bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigation of synergistic effects in trials of combination therapies with immune-checkpoint inhibitors in advanced gastric or gastroesophageal junction cancer.
Authors: Okui Jun , Nagashima Kengo , Matsuda Satoru , Sato Yasunori , Kawakubo Hirofumi , Takeuchi Masashi , Hirata Kenro , Tsugaru Kai , Yamamoto Shun , Nomura Motoo , Tsushima Takahiro , Takeuchi Hiroya , Kato Ken , Kitagawa Yuko
Published: January 2025

405

Background:
Combinations of immune checkpoint inhibitors (ICI) and chemotherapy (CT) have been approved for gastric cancer. However, there is a hypothesis that this combination may blunt antitumor immune responses because most chemotherapeutic agents also target lymphocytes. The primary objective was to investigate that the ICI and CT does not interfere each other’s therapeutic effects in advanced gastric cancer (GC) or gastroesophageal junction cancer (GEJC) patients.
Methods:
The reconstructed individual patient data was electronically extracted from the Kaplan-Meier curve of phase III randomized controlled trials (RCTs). The observed PFS curve of each constituent monotherapies was used to estimate simulated PFS curves expected under a model of independent drug action. If the observed curve demonstrated significantly better PFS than simulated curve, the combination of ICI and CT may have a synergistic effect, implying a superior outcome compared to simply adding the component monotherapy.
Results:
The study included 2,538 unresectable advanced, recurrent, or metastatic GC or GEJC patients from three RCTs comparing pembrolizumab (KEYNOTE-061, KEYNOTE-062 and KEYNOTE-859). In patients with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater, the 1-year and median PFS of the observed and simulated curves were 28.0% vs. 27.9%, and 6.89 months vs. 6.88 months, respectively. One sample log-rank test showed no significant differences between the observed and simulated curves (p = 0.107). In the subgroups with PD-L1 CPS ≥10 or <1, the 1-year PFS of the observed and simulated curves was 34.7% vs 32.8%, and 28.5% vs 26.8%.
Conclusions:
The observed PFS of ICT involving pembrolizumab was comparable to the simulated PFS estimated from the data for each monotherapy regardless of the magnitude of PD-L1 CPS. Although it was not clear whether potential synergies existed for ICT, these findings at least suggest that the benefits of ICI and CT are not interfering each other, thereby providing theoretical support for the efficacy of ICT in patients with advanced GC or GEJC.
A phase II study of fruquintinib plus sintilimab as a second-line therapy for advanced gastric and gastroesophageal junction adenocarcinoma (GC/GEJC): Updated results.
Authors: Jin Min , Yang Shengli , Liu Junli , Zhang Jieying , Zhao Lei , Yu Dandan , Lin Zhenyu , Li Pindong , Wang Jing , Xue Jun , Ma Hong , Hu Jianli , Zhang Tao , Liu Hongli
Published: January 2025

407

Background:
Preliminary results of the open-label, single-arm phase II study (NCT05625737) had demonstrated the combination of fruquintinib and sintilimab as a second-line therapy had a promising anti-tumor activity and an acceptable safety profile in pts with advanced GC/GEJC (ASCO-GI 2024. Poster 332). Here, we update the results with a focus on subgroup analyses.
Methods:
Patients (pts) aged 18-75 years who were HER2-negative and had failed first-line standard treatment were enrolled. Eligible pts received 4mg of fruquintinib orally once daily on days 1-14 and 200 mg of sintilimab intravenously on day 1, with treatment repeated every 3 weeks. An optimal Simon two-stage design was employed. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.
Results:
At data cut-off (August 25, 2024), 29 pts (7 in the first stage; 22 in the second stage) with median age 51 (range 33–73) years old had been enrolled. 41.4% were male, 37.9% had ECOG PS 1, 69% had lymph node metastasis and 72.4% had previously received immunotherapy. Among the 24 efficacy evaluable pts, the ORR was 33.3% (95% CI 15.6–55.3) and DCR was 66.7% (95% CI 44.7–84.4). After a median follow-up of 13.14 months, the median PFS was 5.13 (95% CI: 2.73–7.03) months and OS result was pending maturity. Pts who had lymph node metastasis exhibited higher ORR compared to pts without lymph node metastasis (ORR-47.1 vs 0%). In particular, pts without prior immunotherapies were more likely to achieve higher response rate (37.5 vs 33.3%) and had an obvious trend for longer PFS than pts with prior immunotherapies (9.00 vs 5.13 months). Majority of treatment-emergent adverse events (TEAEs) were grade 1-2 and the most frequently reported ones (≥20%) were white blood cell decreased (33%), hypertriglyceridemia (25%), lymphocyte count decreased (21%), abdominal pain (21%) and decreased appetite (21%). Grade 3/4 TEAEs occurred in only one patient, consisting of increased blood bilirubin levels, aspartate transaminase elevation, and alanine transaminase elevation.
Conclusions:
Fruquintinib combined sintilimab was well tolerated, with encouraging antitumor activity as second-line treatment for advanced GC/GEJC, especially in pts without prior immunotherapies. Further studies in larger cohorts to validate these findings are warranted.
Clinical trial information: NCT05625737
.
Correlation between immune-related adverse events and clinical outcomes in patients treated with first-line nivolumab plus chemotherapy for advanced gastric or gastroesophageal junction cancer: A multi-center retrospective study in Japan.
Authors: Inamoto Rin , Ogura Nozomu , Onishi Misa , Kito Yosuke , Nagashima Kengo , Furuta Mitsuhiro , Machida Nozomu , Shoji Hirokazu , Takahashi Naoki
Published: January 2025

