2 risk factors. Among 28 patients without MVI and treated with LEN as second or later line, the median OS of the patients with 0-2 risk factors was significantly longer than those with 3-4 risk factors (21.7 vs. 7.7 months p = 0.0008). The median PFS in patients with 0-1 risk factor was 14.7 months, even though they had an experience of systemic therapy. Conclusions: LEN is strongly recommended to the patients with ECOG PS0, modified ALBI 1 or 2a, AFP < 400ng/mL, no MVI, and low NLR (< 2.8). When the patients would fulfill all these conditions, the median OS and PFS is over 20 and 12 months, both in patients with and without experience of systemic therapy.
A multicenter phase II trial to assess the efficacy and safety of bevacizumab plus mFOLFOX6 as induction chemotherapy toward R0 surgical resection in advanced colorectal liver metastases with mutant-type KRAS: NEXTO-mt trial.
Authors: Watanabe Genki , Mise Yoshihiro , Oba Masaru , Saiura Akio , Inoue Yosuke , Takahashi Yu , Kishi Yoji , Suyama Koichi , Takayama Tadatoshi , Noie Tamaki , Nishioka Yujiro , Akamatsu Nobuhisa , Arita Junichi , Kokudo Norihiro , Hasegawa Kiyoshi 
Published: January 2022

450 Background: The oncological benefit of bevacizumab plus mFOLFOX6 in advanced colorectal liver metastases (CRLMs) in terms of conversion to curative resection remains unknown. This multicenter phase II trial aimed to evaluate the efficacy and safety of bevacizumab plus mFOLFOX6 as induction chemotherapy for advanced CRLMs harboring mutant-type KRAS. Methods: Patients who had advanced CRLMs (tumor number of ≥5 and/or technically unresectable) harboring mutant-type KRAS were included in this study. The induction chemotherapy of bevacizumab plus mFOLFOX6 was administered and assessed for resectability every 4 cycles. If the unresectable CRLMs were converted to be resectable, liver resection was planned after a waiting period of 4–6 weeks and followed by postoperative chemotherapy up to 12 cycles. The primary endpoint was R0 resection rate. The secondary endpoints were safety, recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS). The trial was conducted following approval from the Institutional Ethics Review Board of all institutions and registered in the University Hospital Medical Information Network Clinical Trials Registry (registration number: UMIN000009530). Results: Between February 2013 and December 2017, 29 patients from six centers were enrolled in this trial. The rates of complete and partial responses were 0% and 62.1%, respectively. R0 and R1 resections were performed in 19 and 1 patient, respectively (R0 resection rate: 65.5%). No mortality after liver resection occurred. During the median follow-up of 30.7 months (range, 7.2–82.6 months), the median OS for the 29 patients was 49.1 months. The 3-year PFS and OS rates were 7.4%, and 64.4%, respectively. The 3-year RFS rate was 10.0% in 20 patients who achieved R0 or R1 resections. Conclusions: Bevacizumab plus mFOLFOX6 achieved a high R0 resection rate with a favorable survival for patients with advanced CRLMs harboring mutant-type KRAS. Clinical trial information: UMIN000009530.
Stereotactic body radiotherapy (SBRT) with functional treatment planning in patients with hepatocellular carcinoma (HCC) and advanced hepatic cirrhosis: Survival outcomes and toxicity.
Authors: Kirichenko Alexander V. , Hasan Shaakir , Liang Yun , Lee Danny , Godla Aishvarya , Renz Paul , Abel Stephen , Uemura Tadahiro , Machado Lorenzo , Thai Ngoc 
Published: January 2022

460 Background: To evaluate outcomes and dosimetric parameters of ablative stereotactic body radiotherapy (SBRT) with functional treatment planning for localized hepatocellular carcinoma (HCC) in patients with Child-Pugh B (CP-B) hepatic cirrhosis. Methods: Liver SPECT with 99mTc-sulfur colloid was co-registered to 3D-CT for identification and avoidance of functional hepatic parenchyma during SBRT in patients with advanced cirrhosis. Functional liver volumes (FLV-SPECT) were compared to anatomical liver volumes, as were dosimetric parameters when radiation dose constraints were adapted exclusively to FLV-SPECT. Hepatic function, toxicity, and radiographic response were documented every 4–6 months following SBRT. Results: With a median follow-up of 25 months 37 patients (48 lesions treated) with CP-B cirrhosis received SBRT to a median dose 48 Gy (4–5 fractions). FLV-SPECT volume loss (509 cc or 41.3%, p < 0.001) was observed in all patients, while the functional and anatomical liver volumes matched well in a control group of non-cirrhotic/non-HCC patients. While tumors received ablative irradiation, mean dose to FLV-SPECT was maintained at 1.3 – 16 Gy (median 9.17 Gy), well below the liver threshold tolerance to radiation. Seventeen patients successfully completed liver transplant at a median time to transplant of 6.5 months. The dropout rate from the transplant list was 9 % with intrahepatic progression outside treated tumors. Eight of 10 patients with intrahepatic progression received additional SBRT during follow-up. Overall 2-year survival rate was 65% with no incidence of RILD or CP class migration from B to C was observed at 6+ months post SBRT. Two patients completed liver SBRT on a hybrid linear accelerator combined with MRI scanner (Unity MR-Linac, Elekta) utilizing Super-Paramagnetic Iron Oxide (SPIO) nanoparticle agent as an alternative contrast media for functionally active liver parenchyma. Prolonged SPIO-contrast retention also allowed per fraction treatment plan adaptation and enhanced tumor imaging. Conclusions: SBRT planning with 99mTc sulfur colloid SPECT allows identification and conformal avoidance of residual functionally active hepatic parenchyma in patients with CP-B cirrhosis. We report high local control and low toxicity leading to satisfactory pre- and post-liver transplant outcomes. Prospective clinical trial investigating MRI-SPIO functional treatment planning for liver SBRT is ongoing at our institution.