bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival after esophagectomy for metastatic esophageal cancer: Should surgery’s role be reconsidered?
Authors: Saeed Samir H , Sinnamon Andrew J , Fontaine Jacques P , Mehta Rutika , Baldonado Jobelle Joyce Anne , Pena Luis R , Palm Russell F , Hoffe Sarah E. , Frakes Jessica M. , Pimiento Jose Mario
Published: January 2024

410

Background: Standard treatment for stage IV esophageal cancer (EC) is systemic therapy, with surgery considered contraindicated. The objective of this study is to assess the impact of surgical resection on outcomes for patients with metastatic EC. Methods: We reviewed our institution’s IRB-approved database of 1334 esophagectomies from 1994 to 2023 and identified 18 patients with distant disease (stage IV) by AJCC8 found prior to or during surgery. Chi-Square, ANOVA, and Kaplan-Meier survival analyses were used to compare demographics, clinical characteristics, and survival from time of surgery in those with metastatic versus non-metastatic EC. Results: Most metastatic patients were male (89%), Caucasian (83%), and had adenocarcinoma (89%). Compared to the non-metastatic cohort, stage IV EC cases were younger (57 vs 63; p=0.03), non-Caucasian (17% vs 6%; p=<0.001), and more likely to get chemotherapy (41% vs 8%; p=0.04) or immunotherapy (23.5% vs 0%; p=0.06), with no difference in gender (89% vs 83%) and receipt of chemoradiotherapy (94% vs 92%). While the difference in intra-operative complication rates was significant (13% vs 2%; p=0.001), both groups had similar rates of post-operative complications ( p=0.95). Non-regional nodal metastasis had the most favorable outcome (mOS NR; median follow-up=14m); while peritoneal/omental disease had the shortest survival (5.2m). Patients receiving surgery more than a year after stage IV diagnosis ( n=6) had better survival than those who either underwent resection within a year after diagnosis ( n=2) or had metastasis identified at time of surgery ( n=8) ( p=0.02). PDL-1 positive and HER2-neu positive tumors also had better outcomes, with neither group reaching median survival. Conclusions: Esophagectomy for highly selected patients with distant disease demonstrates similar post-operative complication rates to locally advanced EC. For stage IV patients, a short interval from diagnosis to surgery is associated with worse survival; however, prolonged diagnosis-to-surgery interval >12m and PDL-1 and HER2-neu positivity demonstrate better outcomes. Surgery’s role in treatment of stage IV EC preferably more than a year after diagnosis of metastasis should be further studied.
Correlation between postoperative systemic inflammatory response and prognosis in patients with advanced gastric cancer.
Authors: Kuroda Kenji , Toyokawa Takahiro , Miki Yuichiro , Yoshii Mami , Kasashima Hiroaki , Fukuoka Tatsunari , Tamura Tatsuro , Shibutani Masatsune , Lee Shigeru , Yashiro Masakazu , Maeda Kiyoshi
Published: January 2024

411

Background: Several studies have shown that postoperative infectious complications correlate with poor prognosis in various malignancies, but the prognostic significance of the postoperative inflammatory response in patients with gastric cancer remains unclear. The aim of study was to examine whether the systemic inflammatory response present in the early phase of the postoperative state correlates with long-term outcomes and to identify markers in patients with advanced gastric cancer. We evaluated C-reactive protein (CRP) and white blood cell (WBC) count as simple and versatile markers of postoperative systemic inflammation in clinical practice that may be suitable for detecting the magnitude of inflammatory reaction. Methods: This study retrospectively reviewed 444 patients who underwent radical gastrectomy for stage II/III gastric cancer. We evaluated maximum serum C-reactive protein (CRPmax) and white blood cell count (WBCmax), defined as the maximum serum CRP level and maximum WBC count during the interval from surgery until discharge, as systemic inflammation markers. Results: In univariate analyses, CRPmax, WBCmax and infectious complications were significantly associated with both overall survival (OS) (p<0.001, p<0.001 and p=0.011, respectively) and relapse-free survival (RFS) (p<0.001, p=0.001 and p<0.001, respectively). Multivariate analysis revealed that high CRPmax (>9.2 mg/dL) was an independent prognostic factor for OS (hazard ratio (HR) 1.69, 95% confidence interval (CI) 1.18–2.42, p=0.004) and RFS (HR 1.42, 95%CI 1.02–1.98, p=0.038), while WBCmax and infectious complications were not. Regarding the pattern of recurrence, hematogenous recurrence was significantly more frequent in the high-CRPmax group (16.7%) than in the low-CRPmax group (3.8%, p<0.001). Conclusions: CRPmax, which reflects the magnitude of systemic inflammation induced by surgical stress and postoperative complications in the early phase after surgery, may be a promising prognostic indicator in patients with stage II/III gastric cancer who undergo curative resection.
Genomic profile and clinical feature of esophageal squamous cell carcinoma, focusing on MSI, TMB, and HRD status: Analysis with the national database of Japan.
Authors: Morita Ryuichi , Ishikawa Takeshi , Doi Toshifumi , Itani Junichiro , Sone Daiki , Iwasaku Masahiro , Konishi Hirotaka , Shiozaki Atsushi , Fujiwara Hitoshi , Konishi Hideyuki , Takayama Koichi , Itoh Yoshito
Published: January 2024