439

Background:
The CheckMate 649 trial and ATTRACTION-4 trial showed the efficacy of first-line nivolumab plus chemotherapy (Nivo-CT) for advanced gastric or gastroesophageal junction (GEJ) cancer. Recent studies have shown that immune-related adverse events (irAEs) caused by immune checkpoint inhibitors were associated with survival benefit in patients with solid tumors. However, there were few data on correlation between irAEs and efficacy of first-line Nivo-CT for advanced gastric or GEJ cancer.
Methods:
This multi-center retrospective study included patients with histologically confirmed advanced gastric or GEJ adenocarcinoma who were started on first-line Nivo-CT between December 2021 and December 2023. We divided the patients into two groups according to occurrence of irAEs; those with irAEs (irAE group) or those without (non-irAE group) and assessed the efficacy in both groups. Efficacy was evaluated by overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Landmark analysis at 2 months after initiating Nivo-CT was performed to adjust effects of early progression or death, in which patients who had events up to 2 months were excluded.
Results:
A total of 271 patients were included (median age, 70 [range 18–85] years; male/female, 64/36%; performance status (PS) 0/1/2, 47/49/4%; primary tumor site gastric/GEJ, 90/10%; status unresectable/recurrent, 81/19%; histology intestinal/diffuse, 30/70%; PD-L1 CPS <1/1~5/>5, 15/33/53%). Median follow-up time was 11.3 (range 1-30) months, and 80 (30%) patients developed irAE. In the landmark analysis, the median PFS was 11.1 months in the irAE group and 7.2 months in non-irAE group (HR 0.70 [95%CI 0.50-0.97], p = 0.034), and the median OS was 22.5 months in the irAE group and 17.9 months in non-irAE group (HR 0.77 [95%CI, 0.50-1.17], p = 0.219). The ORR were 67.4% in the irAE group and 66.7% in non-irAE group (p = 0.934). Multivariate analysis indicated that PS ≥1 (HR 1.66 [95%CI, 1.20-2.30], p = 0.02), elevated ALP (HR 1.61 [95%CI, 1.13-2.27], p = 0.008), and absence of irAEs (HR 1.55 [95%CI, 1.08-2.22], p = 0.018) were associated with poor prognosis. The most frequent irAEs were pneumonitis (n = 16), and grade ≥3 irAEs were observed in 26 (9.6%) patients: pneumonitis (n = 6), hepatitis/hypophysitis (n = 5).
Conclusions:
Development of irAEs was associated with improved outcomes in advanced gastric or GEJ cancer patients receiving first-line Nivo-CT.
Mortality trends and racial disparities in hepatocellular carcinoma associated with metabolic syndrome in the United States and Texas: A 21-year analysis (1999-2020) using CDC WONDER database.
Authors: Naz Sidra , Shaikh Abdullah , Alasadi Mazen , Zhang Hao Chi
Published: January 2025

525

Background:
The prevalence of hepatocellular carcinoma(HCC) and metabolic syndrome (MetS) is increasing globally. This study aims to examine annual trends of mortality in MetS-associated HCC in the United States and its state of Texas, from 1999 to 2020, to evaluate public health initiatives and identify socioeconomic factors.
Methods:
Mortality trends for adults aged ≥25 years with MetS-associated HCC were analyzed using CDC WONDER database, identifying deaths through ICD-10 codes C22.9 “Liver Malignant neoplasms” and E88.9 “Metabolic Syndrome”. Crude and age-adjusted mortality rates (AAMRs) per 100,000 people were extracted. Annual percent changes (APCs) in AAMRs, with 95% confidence intervals, were determined across various demographic (sex, race/ethnicity, age) and geographic (state, urban-rural, regional) subgroups.
Results:
Between 1999 and 2020, 271,046 documented deaths were attributed to HCC due to metabolic syndrome. The AAMR for MetS-related HCC mortality increased in the US from an adjusted rate (AR) (3.7) in 1999 to (4.5) in 2009 (APC:2.10%; 95% CI: -0.13% to 3.10%), after which it increased to (7.6) in 2018 (APC:5.83%; 95% CI:4.25% to 6.99%) and increased to 9.9 in 2020 (APC:13.19%; 95% CI:8.78% to 15.7%). In Texas, AAMR for MetS-related HCC mortality increased from AR (4.9) in 1999 to (8.9) in 2015 (APC:3.95%; 95% CI:3.11% to 4.69%) after which it increased to (15.3) in 2020 (APC:10.64%; 95% CI:8.18% to 17.33%). Men had consistently higher AAMRs than women (12.4 vs. 8). The AAMR in U.S. men increased from (5.1) in 1999 to (12.4) in 2020. The AAMR in U.S. women increased from (2.7) in 1999 to (8) in 2020. The non-Hispanic (NH) American Indian or Alaska Native population has the greatest AAMR (13.4), followed by the NH Black or African American(AA) (12.7) and the Hispanic or Latino population with AAMR (10.9). The low-risk population was NH White with AAMR (9.6) and NH Asian or Pacific Islander (6.6). The AAMR also varied by region (South:11.5; Midwest:9.9; West:9.4; Northeast:7.4) and non-metropolitan areas had higher AAMR (small metro:12.1; non-core areas:11; micropolitan areas:11.7) than metropolitan areas (large central metropolitan: 8.8; large fringe areas: 8.7). The states in the upper 90th percentile of MetS-related HCC AAMRs were Texas, Louisiana, Arkansas, Michigan, Nevada exhibited an approximately two-fold increase in AAMRs, compared to states falling in the lower 10th percentile Nebraska, Wisconsin, Washington, Maine.
Conclusions:
Mortality rates from hepatocellular carcinoma associated with metabolic syndrome have risen in the United States and Texas over the past two decades. However, significant demographic and geographic disparities in MetS-related HCC mortality continue, emphasizing the need for further investigation and the development of targeted treatment strategies.
Racial, gender and socioeconomic disparities in survival outcomes of hepatocellular carcinoma.
Authors: Ogedegbe Oboseh John , Ntukidem Olanipekun Lanny , Bai Sakshi , Cheema Asfand Yar , Sukhera Ahmed Bashir , Rodriguez Vazquez Jorge , Erazo Gloria
Published: January 2025

