bluuebunny/crossref_metadata_2025 huggingface dataset:
Nivolumab plus ipilimumab in advanced hepatocellular carcinoma with Child-Pugh B: A multicenter retrospective study.
Authors: Kim Jung Sun , Kim Youngun , Kang Beodeul , An Chansik , Kim Ilhwan , Kim Hyeyeong , Kim Chan , Chon Hong Jae
Published: January 2025

551

Background:
The phase 3 CheckMate 9DW trial proposed that nivolumab plus ipilimumab (Nivo/Ipi) significantly improved the survival of patients with advanced hepatocellular carcinoma (aHCC) compared with sorafenib or lenvatinib as first-line treatment, but it only included patients with Child-Pugh A. Given the limited treatment options for patients with poor liver function, we aimed to assess the efficacy and safety of Nivo/Ipi in aHCC patients, stratified by liver function.
Methods:
This study included patients with aHCC who received Nivo/Ipi treatment at three referral hospitals between March 2020 and September 2023. Patients received nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) every 3 weeks (four doses), followed by nivolumab (240 mg) every 2 weeks.
Results:
Of 106 patients treated with Nivo/Ipi, 96 evaluable patients were included in the final analysis. Among them, 76 patients had Child-Pugh A, while 20 had Child-Pugh B. The baseline characteristics were generally comparable between the two groups, except for a significantly higher rate of extrahepatic metastasis in patients with Child-Pugh A (86.8% vs. 65.0%, p = 0.043) and a higher incidence of macrovascular invasion in patients with Child-Pugh B (55.0% vs. 27.6%, p = 0.032). The objective response rate (ORR) was 28.9% (22/76, 4 complete responses [CR] and 18 partial responses [PR]) in the Child-Pugh A group and 10.0% (2/20; 0 CR and 2 PR) in the Child-Pugh B group. Disease control rates were 42.1% in the Child-Pugh A group and 25.0% in the Child-Pugh B group. In a median follow-up duration of 29.3 months (95% confidence interval [CI], 28.8-29.8), the median overall survival (OS) was 8.9 months (95% CI, 5.5-17.6) in the Child-Pugh A group and 3.9 months (95% CI, 2.1-4.8) in the Child-Pugh B group (p < 0.001). The median progression-free survival (PFS) was 1.6 months (95% CI, 1.2-3.5) in the Child-Pugh A group and 1.2 months (95% CI, 0.8-2.1) in the Child-Pugh B group (p = 0.003). Adverse events of any grade occurred at a comparable rate between the two groups, although immune-related adverse events were significantly more frequent in the Child-Pugh A group. Multivariable analysis indicated that Child-Pugh B was consistently associated with a worse PFS and OS, while prior exposure to immune checkpoint inhibitors (ICIs) was associated with a poorer PFS. Notably, both responders with Child-Pugh B were both ICI naïve.
Conclusions:
While Nivo/Ipi treatment showed reduced efficacy in patients with Child-Pugh B, identifying potential responders beyond the current clinical trial criteria may offer opportunities to improve outcomes in this challenging population.
Efficacy and safety of endoscopic retrograde cholangiopancreatography (ERCP) vs percutaneous transhepatic biliary drainage (PTBD) for cholangiocarcinoma biliary obstruction: An updated systematic review and meta analysis.
Authors: Ortega-Macias Alan , Borja Montes Oscar Felipe , Escobar Gil Tomas , Maestas Erika
Published: January 2025

557

Background:
Perioperative and/or palliative biliary drainage for the management of cholangiocarcinoma biliary obstruction has been part of the backbone of the multidisciplinary approach that this condition requires. For both intrahepatic and perihilar cholangiocarcinoma, ERCP and PTBD are the two main techniques available. There has yet to be consensus favoring one approach over the other.
Methods:
Following the PRISMA guidelines, a systematic review and meta-analysis were performed to determine if there was a difference in efficacy and safety of ERCP compared to PTBD for Cholangiocarcinoma Biliary Obstruction. Primary outcomes were successful biliary drainage, mean number of needed procedures, length of stay and overall adverse events rate. Data were analyzed using R version 4.2.2. The risk of bias was assessed by the Robins-I and RoB 2 tool. The quality of evidence was graded using the GRADE scale and Newcastle-Ottawa guidelines.
Results:
Three randomized clinical trials and two observational studies described the successful biliary drainage rate of ERCP vs PTBD for cholangiocarcinoma associated biliary obstruction, totaling 340 patients. Meta-analysis test for overall effect, showed no statistical difference between groups (RR = 0.88; 95% CI = [0.69; 1.13]; p = 0.23; Fig. 1). Similarly, in terms of the mean number of needed procedures per patient, a total of three randomized clinical trials and two observational studies, totaling 340 patients were included, no statistically significant difference was found (SMD = 0.64; 95% CI = [- 9.36; 10.63]; p = 0.57; Fig. 2). Likewise, one randomized clinical trial and two observational studies showed no statistically significant difference on the length of stay (days) mean between groups (SMD = 0.06; 95% CI = [- 1.57; 1.68]; p = 0.73; Fig. 3). Although, the three clinical trials and three observational studies showed a mild decreased adverse event and death (within 3 months) rate in the ERCP group, after undergoing statistical analysis, meta-analysis test for overall effect, showed no statistical difference (RR = 0.99; 95% CI = [0.55; 1.77]; p = 0.97; Fig. 4 and RR = 0.61; 95% CI = [0.10; 3.87]; p = 0.22; Fig. 5, respectively). The risk of bias was low with moderate-to-high quality of evidence amongst the included studies.
Conclusions:
Our updated systematic review and meta-analysis demonstrated no statistically significant difference in the successful biliary drainage rate, mean number of needed procedures, length of stay, death within 3 months and adverse event rate between ERCP vs PTBD for management of cholangiocarcinoma biliary obstruction. Further randomized studies are needed to confirm these findings.
A global comparative study on MDT practices in the management of hepatocellular carcinoma in high-income countries (HICs) and low- and middle-income countries (LMICs).
Authors: Zhiyong Huang , Jonas Eduard , Liu Lianxin , Smith Martin , Soliman Hossam El-Deen Mohamed , Li Jiaping , Wang Jizhou , Fan Wenzhe , Zeid Ahmed Elsayed Esmaal , Devar John , Zhang Erlei , Chen Qian , Yin Bichai , Cui Poka Yingjing , Dong Yufang , Su Zoe (Zheng) , Azcue Pablo , Turner Lucy , Campos Partera Maria Teresa , Chen Xiaoping
Published: January 2025