412

Background: In Japan, cancer genome profiling (CGP) testing has been widely used from 2019, and genomic and clinical information integrated into national database (C-CAT database) is now available for secondary use for innovative research. In esophageal squamous cell carcinoma (ESCC), more than 500 patients (as of December 2022) have already undergone CGP testing. MSI-H and TMB-H ESCC are rare, and information is lacking. Using C-CAT data base, we analyzed the clinical and genomic characteristics of ESCC, especially focusing on MSI, TMB, and HRD status. Methods: We retrospectively reviewed data on 535 cases with ESCC enrolled in C-CAT between June 2019 and December 2022. The clinical features, genomic variants classified as oncogenic/pathogenic, MSI/TMB status and response to treatment (response rate; RR and time to treatment failure; TTF) were evaluated. Results: Oncogenic/pathogenic variants were detected in 527 cases (98%), and the Top 5 gene mutations were TP53 (94.6%), CDKN2A (56.6%), CDKN2B (43.7%), CCND1 (42.6%), and FGF19 (38.9%), in order of prevalence. No patient had MSI-H, and number of patients with TMB-H (≥10 Muts/Mb) and HRD were 82 (15%) and 15 (13%), respectively. Regarding the efficacy of first-line chemotherapy (IO-containing regimen in 5 cases, 0.9 %), the TTF was significantly shorter in TMB-H cases than in TMB-L cases (11.8 vs 17.5 weeks, p=0.006). No difference in response to anti-PD-1 antibody was observed depending on TMB status (RR, TMB-L 19 % vs. TMB-H 12 %). Patients with BRCA1/2 mutations tended to respond better to first-line chemotherapy including platinum drugs, although there was no difference in response to treatment with or without other HRR mutations. The percentages of cases delivered new treatments based on CGP testing was 6.8%. The percentage of cases with HRD or TMB-H suggested new treatment based on GCP testing was significantly higher than those without them. Conclusions: Patients with BRCA1/2 mutations are more sensitive to platinum combination chemotherapy and may be good candidates for PARP inhibitors in ESCC. Since TMB-H patients are resistant to standard chemotherapies, we should promote the development of immunotherapy and molecular-based targeted therapies for this population.
Assessing risk stratification in long-term outcomes of rectal neuroendocrine tumors following endoscopic resection: A multicenter retrospective study.
Authors: Seo Yeonjoo , Lee Han Hee , Kim Jin Il
Published: January 2024

42

Background: The detection of rectal neuroendocrine tumors (NETs) has increased with advances in diagnostic endoscopy. Endoscopic resection (ER) is a highly effective treatment option for rectal NETs confined to . We aimed to analyze the long-term outcomes of patients with rectal NETs after ER. Methods: In this multicenter retrospective study, we included patients who underwent ER of rectal NETs from 2009 to 2018 and were followed for ≥12 months at five university hospitals. We classified the patients into three risk groups according to the clinicopathological status of the rectal NETs: low, indeterminate, and high. The high-risk group was defined if the tumors have any of the followings: size ≥ 10 mm, lymphovascular invasion, muscularis propria or deeper invasion, positive resection margins, or mitotic count ≥2/10. Results: In total, 346 patients were included, with 144 (41.6%), 121 (35.0%), and 81 (23.4%) patients in the low-, indeterminate-, and high-risk grouprespectively. In the high-risk group, seven patients (7/81, 8.6%) received salvage treatment 28 (27–67) days after the initial ER. There was no extracolonic recurrence in any of the 7 patients. During the follow-up period of all included patients, 1.1% (4/346) had extracolonic recurrences at 56.5 (54–73) months after initial ER. Three of these patients (75%) were at a high risk without salvage treatment. The risk of extracolonic recurrence was significantly higher in the high-risk group than in the other groups (p=0.039). Conclusions: The prognosis of patients who underwent ER for rectal NETs was favorable. Physicians should be concerned about the possibility of metastasis during long-term follow-up of high-risk patients and consider salvage treatment. [Table: see text]
Hepatic arterial infusion pump chemotherapy in patients with advanced intrahepatic cholangiocarcinoma confined to the liver: A multicenter phase II trial.
Authors: Franssen Stijn , Rousian Merve , Nooijen Lynn E. , ten Haaft Britte H.E.A. , Doukas Michael , Haj Mohammad Nadia , Klümpen Heinz-Josef , Moelker Adriaan , Mostert Bianca , Hagendoorn Jeroen , Swijnenburg Rutger-Jan , Homs Marjolein Y.V. , Groot Koerkamp Bas
Published: January 2024

433

Background: In the ABC-trials, the 3-year overall survival (OS) was only 2.8% for patients with advanced intrahepatic cholangiocarcinoma (iCCA) confined to the liver who received systemic gemcitabine with cisplatin. Hepatic arterial infusion pump (HAIP) combined with systemic chemotherapy had a pooled 3-year OS of 39.5% in a recent meta-analysis. HAIP chemotherapy involves continuous administration of floxuridine (FUDR) directly into the hepatic artery using a subcutaneous pump. The aim of this study was to prospectively assess the effectiveness of HAIP with systemic chemotherapy in patients with advanced iCCA confined to the liver in the Netherlands. Methods: We performed a single arm phase II trial in 3 centers in the Netherlands. Six cycles of HAIP chemotherapy with floxuridine were scheduled with 8 cycles of concurrent systemic chemotherapy with gemcitabine and cisplatin, if not administered previously. The primary endpoint was OS, secondary endpoints were progression-free survival (PFS) and objective response. Results: From January 2020 until September 2022, 50 patients with advanced iCCA were included. Combined HAIP and systemic chemotherapy was administered to 38 patients (76.0%). Eleven patients (22.0%) received HAIP chemotherapy alone, because they had received systemic treatment before enrollment. One patient (2.0%) didn’t start treatment, because he died 19 days after pump implantation due to COVID-19. The median follow-up was 26.4 months (95% CI: 21.7 – 39.0). The median OS was 22.1 months (95% CI: 19.7 – not reached). The 1-year OS rate was 80.0% (95% CI: 69.6% – 91.9%); the 3-year OS rate was 28.6% (95% CI: 16.0% – 51.2%). The median PFS was 10.0 months (95% CI: 8.7 – 12.2). An objective response on imaging (RECIST) was achieved in 27 patients (54.0%) and disease control at 6 months in 43 patients (86.0%). Four patients (8.0%) underwent a resection after HAIP chemotherapy of whom 2 patients had a complete pathologic response. Conclusions: Combined HAIP with systemic chemotherapy for patients with advanced iCCA was associated with a favorable 3-year OS of 28.6% compared with 2.8% after systemic chemotherapy alone in the ABC trials. Clinical trial information: NL8234 .
Epidemiology, treatment patterns, and humanistic and economic burden of biliary tract carcinoma: A systematic and targeted literature review.
Authors: Kamble Shital , Desai Kaushal , Joo Seongjung , Pandey Prabhakar , Swami Shilpi , Habila Magdiel , Malhotra Usha , Hall Adam , Khatri Urvi , Nathani Jyothsna
Published: January 2024