526

Background:
Hepatocellular carcinoma (HCC) is the sixth most commonly occurring cancer worldwide, with mortality rates increasing globally, particularly in the Western world. The 5‐year survival rate of persons with HCC is less than 20%. It is, therefore, essential to investigate the extent to which social determinants of health influence survival outcomes. In this study, we explored the effect of gender, race/ethnicity and socioeconomic factors on survival outcomes among patients with HCC in the United States.
Methods:
We extracted data on patients with a histologic diagnosis of hepatocellular carcinoma from the Surveillance, Epidemiology and End Result (SEER) Registry from 2000-2021. The primary outcome of interest was the cause-specific survival of these patients. According to the International Classification of Diseases for Oncology, Third Edition (ICD-O-3) system, the histological code of HCC is 8170/3. We excluded patients of missing or unknown race, income, location, and patients outside the years of study. Cox proportional hazard regression (SPSS) was utilized to determine the association between patients' race/ethnicity, gender, annual median income, location and cause-specific survival.
Results:
80,445 met the criteria and were included in our study. Gender proved to be a predictor of survival; compared to females, males had worse outcomes, with males HR 1.040 (95% CI; 1.020-1.060, p = <0.001). Race was a predictor of survival outcomes. Using American Indian/Alaska Native as our reference, Asian/Pacific Islander HR 0.847 (95% CI; 0.790-0.90, p = <0.001), Black HR 1.019 (95% CI; 0.950-1.093, p = 0.603), White HR 0.955 (95% CI; 0.893-1.023, p = 0.186). We also analyzed the effects of socioeconomic factors on survival. Patients with higher annual median income had better outcomes. >$120000 HR 0.817 (95% CI; 0.783-0.851, p = <0.001) while patients with lower annual median income had worse outcomes < $40000 HR 1.217 (95% CI; 1.134-1.305, p < 0.001). The effect of location on survival was not significant. Compared to non-metropolitan areas, metropolitan areas HR 0.988 (95% CI; 0.971–1.004, p = 0.138).
Conclusions:
Race/ethnicity, income and gender disparities all played a significant role in cause-specific survival in patients with HCC, with improved survival observed in females, Asians and patients with higher annual median income. More efforts are needed to bridge these survival disparities.
Survival benefits of asymptomatic primary tumor resection after bevacizumab plus FOLFIRI as first-line therapy for patients with metastatic colorectal cancer with synchronous unresectable metastasis.
Authors: Tsai Hsiang-Lin
Published: January 2025

56

Background:
Metastatic colorectal cancer (mCRC) poses a clinical challenge and requires a combination of systemic therapy and conversion surgery. Although first-line chemotherapy and target therapy are considered the standard treatments for mCRC, the role of primary tumor resection (PTR) in asymptomatic synchronous mCRC with unresectable metastatic lesion after initial therapy remains relatively underexplored.
Methods:
A retrospective observational study was conducted from January 2015 to January 2021, involving 74 patients with synchronous mCRC who received bevacizumab plus FOLFIRI as first-line systemic therapy. All 74 patients had unresectable metastatic lesions confirmed through multidisciplinary team (MDT) discussion. Patients' characteristics, PTR data, and radiotherapy (RT) and overall survival (OS) outcomes were analyzed. The patients were categorized into a "PTR" group and a "No PTR" group and then further stratified into IVA, IVB, and IVC subgroups based on the initial mCRC stage. Additionally, four subgroups - namely "PTR(+)/RT(+)", "PTR(+)/RT(-)", "PTR(-)/RT(+)", and "PTR(-)/RT(-)" were formed to assess the combined effects of PTR and RT.
Results:
The median OS for all the patients was 23.8 months (20.5 - 27.1 months). The "PTR" group exhibited a significantly higher median OS of 25.9 months (21.3 - 30.5 months) compared with 21.4 months (15.8 - 27.1 months) in the "No PTR" group (
P
= 0.048). Subgroup analyses revealed a trend of improved survival with PTR in patients with stage IVA and IVB; however, the results were not statistically significant (
P
= 0.116 and 0.493, respectively). A subgroup analysis of PTR and RT combinations revealed no significant difference in median OS rates.
Conclusions:
For asymptomatic mCRC with synchronous unresectable distant metastasis. PTR following first-line therapy with bevacizumab plus FOLFIRI can provide a survival benefit, particularly in stage IVA/IVB patients compared with stage IVC patients. Additionally, RT for primary tumor did not provide an additional OS benefit in mCRC with unresectable metastasis. A prospective randomized trial with a larger sample size is essential to further elucidate the role of PTR in this context.
Association between immune-related adverse events and prognosis after immune checkpoint inhibitor in hepatocellular carcinoma: A meta-analysis and systematic review.
Authors: Hwang Soo Young , Rezaee-Zavareh Mohammad Saeid , Attia Abdelrahman M , Kaymen Emily , Tran Nguyen H. , Abou-Alfa Ghassan K. , Singal Amit , Yang Ju Dong
Published: January 2025