562

Background:
As the sixth most common malignancy worldwide, hepatocellular carcinoma (HCC) accounted for 4.7% of all new cancer diagnoses in 2022. Low- and middle-income countries seem to bear a disproportionate burden of the disease, with over 50% of new HCC cases estimated to occur in China and Africa. Research on multidisciplinary team (MDT) practices in these regions is limited. The objective of this study is to compare MDT practices in the management of HCC in HICs and LMICs.
Methods:
Data on MDT practices from hospitals that manage HCC in Italy, Spain, Switzerland, Germany, Denmark, Canada and the USA, representing HICs, and in China, South Africa and Egypt, representing LMICs were collected through virtual semi-structured interviews and workshops.
Results:
Ten key areas of differences were identified (Table 1) that could be categorized as organizational/regulatory or clinical. In HIC institutions, the focus currently is on optimizing MDTs as standard of care approach accessible to all patients with HCC; MDT principles are often integrated into national policies. In LMICs, emphasis is on establishing MDTs and expanding their capacity; patient access to MDT care is not a mandatory requirement, nor regulated in national policy. Of note, LMICs are seeking early technology adoption to overcome some potential barriers to MDT interactions; online formats are more often explored to facilitate participation and AI-assisted diagnostic tools are explored to compensate for absence of radiologists. Absence of screening and surveillance for early detection in HCC is more common in LMICs, and therefore likely that patients more often present with advanced stage disease. Also, with limited diagnostic modalities, diagnostic work-up and staging may be sub-optimal.
Conclusions:
Significant variation exists in HCC MDT practices between HICs and LMICs. The ultimate goal of this study is to develop a format for clinical MDTs that will facilitate interaction between HICs and LMICs. Consideration for the differences highlighted above is crucial for the development of this concept.

10 key areas highlighting differences identified between HICs and LMICs.

MDT development direction: Standard of Care for all patients vs. specific session for complex cases

National/regional regulatory requirements

Institutionalizing MDT principles

MDT composition (specialists)

Use of digital tools

Reimbursement

Access to therapeutic options

Stage presentation of HCC patients

Use of clinical staging

Patient follow-up after MDT discussion
Leading the way: How leading Chinese institutions drive MDT excellence in hepatocellular carcinoma.
Authors: Li Jiaping , Zhiyong Huang , Chen Xiaoping , Wang Jizhou , Fan Wenzhe , Zhang Erlei , Chen Qian , Yin Bichai , Jia Binghao , Cui Poka Yingjing , Huang Zhihao , Sun Si , Dong Yufang , Su Zoe (Zheng) , Azcue Pablo , Turner Lucy , Campos Partera Maria Teresa , Liu Lianxin
Published: January 2025

563

Background:
HCC MDTs involve specialists collaborating on patient cases to create personalized treatment plans. Implementing MDTs can be challenging in countries with limited resources and high disease burdens. In China, there were 368,000 new liver cancer cases in 2022 representative of 40% of global cases. Therefore, evaluating MDT practices at leading hospitals in China may offer valuable insights that could help improve HCC MDT practices worldwide.
Methods:
This study selected hospitals with distinct MDT models: one for all new patients and one for complex cases. Hospitals handling over 1,000 HCC cases annually were chosen. Desk research and virtual interviews with MDT members from three leading Chinese hospitals—The First Affiliated Hospital of USTC, The First Affiliated Hospital of SYSU, and Tongji Hospital—were conducted to analyze their MDTs and determine key best practices.
Results:
We identified 6 key best practice in HCC MDTs at these leading Chinese hospitals. 1) Quality Control on MDT process: Leading hospitals ensure the MDT’s efficient execution and effective outcomes. E.g., USTC established a quality control team to audit the MDT process. 2) Real-World Evidence: Leading hospitals prioritize the construction of real-world databases linked to MDT-care to inform impact on outcomes. E.g., SYSU's preliminary data shows impact of MDT care on survival rates (From 2006 to 2010, 5,627 patients who underwent radical liver cancer resection with MDT care saw their five-year survival rate reach 60%, a notable improvement over historical averages) 3) Comprehensive Teams: These hospitals typically have robust teams, involving around 10 specialties. E.g., Tongji Hospital’s MDTs involve ~10 specialties for holistic care. 4) Patient Journey Coverage: MDTs manage patients from diagnosis to rehabilitation, providing a holistic approach to patient management. 5) Guideline-based treatment decisions: They follow latest guidelines coupled with access to approved therapies to make treatment decisions 6) Training: Young physicians are invited to actively participate in MDT consultations (e.g., through case preparation and presentation, etc.).
Conclusions:
Evaluation of MDT practices at leading China institutes highlights key best practices that could be adopted to enhance care quality for patients with HCC. The ongoing efforts and successes of these institutions provide a model for broader adoption and standardization of MDT practices across the country.
Lenvatinib plus hepatic arterial infusion chemotherapy of oxaliplatin, fluorouracil, and leucovorin versus lenvatinib alone for advanced hepatocellular carcinoma.
Authors: Shi Feng , Peng Zhenwei , Xia Dongdong , Mai Qicong , Wang Meng , Mei Jie , Kuang Ming , Chen Xiaoming
Published: January 2025