443

Background: Patients with biliary tract cancers (BTC) are typically diagnosed at late stage, with limited treatment options. As such, BTC is associated with poor prognosis, high economic burden and reduced health-related quality of life (HRQoL). As the treatment paradigm is evolving, with multiple immunotherapies showing promise, this study aimed to assess the current disease and treatment landscape. Methods: Systematic literature reviews (Embase, MEDLINE, Cochrane, NHS-EED; database inception to Feb 10, 2023) were conducted for HRQoL and economic burden. Targeted literature reviews (Embase, MEDLINE) were conducted for epidemiology (Jan 01 2017–Feb 06 2023) and treatment guidelines/patterns (Jan 01 2012–Feb 06 2023). Conference abstracts were also searched (2019–2022). Eligibility criteria included global studies (English language) in adults with metastatic and/or unresectable BTC. Results: Overall, 264 studies were included (epidemiology=170, treatment guidelines=14, treatment patterns=50, HRQoL=12, economic burden=18). In the US, Europe and Asia, age-standardized incidence rates were 5.04, 8.39–8.78 and 9.1–10.1 (per 100,000 person-years) and prevalence rates were 0.01%, 0.02–0.34% and 0.02–2.61%, respectively. Treatment pattern studies were mainly from Asia, Europe (n=19 each) and North America (n=10). Gemcitabine [gem]-based chemotherapy was most common in 1L BTC (24–100%) and fluorouracil-based regimens were common in 2L+ BTC (12.3–74.3%). Median overall survival (mOS) for gem-based and fluorouracil-based 1L regimens were 7.7–14.8 months and 7–16.7 months, respectively. Disease progression/toxicity frequently led to treatment discontinuation/dose modifications. In the US, use of non-guideline-based regimens increased by line of therapy (LOT). Among the clinical studies (n=5) reporting HRQoL in 1L, n=4 assessed gem-based combinations. BTC impaired HRQoL domains for anxiety, tiredness (EORTC QLQ-BIL21), work productivity, activity impairment (WPAI scale) and depression (PHQ-9). BTC was associated with substantial economic burden. Mean total all-cause healthcare costs per patient per month (PPPM) increased by LOT (US; 1L: $19,589–25,517, 2L: $22,617–29,721, 3L: $23,256–33,534). US healthcare resource utilization in 1L was driven by outpatient visits (98%), emergency department visits (33–80%) and hospitalization (70–80%). Mean hospital stay ranged from 0.6–7 days PPPM. Conclusions: Epidemiology data varied between Western and Asian populations, but gem-based chemotherapy was identified as the standard of care across regions. There is high unmet need in advanced BTC, as existing options are characterized by poor survival outcomes and considerable economic burden. These findings indicate a need for novel approaches for the management of BTC.
Patient-reported outcomes (PROs) <65 or ≥ 65 years old (yo) from CARES-310 camrelizumab + rivoceranib vs sorafenib as first-line treatment for patients with unresectable hepatocellular carcinoma (uHCC).
Authors: Chan Stephen Lam , Kaseb Ahmed Omar , Shi Wei , Alexander Laura , Meng Xianzhang , Park CheolHee , Ryan Kristin , Vogel Arndt
Published: January 2024

456

Background: CARES-310 (NCT03764293) evaluated the combination of the anti-PD-1 inhibitor, camrelizumab (cam), and the VEGFR-2 tyrosine kinase inhibitor, rivoceranib (rivo), compared to sorafenib (sor) for the treatment of uHCC. Cam + rivo significantly improved OS and PFS compared to sor (OS, 22.1 months [mo] [95% CI 19.1-27.2] vs 15.2 mo [13.0-18.5] HR 0.62 [95% CI 0.49-0.80]; one-sided p<0.0001); PFS, 5.6 mo [95% CI 5.5-6.3] vs 3.7 mo [2.8-3.7]; HR 0.52 [95% CI 0.41-0.65]; one-sided p<0.0001). The most common (≥20%) grade ≥3 treatment-related adverse events for cam + rivo were hypertension (37.5%) and increased AST (16.5%) vs palmar-plantar erythrodysesthesia syndrome (15.2%) for sor. This analysis evaluated PROs stratified by age: <65 yo (baseline, overall cam + rivo n=191, sor n=210) or ≥65 yo (baseline, overall cam + rivo n=81, sor n=61). Methods: Patients completed EORTC QLQ-C30 and EORTC QLQ-HCC18 at baseline, each visit, and post-last-dose follow-up periods. Endpoints included time to deterioration (TTD) with a ≥10-point decrease from baseline of patient reported QoL, physical functioning, role functioning, and patient-reported symptoms. Results: Mean completion rates across questionnaires were 98.56% and 96.78% for cam + rivo and 98.91% and 98.75% for sor in the <65 and ≥65 yo groups, respectively, from baseline through ≥121 weeks of treatment. In the <65 yo group, cam + rivo vs sor had improved TTD in fatigue measured by EROTC-QLQ-C30. In the ≥65 yo group, cam + rivo had significantly longer median TTD of pain measured by EROTC-QLQ-HCC18 and QLQ-C30, respectively. The median TTD of appetite loss in the ≥65 yo group favored cam + rivo. Median TTD for jaundice was significant for sor in both <65 yo and ≥65 yo group. Median GHS/HRQoL in the ≥65 yo group favored cam + rivo. Conclusions: Cam + rivo was associated with improvement in varied QoL aspects in both patient groups. These PRO results support the clinical benefit and use of cam + rivo in patients with uHCC who have not received prior systemic therapy. Clinical trial information: NCT03764293 . [Table: see text]
Real-world experience and outcomes of hepatocellular carcinoma (HCC) treated with transarterial radioembolization (TARE).
Authors: Das Parthib , Min Eric , Paul Samuel , Manne Ashish
Published: January 2024