566

Background:
Immune checkpoint inhibitors (ICIs) have become the preferred treatment for unresectable hepatocellular carcinoma (HCC). Conflicting data exist regarding the prognostic value of immune-related adverse events (irAEs) in these patients. We aimed to explore potential the association between irAEs and prognosis in HCC patients treated with ICIs.
Methods:
We searched PubMed, Scopus, Web of Science, and CENTRAL databases for articles published from inception to June 2024 using keywords including ICI, HCC, and irAEs. Two reviewers independently screened studies for eligibility and relevant data. A random effects model was used for statistical analysis, and subgroup analysis was performed by the grade of irAEs.
Results:
Of 3,028 studies, 25 (n=4,116 patients) met criteria for inclusion. Atezolizumab plus bevacizumab was the most common treatment regimen (n=10 studies). About half (49.5%) of patients experienced irAEs. irAEs were associated with increased objective response rate (ORR) (pooled OR: 1.72; 95% CI: 1.36 – 2.19, I
2
=39%), higher complete response rate (pooled OR: 1.45; 95% CI: 1.21-1.74, I
2
=74%), and longer progression-free survival (PFS) (pooled HR: 0.66; 95% CI: 0.52-0.84, I
2
=71%). Although irAEs were associated with longer overall survival, this difference was not statistically significant (pooled HR: 0.83; 95% CI: 0.62 – 1.11, I
2
=73%). Subgroup analysis showed a survival benefit for patients with grade 1-2 irAEs (pooled HR: 0.50; 95% CI: 0.36-0.67, I
2
=0%) but not for those with grade 3-4 irAEs (pooled HR: 0.95; 95% CI: 0.24-3.72, I
2
=84%).
Conclusions:
The development of irAEs is associated with a favorable prognosis in HCC, including improved PFS and higher ORR. A survival benefit was noted in patients with mild irAEs, but not in those with severe irAEs. Future studies are needed to determine if a differential survival benefit relates to the continuation vs. discontinuation of ICI therapy.
Trastuzumab emtansine as second-line therapy in HER2 positive advanced biliary tract cancers: Single arm prospective phase II clinical trial (TAB-3 trial).
Authors: Ostwal Vikas S. , Bhargava Prabhat Ghanshyam , Kaushal Rajiv Kumar , Yadav Subhash , Wagh Gauri , Naughane Deepali , Garkal Tejashree , Mandavkar Sarika , Chaugule Deepali , Ramaswamy Anant
Published: January 2025

584

Background:
HER2 overexpression or amplification is a therapeutic target of interest in advanced BTC, especially gallbladder cancers (GBC). Limited studies evaluate the role of T-DM1 in these groups of cancers.
Methods:
This study was an investigator-initiated, open-label, single-arm, phase II trial in patients (pts) aged 18 years or older with HER2-positive (defined as IHC 3+ or IHC 2+, and FISH positive), advanced BTCs who had previously received systemic therapy (irrespective of prior additional HER2 targeted therapy). Pts received T-DM1 at 3.6mg/kg q 3 -weekly till disease progression (PD), unacceptable toxicities, or patient choice. The primary end-point of the study was an improvement in 3-month progression-free survival (PFS) from 50% (historical cohort) to 70% in the study arm. Secondary endpoints included overall response rates (ORR), disease control rate (DCR), overall survival (OS), and incidence of grade 3 and 4 treatment-related adverse events (TRAE).
Results:
From July 2023 to July 2024, ‘52’ pts with HER2-positive BTC were screened, and 40 enrolled in the study. A majority of patients had GBC (95%) and most commonly received combination chemotherapy with gemcitabine-cisplatin, with or without nab-Paclitaxel (78%). Six patients (15%) had previously received trastuzumab in combination with chemotherapy. A majority of patients (n=24; 60%) had rapid progression (within 3 months) on prior systemic therapy. With a median follow-up of 7.1 months [95% confidence interval (CI): 5.1-9.1] , 24 patients had disease progression with a 3-month PFS of 51.2% (95% CI: 33.4 - 69) and median PFS of 3.1 months (95% CI: 2.3-3.8); median OS was 7.1 months (95% CI: 5.1-9.1). Partial responses (PR) were seen in 5 patients (12.5 %) and 8 had stable disease (20 %) for a disease control rate of 32.5 %. Patients without rapid disease progression on prior therapy (n=16; 40%) had a 3-month PFS of 70% (95% CI: 44.8 - 95.2) and median PFS of 4.9 months (95% CI: 2.9-6.9). Grade 3 and grade 4 TRAE in the overall cohort were noted in 11 patients (28%), with the commonest being grade 2 fatigue in 6 patients and grade 3 thrombocytopenia in 2 patients.
Conclusions:
T-DM1 was well tolerated in pre-treated HER2 positive advanced BTCs, but did not statistically improve PFS in comparison to historical data. Patients who did not have rapid progression on prior systemic therapy appeared to have a more favorable survival in comparison to rapid progressors and the role of T-DM1 in such favorable cohorts can be explored in larger studies. Clinical trial information: CTRI/2023/07/055785.
A multicenter, phase 2 study of atezolizumab plus bevacizumab (atezo+bev) combination therapy in patients with unresectable hepatocellular carcinoma (HCC) and Child–Pugh class B cirrhosis: CHALLENGE trial final results.
Authors: Ikeda Masafumi , Terashima Takeshi , Yamashita Tatsuya , Okusaka Takuji , Imaoka Hiroshi , Kawaoka Tomokazu , Kobayashi Satoshi , Ogasawara Sadahisa , Hiraoka Atsushi , Nakano Masahito , Nagashima Fumio , Sugimoto Rie , Moriguchi Michihisa , Inaba Yoshitaka , Shinoda Satoru , Ueno Makoto , Kato Naoya , Kudo Masatoshi , Furuse Junji , Nagano Hiroaki
Published: January 2025