580

Background:
Lenvatinib stands out as a first-line therapy for individuals with advanced hepatocellular carcinoma (HCC). Concurrently, hepatic arterial infusion chemotherapy comprising oxaliplatin, fluorouracil, and leucovorin (FOLFOX-HAIC) has emerged as a potential option for those with advanced HCC. It is necessary to investigate the efficacy and safety of lenvatinib plus FOLFOX-HAIC (lenvaHAIC) for advanced HCC in real-world situations.
Methods:
In this retrospective analysis, 127 consecutive patients underwent lenvaHAIC, while 184 patients received lenvatinib alone as first-line treatment at six Chinese academic centers between January 2019 and June 2022. Following 1:1 propensity-score matching, we established paired cohorts (113 patients in each group) for evaluating survival. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR) evaluated by RECIST 1.1 and mRECIST criteria, and safety profiles were compared between the two groups.
Results:
The lenvaHAIC group exhibited significantly prolonged median PFS and OS than the lenvatinib group (PFS: 12.3 vs. 6.2 months; OS: 25.6 vs. 12.3 months; P < .001 for each). In the propensity-score matched cohorts (113 pairs), both PFS and OS were notably extended in the lenvaHAIC group compared with those in the lenvatinib group (P < .001). Multivariate analysis identified lenvaHAIC treatment as an independent factor for improved PFS (hazard ratio [HR] 0.45; P < .001) and OS (HR 0.38; P < .001). Grade 3-4 adverse events, including nausea, vomiting, diarrhea, thrombocytopenia, and neutropenia, were more prevalent in the lenvaHAIC group.
Conclusions:
LenvaHAIC may be a promising treatment in patients with advanced hepatocellular carcinoma, demonstrating enhanced OS, PFS, and ORR and an acceptable safety profile.
Phase II study of modulation of sorafenib (SOR)-induced autophagy using hydroxychloroquine (HCQ) in advanced hepatocellular cancer (HCC).
Authors: Arora Sukeshi Patel , Moseley Jennifer L. , Arellano Luisa Marie , Salazar Mary , Altermatt Brittany , Fuentes Lorena , Pham Vincent Truong , Huang Gang , Sun LuZhe , Michalek Joel , Mahalingam Devalingam
Published: January 2025

586

Background:
SOR is the first systemic therapy approved for advanced HCC, but has shown only modest improvements in survival. Resistance to SOR in pre-clinical models has been attributed to autophagy induction. Autophagy inhibition with HCQ enhanced SOR-induced cell death and apoptosis in early pre-clinic and clinical studies. Data from the phase I study of SOR plus HCQ in advanced solid tumors at showed clinical safety and efficacy. Therefore, we conducted a prospective study to evaluate efficacy of SOR and HCQ in advanced HCC patients (pts) (NCT03037437) and report the final efficacy analysis.
Methods:
Prospective phase II study of SOR 400 mg po BID + HCQ 400 mg daily in pts with advanced HCC (CP A-B8 cirrhosis). Cohort 1: first-line SOR/HCQ. Cohort 2: add HCQ upon progressing on SOR. CP B pts started at 200 mg BID, with dose escalation as tolerated. Cycle = 4 weeks. Primary endpoint: mTTP. Secondary endpoints: mOS, objective response rate (ORR) by RECIST; AEs (NCI-CTCAEv3.0); PD analysis for markers of autophagy and immunity. Pts evaluable for efficacy if completed C1. Historically, the mTTP for patients treated with sorafenib is 5.5 mo (SHARP trial). We predicted the addition of HCQ will improve mTTP by 50% to 8.2 months.
Results:
N=33 completed C1. Median age 64.1 years SD 8.6 (46- 80). 88% Male; 58% Hispanics. ECOG 0-1: 100%. CP B cirrhosis: 35%. Etiology of cirrhosis: HCV 68%, ETOH 32%, NASH 11%. BCLC B 19%, C 81%. AFP>400: 43%, PVT: 27%, extrahepatic/metastases: 68%, post-transplant: 27%. N=5 (14%) were in cohort 2 (prior SOR). Reason off study: PD (n=21), toxicity (n=5), lost to f/u (n=1), withdrew (n=3). mTTP is 8.0 months (95% CI: 4.0-19.0). mOS 10.0 months (95% CI: 6.0-22.0). ORR (CR+PR): 27%. Best response: CR n=1 (3%), PR n=8 (24%), SD n=14 (42%). 4+ cycles: n=19 (58%). AE on treatment: grade 1 (68%), 2 (24%), 3 (7%), 4 (0.6%), 5 (0.3%). No Gr 4/5 related to SOR or HCQ. Dose interruption (20%), dose reduction (10%).
Conclusions:
SOR/HCQ had a better mTTP (8.0 months) than historical control (mTTP=5.5 months, p=0.03), and the trial met its primary endpoint. SOR/HCQ ORR (27%) was higher than historically SOR alone (ORR 2%, SHARP) in pts with advanced HCC, predominantly BCLC C, with CP A and B cirrhosis (35%), and was tolerable. While immune checkpoint inhibitors (ICIs) are taking the forefront in advanced HCC, SOR/HCQ may still have a role in patients with CP B cirrhosis, post-transplant, or contraindications to ICIs. Further, analysis of predictive markers of response is ongoing.
Clinical trial information: NCT03037437
.
Efficacy and safety of durvalumab and gemcitabine-based chemotherapy combined with or without lenvatinib in advanced biliary tract cancer.
Authors: Ding Qi , Yu Haobin , Sun Yubei , Wang Gang , Song Ruipeng
Published: January 2025

595

Background:
Immunotherapy in combination with gemcitabine-based chemotherapy, has now become the standard first-line treatment for advanced biliary tract cancer (BTC). Some small-sample studies have shown that immune checkpoint inhibitors (ICIs), when used in combination with lenvatinib and chemotherapy as first-line therapy, exhibit high anti-tumor activity in BTC. Therefore, we conducted a retrospective study to assess the efficacy and safety of durvalumab and gemcitabine-based chemotherapy with or without lenvatinib, in combination for advanced BTC in the real world.
Methods:
Between January 2021 and September 2024, patients with advanced BTC who received either durvalumab combined with or without lenvatinib, along with gemcitabine-based chemotherapy, were enrolled in this study. The study endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety.
Results:
Thirty patients with advanced BTC were included in this study. Fourteen (46.7%) patients had received durvalumab combined with lenvatinib plus chemotherapy. For all the patients, the median OS was 9.5 months(95% CI: 4.98-14.02), and the median PFS was 5.9 months(95% CI: 4.56-7.24). ORR was 43.4% and DCR was 76.7%. Patients with lenvatinib treatment had a longer median PFS (7.1 vs. 4.6 months, P = 0.06) compared with the non-lenvatinib treatment group. However, the median OS was shorter in patients with lenvatinib treatment group (9.0 vs. 9.5 months, P = 0.915). ORR and DCR in patients with lenvatinib were 57.1% and 92.9%, respectively. However, in patients without lenvatinib treatment group, ORR and DCR were only 31.2% and 62.5%, respectively. All patients experienced adverse events (AEs), addition of lenvatinib does not increase the risk of AEs. The data is still being updated.
Conclusions:
Durvalumab and gemcitabine-based chemotherapy combined with or without lenvatinib has shown to be effective and safe in routine practice. Regarding lenvatinib, its addition has only improved the DCR, ORR, and PFS, but has not been able to prolong OS.
Efficacy and safety of HER2-targeted therapies in biliary tract cancer: A systematic review and meta-analysis of early phase clinical trials.
Authors: Sharma Parth , Kritya Mangesh , Sharma Priyanka , Bansal Vasu , Roth Marc Thomas
Published: January 2025