463

Background: TARE has been the preferred choice of locoregional therapy to advanced HCC in recent years. We attempted to identify factors contributing to the success of TARE in this retrospective review. Methods: HCC patients who received at least one TARE between 1/1/2015 and 8/30/22 at Ohio State University were included in this study. The patient's baseline characteristics at diagnosis (BLC) were extracted by chart review with post-procedural complications and survival outcomes. Descriptive statistics and log-rank test for survival outcomes were conducted using JMP Pro 16 (SAS Institute Inc., Cary, NC). Results: Our cohort had 144 patients with median age of diagnosis (dx) of 65 years, 81 % Caucasians, 81% males, 5% and 51% with hepatitis B and C, respectively; 24% and 21% ascites (As) and hepatic encephalopathy (HE) at dx, respectively; 72% (n=125) had just one procedure (24 had two planned procedures which were considered as 1), 12% (17) and 1% (2) had second and third procedures for recurrence, respectively. Immune checkpoint inhibitor (ICI) and other systemic therapy (tyrosine kinase inhibitor (TKI) or ramucirumab (Ram)) were given to 27% (5 before and 34 after TARE) and 24% (5 before and 30 after TARE), respectively. Other HCC-related BLC includes the number of lesions 1 vs 2-3 vs multiple = 45% vs 33% vs 22%; single lobe vs two lobes = 66 vs 33%; portal vein tumor thrombosis (PVTT) = in main portal vein vs. non-main veins (left or right or lower level) vs no PVTT = 14% vs 10% vs 76%. Median overall survival (OS) and time to recurrence after the first TARE (TTR) were 11 and 4 months (m), respectively. The only BLC that significantly influenced TTR was As (3 vs 4 m, p=0.008). Factors impacting OS were discussed in the table. Follow-up imaging (median = 3m) was available for response evaluation in 107/144 (indeterminate response (IR) reported in 25), and the response noted was reflective of OS (objective response vs. disease progression vs indeterminate, 22 vs 6 vs 8.5 m, p<0.001). Conclusions: Careful patient selection based on BLC and the use of ICI (before or after) could improve the outcomes in HCC patients treated with TRAE. Larger prospective studies are needed to validate the study. [Table: see text]
Defining ablative radiotherapy in patients with hepatocellular carcinoma: An expert consensus.
Authors: Yanagihara Ted K. , Tepper Joel E. , Moon Andrew M , Barry Aisling S , Molla Meritxell , Seong Jinsil , Torres Ferrán , Lawrence Theodore Steven , Reig Maria , Dawson Laura A. ,   mDelphi Committee Members
Published: January 2024

485

Background: External beam radiotherapy (EBRT) is a highly effective treatment in select patients with hepatocellular carcinoma (HCC). However, there are many types of EBRT described in the literature with no formal definition of what constitutes “ablative.” Thus, we convened a group of international experts to provide consensus on the parameters that define ablative EBRT in HCC. Methods: A Steering Committee was convened to generate a series of Key Criteria (KC) that could be used to define ablative EBRT for HCC. KC were based on factors related to dose, fractionation, radiobiology, target identification, and delivery technique. An international panel of experts participated in a modified Delphi (mDelphi) process to independently answer questions for each KC. Respondents were given 30 days to respond in round 1 of the mDelphi and 14 days to respond in round 2. A threshold of ≥ 70% was used to define consensus for answers to each KC. Results: Invitations were sent to 40 individuals and 35 (88%) returned responses. In the first round of the mDelphi, 3 of 7 KC reached consensus. In the second round, 100% of participants returned responses and consensus was reached in 3 of the remaining 4 KC. Based on this mDelphi analysis, there was expert agreement that ablative EBRT for HCC should be defined as 1) a BED10 ≥ 80 Gy, 2) daily imaging and multi-phasic contrast used for target delineation should be used, 3) treatment breaks (e.g., for adaptive EBRT) are allowed, but the total treatment time should be ≤ 6 weeks, 4) the equivalent dose when treating with protons should use a conversion factor of 1.1, and 5) there is no single conversion factor for carbon ions. In one KC, which questioned the expert’s opinion on the α/β ratio of HCC, consensus was not achieved. Conclusions: Using an mDelphi method assessing expert opinion, we provide the first consensus definition of ablative EBRT for HCC. Empiric data are required to define the α/β of HCC.
Efficacy and safety of surufatinib in biliary tract cancer: Preliminary results of a real-world study.
Authors: Zhang Zongli , Ma Changlin , Li Enshan , Gao Yanchao , Bao Guangjian , Lu Jun , Sun Kejian , Zhou Xu , He Qiang , Xu Yunfei , Li Kangshuai , Yang Faji
Published: January 2024