587

Background:
The Phase 2 CHALLENGE trial (jRCTs031210355) evaluated the safety and efficacy of atezo+bev combination therapy in patients with advanced HCC with Child–Pugh class B cirrhosis. Results of the trial’s main analysis demonstrated that atezo+bev was well-tolerated. Here, we present the trial’s final safety and efficacy outcomes.
Methods:
This multicenter, open-label, single-arm, Phase 2 study enrolled patients with advanced HCC and a Child–Pugh score of 7 or 8 who had not received prior systemic therapy. Patients were administered atezolizumab 1200 mg plus bevacizumab 15 mg/kg every 3 weeks. The primary endpoint was the frequency of severe adverse events (SAEs). Secondary endpoints included the objective response rate (ORR), progression-free survival (PFS), time to progression (TTP), overall survival (OS), and frequency of adverse events (AEs).
Results:
A total of 31 patients were enrolled between December 2021 and April 2023. Child–Pugh score was 7 points in 25 patients (80.6%) and 8 points in 6 patients (19.4%). Fourteen patients (45.2%) were classified as having Barcelona Clinic Liver Cancer stage C. We set 30 eligible patients as the population for analysis. The final analysis performed with a median follow-up duration of 517days showed that the frequency of SAEs was 30.0% (95% confidence interval [CI] 14.7–49.4%). ORRs according to RECIST 1.1 and modified RECIST were 40.0% and 46.7%, respectively. Median PFS, TTP, and OS were 240 days (95% CI: 176–526 days), 240 days (95% CI: 176–526 days), and 470 days (95% CI: 256–576 days), respectively. Frequent Grade ≥3 SAEs were blood bilirubin increased (n=3), proteinuria (n=3), hypoalbuminemia (n=2), and hypertension (n=2). Grade ≥3 severe liver-related AEs occurred in 7 patients (23.3%), including blood bilirubin increased (n=3) and esophageal varices hemorrhage (n=2). Grade ≥3 severe immune-related AEs occurred in 2 patients – these were mucositis oral (n=1) and malaise (n=1). The mean Child–Pugh score (±standard deviation) at the start of treatment was 7.2±0.4, and was 7.0±1.0, 7.2±0.9, and 7.6±1.7 at the third and fifth cycles and at the withdrawal study, respectively.
Conclusions:
Atezo+bev was well-tolerated with demonstrable anti-tumor effects in patients with unresectable HCC and Child–Pugh class B cirrhosis. Additional studies are warranted to confirm the efficacy results of atezo+bev in this patient group. Clinical trial information: jRCTs031210355.
Adjuvant capecitabine in resected biliary tract cancers: Real life data from a multicenter study (PRODIGE83-ACABi-PRONOBIL).
Authors: Turpin Anthony , Noe Claire , Chanez Brice , Vernerey Dewi , Lecomte Thierry , Walter Thomas , Assenat Eric , Edeline Julien , Heurgue Alexandra , Tougeron David , Manfredi Sylvain , Hautefeuille Vincent , Neuzillet Cindy , Roth Gael , Lagasse Jean-Paul , Tournigand Christophe , Guillemin Aude , Hollebecque Antoine , Henriques Julie , Parent Pauline
Published: January 2025

596

Background:
Biliary tract cancers (BTCs) are rare and heterogeneous tumors with a poor survival even in early-stage patients treated with a curative surgery. Since 2019 the current standard of care in the adjuvant setting is oral chemotherapy (CT) with capecitabine for 6 months, as an option following BILCAP phase III trial results. Nevertheless, outside of this trial, real-world data are lacking.
Methods:
We conducted a French, retrospective, multicenter study from the ACABi-PRONOBIL cohort. Eligible patients had intrahepatic, perihilar, distal cholangiocarcinoma or gallbladder carcinoma treated by surgery with curative intent without prior therapy. Two groups were compared, patients who received capecitabine (Cape group) as adjuvant CT and patients without adjuvant treatment before 2017 (surveillance group). The primary endpoint was overall survival (OS). Secondary endpoints were disease-free survival (DFS) and toxicity.
Results:
324 patients were included, 200 in the Cape group and 124 in the surveillance group. The median OS was 43.5 months (CI95%= 35.4-48.0) and 44.6 months (CI95% 37.7-54.8) in the Cape and surveillance group, respectively. ECOG performance status ≥ 2, pT3 stage, vascular and node invasion were associated with a poorer OS. The DFS was 15.8 months (CI95%= 14.1-20.3) in the Cape group and 13.3 months (CI95%= 10.1-17.5) in the surveillance group. In inverse probability of treatment weighting (IPTW) analysis we observed a significant statistical association between Cape group and DFS (IPTW HR (CI95%) Cape group vs surveillance group = 0.76 (0.60-0.96), pvalue=0.0224) but not with OS. In the Cape group, 49% of patients had at least one dose reduction, 35% had to discontinue treatment due to toxicity (mainly gastrointestinal,13.3% of grade 3-4; and cutaneous, 27% of grade 3-4).
Conclusions:
In this retrospective analysis, adjuvant capecitabine appears to increase DFS without statistically significant impact on OS in patients undergoing surgery for BTC, confirming in real life the BILCAP study results.
Pembrolizumab and stereotactic radiotherapy combined in subjects with advanced HCC: A phase II study (PEMRAD).
Authors: O'Kane Grainne M. , Mesci Aruz M , Chen Eric Xueyu , Bocaya Cynthia M , Jang Raymond Woo-Jun , Wang Ben X , Prince Rebecca M. , Boukhaled Giselle M , Barry Aisling S , Doherty Mark , Wong David K , Wang Lisa , Dodd Anna , Dawson Laura A. , Knox Jennifer J.
Published: January 2025