599

Background:
Biliary tract cancers (BTC) are a rare type of gastrointestinal malignancy, often presenting in advanced stages and associated with a dismal prognosis. BTC are frequently resistant to conventional chemotherapy, with novel targeted therapies playing a pivotal role in overcoming this challenge.
HER2
has recently emerged as an important actionable target in patients with BTC. We aim to evaluate the efficacy and safety of
HER2
-directed monoclonal antibodies (MOAs), bispecific antibodies, antibody-drug conjugates (ADCs), and their combinations in BTC.
Methods:
A systematic literature search was conducted on PubMed, Embase, and Cochrane Central Register of Controlled Trials for clinical trials investigating
HER2
-directed MOAs, bispecific antibodies, ADCs, and their combinations in BTC. The study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. A random effects model was used to pool the outcomes along with 95% confidence intervals (CI). Statistical analyses were performed using program R version 4.4.1.
Results:
We included 12 clinical trials with three Phase I and nine Phase II trials. The pooled ORR (objective/overall response rate) was 35.5% (95% CI: 26.2-45.3, I
2
: 69%), and the DCR (disease control rate) was 72.2% (95% CI: 65.3-78.8, I
2
: 37%). The median follow-up period for DCR was four months. Trastuzumab, in combination with gemcitabine-cisplatin as first-line therapy, had the highest median progression-free survival of 7 months (95% CI: 6.2-7.8), whereas the combination of trastuzumab and tucatinib had the longest median overall survival 15.5 months (90% CI: 6.5-16.7) reported. The most common treatment-related ≥grade 3 adverse events reported across the cohort were anemia and neutropenia. Three cases of confirmed grade 5 interstitial lung disease were reported in patients who received trastuzumab deruxtecan. Clinical trials included in this study are summarized in the table.
Conclusions:
Advances in precision oncology and the emergence of novel targeted therapies have revolutionized cancer management.
HER2
-directed therapies have shown promising results for patients inflicted with BTC having
HER2
alterations in the early phase clinical trials. Further larger studies are awaited to explore the efficacy of
HER2
-directed therapies in BTC.

Clinical trials of
HER2
-directed therapies in BTC.

HER2-directed therapy
Number of clinical trials
Total number of BTC participants
ORR, in % (95% CI)
DCR, in % (95% CI)

Trastuzumab + chemo
2
124
43.2 (19.4-68.8)
80 (72.3-86.7)

Trastuzumab + pertuzumab
2
45
20.9 (9.1-35.3)
53.4 (37.8-68.8)

Trastuzumab deruxtecan
4
84
27.2 (6.9-52.6)
71.9 (58.4-84)

Trastuzumab + tucatinib
1
30
46.7 (28.5-65.5)
76.7 (57.7-89.7)

Zanidatamab
2
101
40.5 (30.9-50.4)
67.6 (57.9-76.6)

SHR-A1811
1
16
56.3 (29.9-80.2)
81.3 (54.4-96)
Long-term survival outcomes of atezolizumab plus bevacizumab treatment in patients with advanced hepatocellular carcinoma.
Authors: Chen Ching-Tso , Feng Yin-Hsun , Yen Chia-Jui , Chen San-Chi , Hsu Chih-Hung , Shao Yu-Yun
Published: January 2025

600

Background:
Immunotherapy combinations such as atezolizumab plus bevacizumab (Atezo-Bev) or STRIDE have been established as standard therapies for patients with advanced hepatocellular carcinoma (HCC). After dual immunotherapy treatment, durable responders and long-term survivors had been reported. However, the longevity of such outcomes following Atezo-Bev treatment remains to be evaluated.
Methods:
We analyzed medical records of four medical centers in Taiwan for patients with Child-Pugh class A liver reserve who received first-line Atezo-Bev treatment for advanced HCC from January 2018 to May 2021, to evaluate their survival outcomes after a long-term follow-up.
Results:
We enrolled 54 patients, predominantly male (90.7%) with the median age of 65 years. The main hepatitis etiology was viral hepatitis (92.6%), including 68.5% chronic hepatitis B. After a median follow-up of 61.9 months, the median overall survival (OS) was 21.0 months (95% confidence interval 10.4 – 31.6 months). The 3-year, 4-year and 5-year OS rate was 36.4%, 25.7% and 25.7%, respectively. For patients with tumor response (N = 19, 34.5%) or disease control (N = 44, 80.0%), the 3-year, 4-year, and 5-year OS rates are listed at Table 1. In univariate analysis, younger age (≤ 70 years), absence of intrahepatic tumor, lack of macrovascular invasion (MVI), and ALBI grade 1 were associated with an OS > 3 years. In multivariate analysis, after adjusting sex, viral hepatitis, MVI, extrahepatic spread, and initial alpha-fetoprotein > 400 ng/ml, the absence of intrahepatic tumor (Odds ratio [OR] = 5.36,
p
= 0.047) and ALBI grade 1 (vs grade 2, OR = 10.02,
p
= 0.037) remained independent predictors for OS > 3 years.
Conclusions:
In patients with advanced HCC, Atezo-Bev treatment led to a notable proportion achieving long-term survival, especially in patients with good response to the treatment. Absence of intrahepatic tumors and preserved liver function are predictive of prolonged survival.

3-year, 4-year and 5-year OS rate of patients who receive Atezo-Bev treatment, stratified by treatment response.