486

Background: When applied in the second-line treatment for biliary tract cancer (BTC) pts, surufatinib (a small-molecule inhibitor of VEGFR1-3, FGFR1 and CSF-1R) monotherapy has demonstrated moderate clinical efficacy and has demonstrated favorable tolerability and safety profiles. This study was to evaluate the efficacy and safety of surufatinib as a therapy for BTC in a real-world setting. In particular, pts who received resection for BTC with positive margins would be eligible for this study. This population indicates a poor prognosis, for their tumor environment is complex, which is an obstacle to R0 resection. However, no proper treatment for this population has been recommended yet. Methods: This is an ongoing single-arm, multi-center, open-label real-world study conducted in China. The study would enroll 200 pts with unresectable or surgical resection with positive margins BTC. Pts would receive surufatinib with or without combination as adjuvant (namely pts with positive margin after resection), first- or further-line therapy, at a proper dose (200-300mg) judged by physicians once per day in 28-day cycles. The primary endpoint is relapse-free survival (RFS) for pts whose primary lesions were resected, and progression-free survival (PFS) for those had evaluable lesions. If available, tumor assessments were performed every 2 cycles ± 7 days according to RECIST version 1.1. Results: By Sep 10, 2023, 56 eligible pts had been enrolled, of whom 16 (28.6%) were female. The median age was 64 (range: 39-81). 28 (50.0%), 24 (42.9%), and 4 (7.1%) pts received surufatinib as adjuvant, first-line, and above treatment, respectively. As to location, 23 cases were intrahepatic cholangiocarcinoma (ICC), and 33 cases were extrahepatic cholangiocarcinoma (ECC) or gallbladder cancer (GBC). With a median follow-up time of 9.5 (range: 1.1-20.3) mo, the global mRFS/mPFS was 10.4 (95% CI: 9.0-13.9) mo. The mRFS of pts who received surufatinib as adjuvant treatment was 11.3 (95% CI: 10.4-NA) mo, and mPFS of those who received surufatinib as systematic treatment was 9.0 (95% CI: 7.8-10.8) mo. Pts with ICC demonstrated an mRFS/mPFS of 10.4 (5.8-NA) mo, and those with ECC or GBC demonstrated 10.4 (9.5-NA) mo. The global mOS was 15.8 (12.4-NA) mo. Among those with primary lesion unresected (n=28), 2 pts (7.1%) achieved CR, 5 (17.9%) pts PR, 16 (57.1%) pts SD, and 5 (17.9%) pts suffered PD. The ORR was 25.0%, and DCR was 82.1%. No new safety signal was observed. Conclusions: Surufatinib exhibited promising efficacy and manageable toxicity on pts with BTC in the real-world setting. Clinical trial information: NCT05064852 .
Recurrence in the pelvic side wall after lateral lymph node dissection for rectal cancer.
Authors: Takao Misato , Kawai Kazushige , Takagi Maki , Funatsu Nozomi , Natsume Soichiro , Nakano Daisuke , Yamaguchi Tatsuro
Published: January 2024

49

Background: Locally advanced rectal cancer poses a persistent challenge due to the risk of local recurrence, which impacts patient outcomes and quality of life. To address this, lateral pelvic lymph node dissection (LPND) has emerged as a surgical approach to improve local control. However, comprehensive studies evaluating the outcomes and patterns of recurrence after LPND are limited. This retrospective study aimed to fill this gap and provide insights into the effectiveness of LPND. Methods: We conducted a retrospective analysis of 515 patients diagnosed with stage II-III lower rectal cancer who underwent TME and LPND between January 2005 and August 2022. Clinicopathological data were collected, and tumor staging followed the TNM classification system. Recurrence patterns, survival rates, and factors influencing lateral pelvic recurrence were assessed. Results: In our cohort, 18.8% of patients had pathologically positive lateral lymph nodes. Patients with lateral lymph node metastasis exhibited significantly lower 5-year relapse-free survival (31.6%) and overall survival (47.8%) rates compared to those without metastasis (69.5% and 84.7%, respectively). Local recurrence occurred in 20.1% of all patients, with 6.7% experiencing lateral pelvis recurrence (LPR) and 17.4% central pelvis recurrence. Multivariate analysis identified age over 75, lateral lymph node metastasis, and adjuvant chemotherapy as independent risk factors for LPR. Conclusions: Lateral pelvic lymph node dissection remains a valuable tool in managing locally advanced rectal cancer. Our findings underscore the importance of surgeon expertise in performing LPND and the potential benefits of combining treatments to further reduce lateral recurrence. LPND should continue to be explored and refined to enhance patient outcomes in this challenging clinical scenario.
Qualification of major pathological response as a surrogate endpoint for relapse-free survival following neoadjuvant immunotherapy for hepatocellular carcinoma.
Authors: D'Alessio Antonio , Stefanini Bernardo , Blanter Julia , Adegbite Benjamin , Fulgenzi Claudia A.M. , Celsa Ciro , Manfredi Giulia F , Pai Madhava , Goldin Robert D. , Shu Daniel , Su Yung-Yeh , Baretti Marina , Anders Robert A. , Yarchoan Mark , Hsu Chiun , Marron Thomas Urban , Pinato David James
Published: January 2024