602

Background:
Combination approaches of immune-checkpoint inhibitors and locoregional therapies have an increasing role in advanced HCC.
Methods:
The PEMRAD phase II trial investigated the efficacy of combination pembrolizumab and stereotactic body radiation (SBRT) following progression on sorafenib. Patients with advanced HCC, ECOG 0-1 and Childs-Pugh A were eligible. Patients received pembrolizumab on day 1 followed by SBRT starting Day 2 and delivered in five fractions. Pembrolizumab was continued every 21 days until progression, unacceptable toxicity or patient withdrawal. The primary endpoint was objective response rate (ORR) as measured by RECISTv 1.1. hypothesizing an increase to 40% with the combination. Tissue and liquid biopsies were collected for correlative analyses including multiplex IHC, longitudinal CyTOF and dynamic cytokine changes.
Results:
The trial was stopped early due to a shift in the treatment landscape. Between March 2018 and March 2023 18 patients of a planned 22 patients were enrolled and treated with combination therapy. Of these 10 (55%) had evidence of macrovascular invasion (MVI) and 15 (83%) had extrahepatic disease; viral hepatitis was the underlying etiology in 50%. The ORR was 41% meeting the proposed endpoint. Median number of cycles of pembrolizumab was 7.5 (2-35) .The median number of lesions treated by SBRT was 3 (1-5) and the median dominant gross tumour volume was 184 cc (IQR 69-285). The median PFS was 5.4 (2.8-9.9) months and median OS 12.6 (5.7-25.8) months. Of the 10 patients with macrovascular invasion 5 (50%) had evidence of a vascular thrombus response by RECIST criteria including 1 complete response. Treatment related adverse events ≥ grade 3 were reported in 5 patients (28%). One death due to myocarditis was attributed to treatment.
Conclusions:
In a poor prognostic group of patients in the second line setting, the combination of SBRT and pembrolizumab demonstrated high ORR and may have a specific role in patients with MVI. Correlative analyses will be presented at the meeting.
Clinical trial information: NCT03316872
.
Modified Frailty Index (mFI-5) as a prognostic tool of mortality, complications, and readmissions in patients undergoing hepatic ablation for hepatocellular carcinoma.
Authors: Ingawale Sushrut , Vellek John , Ganguly Arup , Farhan Mariam
Published: January 2025

610

Background:
Hepatocellular carcinoma (HCC) is a leading cause of cancer deaths, often diagnosed late, limiting curative options. Transarterial chemoembolization, Y-90 radioablation, radiofrequency ablation, and thermoablation are commonly used for downstaging, transplant bridging, and palliation in unresectable HCC. Frailty, linked to postoperative complications, has not been studied in hepatic ablation patients. This study evaluates the predictive value of the modified frailty index (mFI-5) for mortality, readmissions, complications, redo procedures, and discharges.
Methods:
We utilized the National Surgical Quality Improvement Program (NSQIP) database from 2015 to 2019, querying cases of hepatic ablation for CPT codes: 47370 (closed hepatic ablation, single site) and 47380 (open hepatic ablation, single site). Selected cases were analyzed for frailty using the mFI-5 criteria. A multivariate analysis was performed using mFI-5 frailty scores, stratified into non-frail (0), pre-frail (1), frail (2), and severely frail (3+). The outcomes analyzed included mortality, discharge to a destination other than home, major complications, minor complications, readmission, and reoperation.
Results:
We identified 1921 patients as: 737 non-frail, 701 pre-frail, 442 frail and 41 severely frail. The rates of readmission (5.4%), reoperation (1.4%), major (5.3%) and minor (3.5%) complications were low. Eight patients died following hepatic ablation, and 79 patients were discharged to a destination other than home. In multivariate analysis, most outcomes were not significantly associated with increasing frailty. However, discharge to a destination other than home was significantly more likely in patients with higher frailty scores. In frail patients, the odds ratio (OR) was 2.325 (95% CI 1.228–4.402), and in severely frail patients, this increased to 8.720 (95% CI 3.389–22.435).
Conclusions:
Hepatic ablation is generally well tolerated with low complication rates; however, frailty significantly influences postoperative outcomes. Frail and severely frail patients are more likely to be discharged to care facilities rather than returning home, suggesting that even in the absence of major complications, these patients require a higher level of post-procedural care. This underscores the need for tailored discharge planning and resource allocation based on patient frailty.
Analysis of clinically actionable alterations in baseline tumor versus plasma samples in participants of the TOPAZ-1 study of durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer.
Authors: Oh Do-Youn , Qin Shukui , Antonuzzo Lorenzo , Tougeron David , Lee Choong-kun , Tan Benjamin R. , Ikeda Masafumi , Wang Julie , Lin Hung-Ying , Lee Young S , McCoon Patricia , Valle Juan W.
Published: January 2025

625

Background:
In the TOPAZ-1 study (NCT03875235), durvalumab + gemcitabine and cisplatin (D+GC) significantly improved overall survival (OS) versus placebo + GC (P+GC) in participants (pts) with advanced biliary tract cancer. Updated results have shown a clinically meaningful long-term OS benefit for D+GC versus P+GC at 3 years. This exploratory analysis tested circulating tumor DNA (ctDNA) in plasma samples for blood-based detection of clinically actionable alterations (CAAs) and investigated the potential of this method to guide treatment decisions.
Methods:
Baseline genomic alterations were retrospectively assessed in evaluable tumor (FMI biomarker evaluable population [BEP], n=441) and plasma samples (GH BEP, n=643) using FoundationOne (Foundation Medicine Inc., Cambridge, MA) and Guardant INFINITY (Guardant Health, Redwood City, CA) assays, respectively. Mutation prevalence and association with outcomes were compared in the FMI BEP and GH BEP. Positive and negative percent agreement of CAAs detected in tumor versus ctDNA were assessed in 419 pts with both tumor and plasma samples (FMI-GH BEP).
Results:
The FMI BEP and GH BEP represented 64% and 94% of the TOPAZ-1 final analysis set (685 pts), respectively. The relative prevalence and overall mutational landscape detected in plasma ctDNA was consistent with that observed by tumor profiling, with the notable exception that genes harboring complex alterations (e.g. gene amplification, rearrangements, or homozygous deletions) were less frequently detected in ctDNA (e.g.
ERBB2
,
FGFR2
, and
CKDN2A/2B/MTAP
). The most common alterations (>15% prevalence in both BEPs) observed were in
TP53
(49%/52%),
KRAS
(24%/17%), and
ARID1A
(21%/16%) (in the FMI/GH BEPs, respectively). The relative prevalence of alterations within geographic and anatomic subgroups was similar in tumor versus plasma for most CAAs. The overall percent agreement in CAAs was ≥93%, and negative percent agreement was ≥97%. However, positive percent agreement was notably low for
ERBB2
amplification (52%) and
FGFR2
fusions (47%). OS hazard ratios for D+GC versus P+GC in the GH BEP were <1 for both CAAs and wild-type, except for
ERBB2
amplification, as previously reported in the FMI BEP.
Conclusions:
The overall concordance and relative prevalence of simple mutations (e.g. single nucleotide variants) were similar using the FoundationOne tumor assay and Guardant INFINITY ctDNA assay, suggesting that plasma ctDNA testing has potential utility in clinical practice. However, negative status by ctDNA for the complex alterations found in
FGFR2
and
ERBB2
would require further testing of tumors, based on their low detectability in plasma.
Clinical trial information: NCT03875235
.
Safety and efficacy of anti-HER2 agents in the treatment of biliary tract cancers: A systematic review.
Authors: Naleid Nikolas , Pawar Omkar , Chakrabarti Sakti , Jin Zhaohui , Mangla Ankit , Mahipal Amit
Published: January 2025