Landmark survival
OS rate (%) by treatment response

Disease control
Responder

3 years
35.6
52.2

4 years
30.3
52.2

5 years
30.3
47.7

Responder: patients who achieved a best response of complete response or partial response after treatment with Atezo-Bev.

Disease control: includes responders and patients who achieved a best response of stable disease following Atezo-Bev treatment.
Updated results of ALTER-H006: A phase II study of benmelstobart (PD-L1 inhibitor) plus anlotinib as adjuvant therapy in hepatocellular carcinoma (HCC) with high risk of recurrence after radical resection.
Authors: Ma0 Xianhai , Duan Xiaohui , Wu Dongde , Zhou Cuncai , Tian Yifeng , Shen Jian , Xu Guohui , Bai Yannan
Published: January 2025

601

Background:
Although radical resection offers one of the most favorable prognosis for hepatocellular carcinoma (HCC), the rate of postoperative recurrence remains high, which is the primary cause of mortality in HCC patients. The optimal adjuvant treatment strategy for patients is still under active investigation. Herein we evaluated the efficacy and safety of the anti-angiogenic tyrosine kinase inhibitor, anlotinib, plus benmelstobart, a novel programmed death-ligand 1 (PD-L1) inhibitor as an adjuvant treatment for HCC with high risk of recurrence after radical resection.
Methods:
This study enrolled patients diagnosed with HCC confirmed through histological or cytological examination, whose age was 18-75, with ECOG 0-1, Child-Pugh class A, 4~8 weeks after R0 resection with any of the following high-risk factors for recurrence: a) tumor nodules ≥4; b) portal vein tumor thrombus (PVTT): vp1 or vp2; c) hepatic vein tumor thrombus (HVTT): vv1 or vv2. Enrolled patients received anlotinib (12 mg, p.o., qd, d1-14, q3w) plus benmelstobart (1200 mg, i.v., d1, q3w) until disease recurrence or unacceptable toxicity or up to 18 cycles (~1 year), whichever occurred first. Tumor assessment was performed at the end of the second cycle and every four cycles thereafter, according to RECIST v1.1. The predefined sample size was 37. The primary endpoint was 1-year recurrence-free survival (RFS) rate. Secondary endpoints included RFS, 1-year overall survival (OS) rate, and safety.
Results:
As the cutoff date of September 13,2024, a total of 38 patients (pts) were enrolled and 35 pts included in per-protocol set analysis. The majority of the 38 pts were male (94.7%, n = 36), and the median age was 56.5 years (range: 33-75). 18 pts (47.3%) had CNLC Stage IIb and 20 (52.6%) had CNLC Stage IIIa HCC. Among them, 35 pts received at least once tumor assessment. According to RECIST 1.1, of the 35 pts, 18 had no recurrence, 15 experienced relapse, 1 dropped out and 1 discontinued due to serious adverse events. The 1-year RFS rate was 59.97% (95%CI: 39.12-79.68) and the primary median RFS was 16.89m(95%CI: 6.82-26.96). The 1-year OS rate was 91.47% (95%CI: 69.23-97.86). 34 of 38 pts (89.5%) experienced treatment-related adverse events (TRAEs). The most common grade 3 TRAEs occurred in 17 pts (44.7%) including hypertension (32%) and neutropenia(5.3%). No grade 4 or 5 TRAEs were observed.
Conclusions:
The present study indicated that anlotinib plus benmelstobart as adjuvant treatment for HCC with high risk of recurrence after radical resection exhibited promising efficacy and tolerable safety profile. The conclusion should be validated in more participants included subsequently.
Clinical trial information: NCT05111366
.
Development and regulatory approval of a new systemic targeted therapy for advanced hepatocellular carcinoma.
Authors: Pasche Boris , Benson Al B. , Kudo Masatoshi , Shields Anthony F. , Jimenez Hugo , Azmi Asfar S. , Barbault Alexandre
Published: January 2025

613

Background:
There are no commercially available devices for the treatment of patients with advanced hepatocellular carcinoma who have failed 1st line and 2nd line therapy. We have identified tumor-specific modulation frequencies in patients with advanced hepatocellular carcinoma. We exposed patients to radiofrequency electromagnetic fields, which are amplitude-modulated from 0.1 Hz to 100 kHz and measured changes in pulse pressure. Frequencies eliciting measurable changes in pulse pressure were selected as tumor-specific frequencies.
Methods:
Treatment is administered to patients with advanced hepatocellular carcinoma by means of a battery-operated portable device emitting 27 MHz radiofrequency electromagnetic fields, which are amplitude-modulated at hepatocellular carcinoma frequencies. The device is connected to a coaxial cable ending with a spoon-shaped antenna placed on the anterior part of the patient's tongue during treatment. Treatment is administered three times a day for one hour.
Results:
A total of 69 patients with advanced hepatocellular carcinoma received treatment with the TheraBionic device until progression or death. The median overall survival of patients who received treatment with the TheraBionic device after failing 1st line and 2nd line therapy was 9.15 (95% CI 1.6-34.8) months and the median overall survival of Child-Pugh A patients was 9.5 months, which are comparatively longer than the 7.8 months pooled estimated medians of the placebo arms of 11 randomized 1st line and 2nd line placebo-controlled studies assessing the safety and efficacy of new agents for the treatment of Child-Pugh A advanced HCC (Llovet, Montal et al., J Hepatol 2019). We also analyzed the survival of patients who had received two lines of systemic therapy and did not receive any additional cancer treatment while and after receiving treatment with the TheraBionic device. The median OS of these patients was 9.8 months and the median OS of the Child-Pugh A patients was 17.2 months, which are comparatively longer than the 7.74 months pooled estimated medians of the placebo arms of the above cited 11 randomized studies. To assess unknown device-related adverse events, we assessed patient reported symptoms using the same scale in the SHARP and Asian Pacific Sorafenib studies. The incidence of any grade adverse events among Child-Pugh A who received treatment with the TheraBionic device was not different from the Placebo group of the SHARP and Asian Pacific Sorafenib studies. There were no NCI Grade 2, 3 or 4 toxicities. One patient developed grade 1 mucositis and one patient developed grade 1 fatigue.
Conclusions:
The data presented here provide reasonable assurance of safety and probable benefit in patients with advanced hepatocellular carcinoma who have failed 1st line and 2nd line therapy:
https://www.fda.gov/medical-devices/recently-approved-devices/therabionic-p1-h220001
.
Impact of HER2-positivity on prognosis and targeted therapeutic outcomes in advanced biliary tract cancer.
Authors: Lee Choong-kun , Seo Dong Hyun , Fox Daniel Aaron , Haro-Silerio Jaime , Chung Taek , Kim Chang Gon , Bhamidipati Deepak , Meric-Bernstam Funda , Pant Shubham , Javle Milind M. , Lee Sunyoung S.
Published: January 2025