506

Background: Neoadjuvant use of immune checkpoint inhibitors (ICI) is feasible and achieves pathological responses in a subset of patients with hepatocellular carcinoma (HCC). However, it is not clear whether pathological response to ICI translates into long-term survival benefit. Methods: We analysed patient-level data from 86 subjects recruited to 4 prospective phase I/II clinical trials of ICI prior to liver resection (LR) in 9 centres in the United States, Europe, and Asia and included a cohort of 23 patients (pts) receiving neoadjuvant ICI off trial. Radiological response was assessed with RECISTv1.1. Major (MPR) and complete pathological response (pCR) were considered as ≥70% and 100% non-viable tumour in the resected specimen, respectively. Pathological responses were correlated with radiologic overall response rates (ORR) and relapse-free survival (RFS). Results: Out of 109 pts treated between 10/2017 and 09/2023, 55 pts (50.5%) received a double ICI combination, 35 (32.1%) ICI monotherapy, and 19 (17.4%) an antiangiogenic/ICI combination. In 19 pts (17.4%) an adjuvant ICI course was administered for a median time of 5.5 months (m) (interquartile range [IQR] 3.7-6.0). Most of pts were male (77.6%) with underlying viral chronic liver disease (68.2%), performance status 0 (83.5%), BCLC 0-A (55%), a median tumour diameter of 6.0 cm (IQR 3.9-9.9) without portal vein thrombosis (75.7%). After a median follow-up of 27.3 m (95% CI 21.5-33.0), 35 (32.1%) relapses and 14 (12.8%) deaths occurred. Radiologic ORR was 28.5% (n=31), with 3.7% complete responses (CR, n=4) and 24.8% partial responses (PR, n=27). Out of 100 pts evaluable for a pathological response, 33% achieved MPR and 19% pCR. MPR was more likely in patients who had achieved a radiologic PR or CR (82%) as compared to those who did not (14% p<0.001), however linear correlation suggested an imperfect correlation between ORR and MPR (R2 0.43, p<0.0001). Median RFS was 43.5m (95%CI, 27.5-59.6), while median overall survival was not reached (NR). mRFS was significantly improved in pts with MPR (NR vs 28.3m [95%CI, 13.1-43.5], hazard ratio [HR] 0.27 [95%CI, 0.11-0.69], p = 0.003) and with pCR (NR vs 32.8m [95%CI, 15.2-50.4], HR 0.20 [95%CI, 0.05-0.82], p=0.013). Conclusions: This study is the first to qualify the role of MPR as a putative surrogate endpoint for recurrence-free survival in pts treated with neoadjuvant immunotherapy for HCC. Validation in larger phase III clinical trials is warranted.
Update results from ALTER-H004 study: Anlotinib combined with TACE as adjuvant therapy in patients with hepatocellular carcinoma (HCC) at high risk of recurrence after surgery: A single arm, multi-center, phase II clinical trial.
Authors: Wu Zheng , Wang Zheng , Zhang Lei , Song Xiaojing
Published: January 2024

513

Background: High recurrence rate after curative resection significantly compromised the long-term survival of patients with HCC patients (pts). TACE as adjuvant therapy was proved to improve clinical outcomes for pts with high recurrence risk factors after hepatectomy. However, the prognosis of TACE reminded unsatisfactory and controversial. Therefore, this study aimed to identify the efficacy and safety of anlotinib as maintenance adjuvant treatment following inductional TACE in pts with HCC. The update results were reported here with longer follow-up duration. Methods: HCC pts with one of the following high risk factors after hepatectomy: ≥5 cm and <10 cm of tumor diameter, tumor number ≥3, tumor microvascular invasion M1 or M2, portal vein tumor thrombus resection (Cheng's classification I/II) were recruited. Eligible pts received cTACE treatment within 1-2 months after hepatectomy, on the 3-5th day after cTACE, oral anlotinib (12mg, qd, d1-d14, q3w) was given until disease recurrence or unacceptable toxicity. The predefined sample size was 30. The primary endpoint was disease free survival (DFS). Secondary endpoints included 1-year DFS rate, time to recurrence and safety. Results: The data cut-off date was March 2023, 29 pts were enrolled and 27 pts received at least once tumor assessment. The median follow-up was 21.8 (IQR, 17.3-26.3) months. Of 27 with assessable efficacy, mDFS was 24.2 (95% CI, not applicable-not applicable) months, with 12-, and 24-month DFS rates of 72.2% (95% CI, 50.4%-85.7), and 61.8% (95% CI, 38.8%-78.3%), respectively. 18 of 27 pts (66.7%) experienced treatment-related adverse events (TRAEs). Grade 3 TRAEs occurred in 4 pts (14.8%) included hypertension (7.4%), leukocytopenia (7.4%) and ascites (3.7%). No grade 4 or 5 TRAEs occurred. Conclusions: Anlotinib combined with TACE as adjuvant therapy in HCC pts at high recurrence risk exhibited encouraging efficacy and tolerable safety profile. And the conclusions needed to be confirmed in large scale clinical trials subsequently. Clinical trial information: NCT04213118 .
Histopathologic and genomic profile characteristics of biliary cancers related to pancreaticobiliary maljunction.
Authors: Tohyama Shodai , Ohyama Hiroshi , Ohno Izumi , Amemiya Kenji , Hirotsu Yosuke , Sakai Miho , Watabe Kazuki , Yamada Nana , Sugihara Jihei , Ohuchi Mayu , Kan Motoyasu , Nagashima Hiroki , Takahashi Koji , Okitsu Kohichiro , Mishima Takashi , Takayashiki Tsukasa , Mochizuki Hitoshi , Ohtsuka Masayuki , Kato Naoya , Omata Masao
Published: January 2024