639

Background:
Limited treatment options exist for patients with locally advanced or metastatic biliary tract cancers (BTCs). Recently, several clinical trials provided preliminary evidence for human epidermal growth factor receptor-2 (HER2) as a new target for patients with HER2 expressing BTC. We conducted a systematic review and pooled analysis of the safety and efficacy of anti-HER2 agents in patients with advanced BTC.
Methods:
A comprehensive search of PubMed/MEDLINE and EMBASE was performed to identify phase 1, 2, or 3 clinical trials published between January 2019 and March 2024 that evaluated anti-HER2 therapy in locally advanced or metastatic BTC. Primary endpoints included objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS). Secondary endpoints included the incidence of treatment-related adverse events (TRAEs), rate of treatment discontinuation, and death. Forest plots were generated to summarize the results and demonstrate the effect size estimates for each study, along with their confidence intervals and the pooled estimate from the random-effects model. The random-effects models were configured to use the Restricted Maximum Likelihood method for estimating between-study variance for all analyses.
Results:
After excluding duplicate and irrelevant articles, data extraction and analysis were performed on eight selected clinical trials. The analysis included 368 patients with a median age of 64 (range 49-68), with 55% being female. Patients were treated with several anti-HER2 agents, including zanidatamab, pertuzumab plus trastuzumab, tucatinib plus trastuzumab, trastuzumab deruxtecan, trastuzumab plus chemotherapy, trastuzumab-pkrb plus chemotherapy and neratinib. The pooled ORR and DCR were 34% (95% CI 24-44) and 64% (95% CI 51-77) respectively. The pooled weighted PFS and median OS survival were 4.8 and 9.4 months, respectively. The pooled duration of response was 5.0 months. In our subset analysis, which included only patients who had received ≥1 prior therapy, the pooled ORR was 30% (95% CI 22-39), the pooled DCR was 62% (95% CI 48-75), and the pooled median PFS was 4.4 months. In the study cohort, 82.6% of patients experienced any adverse event, and 32.1% experienced a grade 3-4 adverse event. Only 5.7% of the patients discontinued treatment secondary to TRAEs.
Conclusions:
In patients with HER2 expressing BTCs, anti-HER2 therapies demonstrated preliminary signals of efficacy with manageable toxicities, particularly in the second-line setting.
Automated radiomics model for preoperative pancreatic neuroendocrine tumor grade prediction.
Authors: Chandra Pratik , Nasar Naaz , Ghahremannezhad Hadi , Soares Kevin , Balachandran Vinod P. , Drebin Jeffrey A. , D'Angelica Michael Ian , Kingham T. Peter , Jarnagin William R. , Chakraborty Jayasree , Wei Alice Chia-chi
Published: January 2025

655

Background:
Pancreatic neuroendocrine tumors (PNETs) have varying biologic behavior based on factors including tumor grade. Many prognostic factors can only be determined post-pancreatectomy; thus, are unable to guide clinical decision making preoperatively. This is particularly relevant in small, non-functional (NF)-PNETs. Imaging analysis with radiomics may be able to elucidate biologic data such as tumor grade, without the need for tissue sampling. Our study aims to create an automatic pipeline from segmentation to radiomics-signature building to preoperatively predict tumor grade.
Methods:
Patients that underwent resection between 2003-21 with adequate preoperative arterial phase CT scans were divided into training and validation cohorts. In the training cohort, the pancreas and tumor region were manually segmented and used to train an auto-segmentation model. The validation cohort then underwent automatic segmentation. A total of 255 radiomics features were extracted from the tumor region. Correlated features were removed, and the minimum redundancy maximum relevance (mRMR) method was used to select the final feature set. These features were used to train a Support Vector Machine (SVM)-based classifier through the training cohort to predict grade, which was dichotomized into grade I versus II/III. The radiomic based prediction model was then evaluated in the automatically segmented validation cohort.
Results:
A total of 186 patients were identified and divided into training (n = 140) and validation (n = 46) cohorts. Median age was 57 (27, 85) and 52% were male. 113 (62%) and 70 (38%) patients were grades I and II/III, respectively. Median tumor size was 24 mm (6, 200) and 43 (26%) patients had positive nodal disease. The auto-segmentation model was able to accurately segment the tumor region in 33 (72%) patients of the validation cohort. In the training cohort (n = 140), the radiomics-signature produced an area under the curve (AUC) of 0.87 (0.81, 0.93). Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were 0.94 (0.9, 0.98), 0.74 (0.66, 0.81), 0.72 (0.65, 0.80) and 0.97 (0.94, 1.00) respectively. In the auto-segmented validation cohort (n = 33), the radiomics model produced an AUC of 0.75 (0.61, 0.90). Sensitivity, specificity, PPV and NPV were 0.88 (0.77, 0.99), 0.62 (0.46, 0.79), 0.71 (0.56, 0.87) and 0.83 (0.71, 0.96), respectively.
Conclusions:
The proposed auto-segmentation model was able to automatically identify tumor regions with a high degree of accuracy. Similarly, the subsequent radiomics-signature was also able to strongly discern PNET grade. This automatic pipeline bypasses manual segmentation and could help incorporate a radiomics-signature into preoperative clinical decision-making for PNETs.
Beyond Khorana score 2: Molecular correlates of venous thromboembolism in pancreatic cancer.
Authors: Gerstein Jonathon Jonah , Chan-Seng-Yue Michelle , O´Kane Grainne , Jang Gun Ho , Fischer Sandra , Dodd Anna , Holter Spring , Wilson Julie , Zogopoulos George , Monajemzadeh Maryam , Elimova Elena , Prince Rebecca M. , Jang Raymond Woo-Jun , Moore Malcolm J. , Biagi Jim Joseph , Notta Faiyaz , Grant Robert C , Gallinger Steven , Knox Jennifer J. , Tsang Erica S
Published: January 2025