629

Background:
HER2 overexpression and amplification have been identified as a promising druggable target in biliary tract cancer (BTC). This study aims to characterize the clinical and molecular outcomes associated with HER2 positivity in BTC and evaluate the prognostic implications of HER2-targeted therapies.
Methods:
A retrospective study was conducted involving patients with advanced BTC diagnosed at Yonsei Cancer Center (YCC) and the University of Texas MD Anderson Cancer Center (MDACC) between 2009 and 2023. Patients were classified as HER2-positive either by immunohistochemistry (IHC 3+ or 2+/ISH+) or by next-generation sequencing (NGS,
ERBB2
amplification). Overall survival (OS) and palliative first-line progression-free survival (PFS) were analyzed using Kaplan-Meier and Cox regression methods.
Results:
A total of 389 advanced BTC patients were initially screened (310 from YCC; 79 from MDACC). Among the 310 BTC patients from YCC with available HER2 IHC results, 78 (25.2%) were HER2-positive and 232 (74.8%) were HER2-negative. HER2 positivity was significantly more common in gallbladder cancer (55.1%) compared to its prevalence in intrahepatic or extrahepatic cholangiocarcinoma (22.8%, p<0.001). Of the 201 patients with available NGS data, 186 (92.5%) were
ERBB2
non-amplified; among these, 27 (14.9%) were HER2-positive by IHC. For survival analysis, 310 patients were eligible: 239 from YCC (both HER2-positive and negative) and 71 from MDACC (all HER2-positive). Kaplan-Meier survival analysis indicated a trend towards shorter OS in HER2-positive patients compared to HER2-negative patients (median OS, 13.7 vs. 17.1 months, p=0.084, HR=1.246, 95% CI=0.97–1.60) regardless of exposure to HER2-targeted therapy, while first-line PFS on chemotherapy only was significantly shorter in the HER2-positive group (5.1 vs. 7.4 months, p<0.001, HR=1.906, 95% CI=1.46-2.48). Among HER2-positive patients, 56.8% received HER2-targeted therapy in the second line setting. HER2-positive patients who did not receive HER2-targeted therapy had a significantly poorer prognosis compared to HER2-negative patients (median OS 8.1 vs. 17.1 months, HR=2.46, 95% CI=1.73-3.48), whereas those receiving HER2-targeted therapy had comparable OS to HER2-negative patients (median OS 18.2 vs. 17.1 months, HR=0.95, 95% CI=0.71-1.27). Multivariable analysis identified a history of surgical treatment, radiation therapy, HER2 positivity, and HER2-targeted therapy as independent prognostic factors for OS.
Conclusions:
HER2 positivity is associated with a poorer prognosis in advanced BTC. However, HER2-targeted therapies improve outcomes, suggesting their potential inclusion in standard care for HER2-positive subgroups. Discrepancies between IHC and NGS in HER2 assessment emphasize the need for optimized testing guidelines in BTC.
Extra-hepatic (ehCCA) and intra-hepatic cholangiocarcinomas (iCCA): A genomic landscape comparison of peri-hilar (phCCA), common bile duct (cbdCCA) and gallbladder (gbCCA) with iCCA.
Authors: Sampat Parth J. , Pavlick Dean , Ross Jeffrey S. , Basnet Alina
Published: January 2025

630

Background:
Metastatic CCAs have poor prognosis. Comprehensive genomic profiling (CGP) was used to compare genomic alterations (GA) in phCCA, with cbdCCA, gbCCA and iCCA. Frequencies of GA in therapy targets such as FGFR2, IDH, ERBB2 & BRAF, & Immuno-oncology (IO) drug response predictors (MSI status, TMB & PDL1) were examined.
Methods:
DNA extracted from 110 cases of phCCA, 743 cases of cbdCCA, 2983 cases of gbCCA and 9178 cases of ihCCA underwent hybrid capture based CGP to evaluate classes of genomic alterations (GA), MSI status, TMB levels, genomic ancestry, genomic signature, HRD score and germline status. phCCA cases were confirmed at surgery and pathology as originating from either left, right or common hepatic ducts. cbdCCA cases were confirmed by cbd biopsies or Whipple procedures. PD-L1 expression was determined by IHC using the Dako 22C3 assay using tumor proportional score (TPS) system.
Results:
The pt age distributions were similar; female gender was more frequent in gbCCA. gbCCA featured higher GA/tumor (P=.0001). The frequencies of FGFR2 & IDH1 targetable GA in phCCA, cbdCCA and gbCCA were uncommon especially when compared iCCA (P<.0001). GA in BRAF, CDKN2A, MTAP and PIK3CA in gbCCA were like phCCA and cbdCCA. At 16.5%, the frequency of GA in ERBB2 were highest in gbCCA and in all ehCCA when compared with iCCA (P<.0001). The frequencies of KRAS GA including KRAS G12C were greater in both phCCA and cbdCCA when compared with gbCCA (P=.0015) and iCCA (P.0001). TP53 GA were highest in gbCCA (P=.0007). IO biomarker frequencies were similar in all. The frequencies of HRD positive (gLOH) status and MMR genomic signature were similar in all.
Conclusions:
ehCCA subtypes feature characteristic GA profiles that have potential to influence therapy selection with lower frequencies of FGFR2 & IDH1 when compared with iCCA. In contrast, targetable ERBB2 & KRAS G12C are more frequent in ehCCA than iCCA, and highest in gbCCA & cbdCCA.

peri-hilarCCA
cbdCCA
P-value (phCCA vs cbdCCA)
gbCCA
P-value (phCCA vs gbCCA)
ihCCA
P-value (phCCA vs iCCA)