527

Background: Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic duct and bile duct anatomically merge outside the duodenal wall, and is associated with a high rate of biliary cancer. It has been reported that TP53 and KRAS mutations are found not only in the cancerous area but also in the noncancerous area. However, there is no report of precise mapping of genetic mutations throughout the gallbladder and bile ducts. Methods: Ninety-seven patients (including 31 patients with biliary cancer) who underwent cholecystectomy and cholangiectomy for PBM between 1990 and 2023 at our hospital and affiliated hospitals were included in the study, and consent forms were obtained from 36 patients. The panel targeting 60 genes frequently identified in biliary tract cancer was created in-house and deep sequenced to compare with clinicopathological features. To date, we have analyzed 4 patients with biliary tract cancer and 5 patients without it (with prophylactic resection). The same analysis was also performed on cancerous and noncancerous parts of patients of gallbladder cancer and cholangiocarcinoma without confluence abnormalities for comparison. Results: A total of 33 Samples (7 cancerous parts and 26 noncancerous parts) were examined for biliary tract cancer. We found a variety of functional gene abnormalities, including driver mutations such as TP53, ARID2, and BRCA2, in 9 non-cancerous areas including hyperplasia and normal bile duct mucosa. Some of these mutations were not shared with cancerous areas. On the other hand, in 46 samples from 5 patients who did not develop gallbladder cancer (prophylactic resection), Driver mutations were found in only 3 sites. Pathological findings of dysplasia/hyperplasia in these prophylactic resections were observed in 28 of the 46 sections. In addition, Driver mutations were rarely observed in noncancerous areas in patients with normal gallbladder or cholangiocarcinoma. Conclusions: Unlike conventional biliary tract cancers, the patients with PBM showed a great variety of genetic abnormalities in both cancerous and noncancerous areas. On the other hand, in patients of prophylactic resection without cancer, driver mutations were almost completely absent despite the presence of mucosal changes. We believe that these findings can develop better strategy for biliary cancers with PBM.
The role of pre-operative ctDNA in resectable intrahepatic cholangiocarcinoma.
Authors: Choi Woo Jin , Li Zhihao , Magyar Christian , Tin Antony , Spickard Erik , Sethi Himanshu , Liu Minetta C. , Bucur Roxana , Grant Robert C , Vogel Arndt , Knox Jennifer J. , Liu Geoffrey , Gallinger Steven , Sapisochin Gonzalo , O'Kane Grainne M.
Published: January 2024

528

Background: Genomic profiling of circulating tumor DNA (ctDNA) is increasingly used in intrahepatic cholangiocarcinoma (iCCA) to inform precision oncology approaches and determine resistance mechanisms to targeted therapies. The application of pre-operative ctDNA testing in the management of iCCA for prognostication remains unclear. Methods: In this retrospective study, we analyzed pre-operative plasma samples from 14 patients who underwent curative resection for iCCA without neoadjuvant therapy. A personalized and tumor-informed assay (Signatera; Natera, Inc.) was used for the detection and quantification of ctDNA. We correlated ctDNA profiles with baseline tumour characteristics and clinical outcomes. Results: The mean interval between pre-operative blood collection and surgery was 43 days (range: 1 to 90 days). ctDNA was detected in all patients except for one with stage Ia (AJCC 8th) disease (Table). The mean pre-operative ctDNA concentration was lowest in the stage Ia group [4.2 mean tumor molecules (MTM)/mL] and highest in the stage II group (134.0 MTM/mL). The mean pre-operative ctDNA concentration did not exhibit a linear correlation with disease recurrence or mortality rates, however, it showed a moderate-to-good linear correlation with the largest pathologic tumor size (R2 = 0.55). Among the three patients who had IDH1/2 mutations tracked in the plasma by Signatera, two patients had positive IDH1/2 detection in ctDNA with mean ctDNA concentrations of 83.7 MTM/mL (range: 33.8 to 133.5 MTM/mL). The patient with the second-highest ctDNA concentration (133.5 MTM/mL and 1818 days follow-up) had stage Ib disease with an IDH1 mutation but has shown no evidence of recurrence. Conclusions: In the pre-operative setting for iCCA resections, ctDNA can be reliably detected across all disease stages using a tumor-informed approach, even when blood is collected up to 90 days before surgery. While single time-point pre-operative ctDNA concentration levels do not appear to correlate with outcomes, similar to previous reports in colon adenocarcinoma, they may correlate with tumor volume. Further studies are needed to evaluate the utility of tumor-informed ctDNA testing in the post-operative setting to detect molecular residual disease for improved prognostication. [Table: see text]
Cost-utility analysis of sequential therapy with sorafenib followed by regorafenib versus single-line therapies in advanced hepatocellular carcinoma.
Authors: Grossman Jamie , Fawsitt Chistopher , Aceituno David , Paracha Noman , Özgürdal Kirhan , Thom Howard
Published: January 2024

529

Background: Regorafenib is the only licensed second-line therapy available for patients with advanced hepatocellular carcinoma (HCC) that progress on first-line sorafenib in the UK. We evaluated the lifetime cost-effectiveness of a sequence of treatment with sorafenib followed by regorafenib (SOR-REG) compared with licensed single-line therapies for which there is no clear sequencing options available, including atezolizumab plus bevacizumab (ATEZO+BEV), which has become the standard of care in first-line treatment, as well as lenvatinib (LEN), followed by best supportive care (BSC). Methods: Assuming a UK National Health Service and Social Services perspective, we developed a probabilistic individual-level semi-Markov model with states reflecting progression-free survival, progression following first-line treatment, further progression following second-line treatment, and death. First-line overall survival (OS) and progression free survival (PFS) were informed by fractional polynomials network meta-analysis of published trials. Individual patient data from a phase 3 trial (RESORCE) on regorafenib and BSC informed OS and PFS in the second-line setting. Costs and utilities were sourced from published studies. Cost-effectiveness was summarized using incremental net monetary benefit (INMB), which could be positive or negative depending on direction of expected benefit associated with SOR-REG, and cost-effectiveness acceptability curves at willingness-to-pay (WTP) thresholds. Results: We found 1000 probabilistic samples and 1000 patients were sufficient for convergence. Lifetime costs were highest with ATEZO-BEV ([£80,963 [95% CI: £11,022, £97,369]), followed by SOR-REG (£38,373 [£31,064, £43,420]) and LEN (£37,351 [£5,020, £55,800]). Quality-adjusted life years (QALYs) were highest with ATEZO+BEV (1.021 [0.152, 1.239), followed by SOR-REG (0.942 [0.802, 1.057]) and LEN (0.755, [0.094, 1.092]). At a WTP threshold of £30,000 / QALY gained, SOR-REG had an INMB of £40,211 (95% CI -£2,099, £52,731) and £4,589 (-£8,044, £14,481) versus ATEZO+BEV and LEN, respectively. Conclusions: A sequence of SOR-REG for patients with advanced HCC is cost-effective at WTP thresholds of £30,000 / QALY gained due to lower lifetime costs and broadly comparable QALY gains with single-line ATEZO-BEV and LEN in the UK. Broader second-line treatment options are needed for patients receiving ATEZO+BEV and LEN as first-line therapies.
Prognostic value of minimal residual disease profiling in resectable hepatocellular carcinoma.
Authors: Hu Jie , Zhou Jian , Tang Haoran , Jia Cancan , Xie Feng , Zhang Yue , Jia Shidong
Published: January 2024