751

Background:
Pancreatic ductal adenocarcinoma (PDAC) is associated with a hypercoagulable state leading to thrombosis. Risk models such as the Khorana score automatically classify PDAC as intermediate-high risk, and recent guidelines recommend consideration of thromboprophylaxis. However, little is known about the molecular correlates of PDAC for venous thromboembolism (VTE).
Methods:
We examined clinical and genomic data from the prospective multi-institution COMPASS trial (NCT02750657), which enrolled patients with treatment-naïve metastatic PDAC who underwent a fresh tumor biopsy for real-time whole genome and transcriptome sequencing. Laser capture microdissection was performed. Patients underwent restaging scans at 8-week intervals. Detailed chart review was conducted to focus on VTE risk factors, timing of VTE diagnosis, and anticoagulation. We also compared clinical and molecular factors based on timing of VTE diagnosis. Overall survival was defined as time from VTE to death.
Results:
Of 268 patients enrolled in the COMPASS trial, 166 patients had detailed clinical data available regarding VTE status. 82 patients (49%) developed a VTE, where 16 (20%) had breakthrough clots. Baseline epidemiological variables were similar for those with and without VTE, including no differences between age, sex, BMI, and baseline CA 19-9. No patients were on routine prophylactic anticoagulation. SMAD4 mutations were more frequently seen in the VTE subgroup (57% vs. 40%, p= 0.04), but no differences were seen in other driver genes (KRAS, TP53, CDKN2A), Moffitt subtype, or homologous recombination deficiency status. Patients who developed an early VTE (within 3 months) had a higher baseline CA 19-9 (median 4015 vs. 891, p= 0.02), and none were port-associated. A higher incidence of KRAS wildtype cases (10%) were observed in the early vs. later VTE groups (p= 0.03), but no differences in KRAS allelic status. There were no differences in burden of SNVs, indels, or SVs. Early VTE occurred in 46% of all basal cases, which are typically more aggressive, and only in 37% of classical subtypes. Overall survival was shorter with early VTE (HR 1.74, p= 0.02).
Conclusions:
A higher incidence of SMAD4 alterations were observed among patients with metastatic PDAC who developed VTE. VTE diagnosed earlier were associated with shorter survival, suggesting that early thromboprophylaxis should be considered at the time of diagnosis.
Clinical trial information: NCT02750657
.
Observational study of the extent of lymph node metastasis among patients who underwent pancreatoduodenectomy for non-ampullary duodenal cancer using the National Clinical Database in Japan.
Authors: Kodera Yasuhiro , Hayashi Masamichi , Yamamoto Hiroyuki , Kurimoto Keisuke , Tanaka Haruyoshi , Takami Hideki , Kakeji Yoshihiro
Published: January 2025

798

Background:
Non-ampullary duodenal cancer (NPDC) is a rare cancer that occurs in 0.3% of all cancers of the gastrointestinal tract. The first Japanese guidelines for this entity were published in 2021, and resection by pancreatoduodenectomy was weakly recommended as a standard treatment. Although presence of regional lymph node metastasis was identified as a prognostic factor among patients who underwent resection with curative intent, the recommendation concerning the optimal extent of lymphadenectomy based on big data was lacking.
Methods:
We conducted an observational study of patients who underwent pancreatoduodenectomy for NPDC between 2018 and 2021 in Japan, using the National Clinical Data (NCD) database. The NCD database is web-based, is linked with the board certification systems of several domestic surgical societies and covers >95% of the operations carried out by surgeons at 5,728 institutions in Japan. All cases of pancreatoduodenectomy for NPSC were retrieved from the NCD database after rigorously checking appropriateness of the patient selection, and surgeons in charge of these patients were invited by e-mails to fill in some additional data for this study during a time slot of Oct 2022 ~March 2023. Data thus obtained were the analyzed with particular focus on the incidence of metastases to each lymph node station, stratified by the tumor location in relation to the papilla. In addition, safety of surgery was compared between high-volume (institutions conducting ≥30 major hepatobiliary-pancreatic surgery) and low-volume (<30) hospitals. The study was funded in part by the Japanese Ministry of Health, Labor and Welfare as a project to create guidelines for rare cancers.
Results:
Data of 881 patients from 600 institutions were obtained for the analysis. Male constituted 68% and the median age was 70 years. The depth of invasion and presence of nodal metastasis were significant prognostic factors. The median number of lymph node retrieval was similar between the high-volume and low-volume hospitals (19: 95%CI 12~27 versus 18: 95% CI 11~25). Distribution of metastatic nodes depended on the location of tumor. Incidence of nodal metastasis exceeded 10% in lymph node station Nos. 5, 6, 7, 8 and 9 in cancers located on the oral side of the papilla. Thus, stomach-conserving pancreatoduodenectomy was considered appropriate only for cancers located distal to the papilla. The incidences of Grade IIIb~IVb complications (4% versus 7.1%), Grade V complications (0.4% versus 1.9%), and mortality within 30 days (0.4% versus 2.6%) were lower in high-volume hospitals.
Conclusions:
Stomach-preserving pancreatoduodenectomy is recommended only for NDPC located distal to the papilla. Centralization of surgery may be desirable.