BRAF
3.6%
4.7%
NS
2.4%
NS
5.1%
NS

ERBB2
14.5%
10.6%
NS
16.5%
NS
5.1%
0.002

FGFR2
0.9%
2.0%
NS
1.5%
NS
11.7%
0.001

IDH1
3.6%
0.8%
NS
0.6%
NS
13.9%
0.006

KRAS
29.1%
46.2%
0.015
14.2%
0.0015
19.8%
0.071

TP53
45.5%
63.8%
0.011
65.7%
0.0007
33.9%
0.061

MSI-high
1.8%
1.3%
NS
1.2%
NS
1.8%
NS

TMB≥10 mut/mb
3.6%
4.2%
NS
5.2%
NS
3.6%
NS

PD-L1 low positive
21.1%
31.3%
NS
23.5%
NS
23.7%
NS
Survival disparities in small intestine carcinoid tumors: A SEER-based analysis.
Authors: Dharia Adit , Borra Rahul , Peshin Supriya , Ser-Manukyan Haik , Mahayni Abdulah Amer , Mangu Sainarayana , Patel Dharmik M. , Muddassir Salman
Published: January 2025

653

Background:
Small intestine carcinoid tumors (SI-carcinoids) are rare neuroendocrine neoplasms with variable survival outcomes. This study examines the impact of age, sex, race, income, and geographic location on overall survival (OS) in patients with SI-carcinoid tumors.
Methods:
A retrospective cohort study was conducted using the Surveillance, Epidemiology, and End Results (SEER) registry 22 to identify patients aged 20 and above with SI-carcinoid tumors from 2000 to 2021. Kaplan-Meier survival analysis and log-rank tests were used to assess differences in survival. Cox proportional hazards models estimated hazard ratios (HR) for Overall Survival (OS).
Results:
20,777 patients were included, with 7,029 deaths recorded. Median OS varied significantly by age, sex, race, income, and tumor site. Patients aged 60-85 had a median OS of 10 months (95% CI: 9.75-10.42), while those over 85 had 2.92 months (95% CI: 2.67-3.33). Females had better OS (13.92 months; 95% CI: 13.42-14.42) than males (12.83 months; 95% CI: 12.42-13.25). Non-Hispanic Black patients had worse OS (12.33 months; 95% CI: 11.50-13.33) compared to Non-Hispanic Whites (13.25 months; 95% CI: 12.92-13.67). Patients earning less than $50,000 had worse OS (11.42 months; 95% CI: 10.67-12.42) than those earning $100,000–$120,000 (15.42 months; 95% CI: 14.25-17.83). Geographic disparities were noted, with nonmetropolitan areas showing worse OS (11.42 months; 95% CI: 10.83-12.92) compared to large metropolitan areas (14.00 months; 95% CI: 13.50-14.42). Cox models confirmed age (HR for 85+ years: 21.99; 95% CI: 17.40-27.81), male sex (HR: 1.12; 95% CI: 1.07-1.17), and Black race (HR: 1.29; 95% CI: 1.18-1.42) were linked to worse OS. Tumor site also affected OS, with ileal tumors showing better survival compared to duodenal tumors (HR: 0.89; 95% CI: 0.84-0.94).
Conclusions:
Age, sex, race, income, and geographic location significantly affect OS in patients with small intestine carcinoid tumors, highlighting the need for tailored interventions for vulnerable groups.
Efficacy and safety of surufatinib in unresectable or metastatic grade 3 pancreatic neuroendocrine tumors (NET G3): Real-world analysis.
Authors: Wang Jian , Liang Yun , Long Jiang , Chi Yihebali , Zhang Suzhen , Wu Yinying , Wang Yu , Bai Chunmei , Hu Weiyu , Hu Hanguang , Zhang Lin , Chen Jie , Hao Jing
Published: January 2025

657

Background:
Currently, there is limited exploration regarding the treatment of NET G3, resulting in restricted treatment options. Therapeutics for NET G1/2 may serve as an alternative. Surufatinib, with its potent targeting of VEGFRs, FGFR1, and CSF-1R, not only exerts inhibitory effects on tumor angiogenesis but also modulates the immune microenvironment. Due to its demonstrated efficacy and manageable safety profile, it has secured approval for the treatment of G1/2 NETs.
Methods:
This is a multi-center real-world study that retrospectively analyzes the clinical data of pts with NET G3 who received surufatinib-based treatment from December 2021 to February 2024, aiming to assess its efficacy and safety. Eligible pts were unresectable or metastatic p-NET with ki-67>20%. The primary endpoint was PFS, with secondary endpoints were ORR, DCR, and safety.
Results:
As of September 2024, data from 37 pts were analyzed. The median age was 54 years (range: 32-80), with 59.5% male. The median Ki-67 index was 30% (range: 25-70%), and 94.6% of the cases were non-functional p-NETs, with 89.2% having liver metastases and 35.1% having bone metastases. In terms of prior treatments, 18.9%, 40.5%, and 40.5% of pts had received 0, 1, and ≥2 systemic therapies, respectively. Among them, 81.1% had previously undergone chemotherapy, 35.1% had received interventional therapy of liver metastases, and 13.5% with everolimus or anti-angiogenic agents. 48.6% pts had surufatinib-based combination treatment. The median PFS was 9.30 months (mo, 95% CI: 8.02–13.02), with an ORR of 21.6% and a DCR of 81.1%. First-line (1L) treatment showed a higher ORR (42.9% vs. 16.7%) and a trend of better PFS (9.67 vs. 9.04 mo, p=0.7) compared to ≥2L treatment. Combination therapy improved ORR (33.3% vs. 10.5%) with a similar PFS (9.30 vs. 9.44 mo, p=0.93) compared to surufatinib monotherapy. Liver metastases had limited impact on PFS (9.93 vs 9.30 mo, p=0.55). Common grade ≥3 adverse events included hypertension (8.1%), proteinuria (5.4%), and elevated bilirubin (5.4%).
Conclusions:
Surufatinib has demonstrated initial efficacy and manageable safety in pts with NET G3, providing a new treatment option for these pts. First-line therapy may be a favorable factor for improving PFS. To delve deeper into these findings, additional subgroup analyses, with a particular emphasis on pts with ep-NET G3 will be conducted in the future.
Phase II study of mFOLFIRINOX efficacy as first and subsequent lines of advanced gastrointestinal neuroendocrine tumors G3 and neuroendocrine carcinomas therapy.
Authors: Zhulikov Yaroslav , Evdokimova Ekaterina , Gorbunova Vera , Emelianova Galina , Markovich Alla Anatolievna , Kachmasova Abidat , Delektorskaya Vera , Kovalenko Elena , Gadzhieva Kizler , Artamonova Elena
Published: January 2025

659

Background:
Gastrointestinal (GI) neuroendocrine carcinomas (NEC) are rare tumors and account for 3% of all NECs. Despite the differences in genetic characteristics, treatment principles of GI NECs are extrapolated from lung NECs. The standard first-line therapy is platinum and etoposide-containing regimens, which allow to achieve a median PFS of 5-6 months. A small retrospective study demonstrated the potential effectiveness of the mFOLFIRINOX regimen with a median PFS of 5.4 months, despite that the majority of patients (pts) received this regimen as second or subsequent lines. The aim of this study is to evaluate mFOLFIRINOX +/- somatostatin analogues (SA) efficacy in GI NEC subgroup.
Methods:
This prospective, single center phase II study used a two-stage Simon design. The primary endpoint is disease control rate (DCR) ≥ 6 months. Statistical hypothesis: investigated therapy improves DCR compared with historical control from 50 to 70%. Secondary endpoints are progression-free survival (PFS), overall survival (OS), objective response. At the first stage, enrollment of 16 pts was planned (α=0.05, power 80%). If a disease control ≥ 6 months was achieved in at least 9 of the 16 pts, it was planned to continue enrollment up to 39 pts. Here we present results of the first stage of this study. Inclusion criteria: pts ≥18 y.o. with histologically confirmed advanced GI NEC or neuroendocrine tumor (NET) G3 ki67≥55%; ECOG 0-2. Recruitment of pts was carried from 2019 to February 2024.
Results:
The study included 16 pts, 12 male and 4 female. The most common sites of primary tumor are stomach (N=8, 50%) and pancreas (N=5, 31.3%). 10 (62.5%) pts had large cell carcinoma, 1 – small cell carcinoma (6.3%), 5 (31.3%) – NET G3. The median ki-67 was 70% (40-95%). 15 pts (93.7%) had IV stage, 1 (6.3%) – III. The most common site of metastases is liver – 11 (68.8%), more than half of pts have isolated metastases in liver (N=9, 56.3%). ECOG status was evaluated as 0-1 in 15 (93.7%) cases. Majority of pts (N=14, 87.5%) received mFOLFIRINOX as first line therapy. 7 pts (46.7%) had positive expression of SSTR-2A or -5 and received concurrent treatment with SA. ORR was 62.5% (N=10/16), stable disease – 37.5% (N=6/16). DCR ≥ 6 months was 93.7% (N=15). With a median follow-up of 13.2 months, median PFS was 10.8 months (95% CI 7.57-14.1). One pts had serious adverse event - myocardial infarction, no grade 5 toxicity was observed.
Conclusions:
Chemotherapy with mFOLFIRINOX showed promising results in GI NECs or NETs G3 ki67≥55% treatment. Primary endpoint was met, enrollment of patients in the study continues.
Adjuvant therapy with somatostatin analogs for recurrent gastric neuroendocrine tumors type 1.
Authors: Markovich Alla Anatolievna , Zhulikov Yaroslav , Evdokimova Ekaterina , Gorbunova Vera , Emelianova Galina , Gadzhieva Kizler , Malikhova Olga , Karasev Ivan , Delektorskaya Vera , Kuvshinov Yuri , Kuznetsova Anna , Artamonova Elena
Published: January 2025

665

Background:
Neuroendocrine gastric tumors (gNETs) type 1 are associated with chronic autoimmune atrophic gastritis, hypergastrinemia and usually have multifocal lesions and high frequency of recurrence (up to 70% for 2 years). Somatostatin analogs (SA) showed promising data in neoadjuvant setting with 84% of complete responses in a small retrospective trial. The aim of this study was to evaluate the efficacy of adjuvant treatment with SA for recurrent gNETs type 1.
Methods:
This retrospective, single-center study included patients (pts) with recurrent gNETs who received adjuvant treatment with SA. Recruitment of pts was carried out from 2012 to February 2024.
Results:
The study included 35 pts, 33 females and 2 males. Endoscopic mucosal resection (EMR) was performed in 34 cases (97.1%), gastric resection in 1 (2.9%). The median of previous EMR was 2 (1-6) procedures. Most of the pts have multifocal lesions – 28 (80%), the median of lesions is 5. The median tumor size – 6 mm, tumor size >10 mm was observed in 2 cases (5.7%), one of them had N+. The median of ki67 was 3,5% (1-10%), grade 1 (G) - 14 (40%) and G2 - 21 (60%). All pts received adjuvant therapy with SA, 33 (94.3%)long-active releasing octreotide30 mg and 2 (5.7%) lanreotide 120 mg every 4 weeks. The time of SA therapy was <12 months in 23 cases (65.7%) and ≥12 months in 12 (34.3%). The median of follow-up was 30.5 months. The median disease-free survival (DFS) was not reached (95% CI, 67-NR). We compared median DFS after previous EMR (DFS1) without adjuvant SA and DFS after EMR with adjuvant SA (DFS2). The DFS2 was significantly higher – median of DFS1 was 8.8 months (95% CI, 2.7-14.9) not reached (95% CI, 67-NR, p<0.01) . Adjuvant treatment with SA ≥12 months was associated with improved DFS compared to <12 months – not reached (95% CI, 58.1-NR) versus 61 months (95% CI, 26.2-96.2, p=0.05). Adjuvant SA reduced gastrin levels after a year of therapy by ≥50% from baseline in 13 cases (37.1%).
Conclusions:
Adjuvant treatment with SA significantly improved DFS and should be considered for recurrent and multifocal gNETs type 1. Duration of therapy ≥12 months was significantly associated with improvement in DFS compared with shorter duration of therapy.