530

Background: Detecting post-surgical residual disease is a critical clinical requirement in resectable hepatocellular carcinoma (HCC). Previous studies focused on specific genomic regions have indicated that ctDNA holds promise as a tool for prognostic assessment. Nevertheless, these methods exhibited limited sensitivity and failed to meet the minimal residual disease (MRD) threshold. Here we report the prognostic value of MRD profiling in HCC patients who have undergone hepatectomy. Methods: This retrospective study involved 88 HCC patients who underwent surgical resections in China, from January to May in 2016. During surgery, tumor and normal tissue specimens were collected. Plasma samples were obtained 7 days post-surgery. PredicineBEACON, a baseline tissue- or blood-informed MRD assay, was used for MRD profiling. This entailed identifying tumor-specific mutations through whole exon sequencing of tissue samples. Subsequently, a personalized MRD panel, selecting up to 50 mutations via bioinformatics pipelines merged with a fixed panel featuring 500 tumor actionable hotspots, was created for each patient. To detect MRD in post-surgery plasma samples, we employed ultra-deep sequencing at a coverage of 100,000X, utilizing the designed panel. Results: In the cohort of 88 patients, the distribution based on Barcelona Clinic Liver Cancer (BCLC) staging was as follows: 79.5% stage A (N=70), 12.5% stage B (N=11), and 8.0% stage C (N=7,). The MRD assay identified 36 patients as MRD+ and 52 patients as MRD-. We observed significant correlations between MRD status and both relapse-free survival (RFS) and overall survival (OS). For MRD+ patients, the median RFS was 17.1 months, while it was not reached for MRD- patients (p=0.0013). Likewise, the median OS for MRD+ patients was 40.1 months, in contrast to it not being reached for MRD- patients (p=0.0012). The MRD positivity rate stood at 100% in stage C patients, a significantly higher percentage compared to the rates observed in stage B (36.4%, p=0.0256) and stage A (36.2%, p=0.0042). Significantly, MRD status emerged as a pivotal prognostic differentiator among clinically low-risk patients in stage A: among MRD+ patients, the median RFS was 23.3 months, whereas it was not reached for MRD- patients (p=0.05). Additionally, the median OS of both MRD+ and MRD- was not reached but their survival curves showed significant differences (p=0.038). Conclusions: This study demonstrated the clinical utility of ctDNA MRD assay in patients with resectable HCC, as notably evident in the robust detection of MRD using plasma samples collected 7 days after surgery. Furthermore, the assessment of post-surgical MRD status provided valuable prognostic insights into both patient survival and the risk of disease relapse. ctDNA MRD status played a pivotal role as a prognostic differentiator, particularly among clinically low-risk patients.
Molecular differences with therapeutic implications in early-onset compared to average-onset cholangiocarcinoma.
Authors: Jayakrishnan Thejus , Baca Yasmine , Xiu Joanne , Patel Mehrie , Weinberg Benjamin Adam , Lou Emil , Datta Jashodeep , Khushman Moh'd M. , Gulhati Pat , Goel Sanjay , Biachi de Castria Tiago , Florou Vaia , Nair Kanika G. , Kamath Suneel Deepak , Khorana Alok A.
Published: January 2024

536

Background: Early-onset cholangiocarcinoma (eoCCA) is among early-onset cancers with the fastest rising rates, yet little is known about its biology. We sought to compare the molecular characteristics of eoCCA with average-onset CCA (aoCCA) with an age cut-off of 50 years, utilizing a real-world multi-omics dataset. Methods: The study comprised patients whose tumors underwent molecular analysis at Caris Life Sciences (Phoenix, AZ) using whole exome and whole transcriptome analyses. Patients were categorized by age as eoCCA defined as <50 years and aoCCA >50 years. Gene expression profiles were analyzed for transcriptional signatures predictive of immunotherapy response including the T-cell inflamed score (TIS) and interferon-gamma (IFG) score. P values (adjusted for multiple testing) were considered significant at False Discovery Rate (FDR) P<0.05 for molecular comparisons and FDR P<0.25 for Gene Set Enrichment Analysis (GSEA). Insurance claims data was used for survival comparison using Kaplan-Meier estimates. Results: The study included 5587 patients - 453 patients with eoCCA and 5134 with aoCCA (Table). Of targetable mutations ( FGFR2, IDH1, IDH2, ERBB2, BRCA, BRAF), FGFR2 fusion was significantly more prevalent in eoCCA (15.7% vs 5.9% in aoCCA, FDR P<0.001). Rates trended higher in eoCCAfor MSI-H tumors (4.1% vs 2.4%), and high tumor mutational burden (6.1% vs 5.1%) but not significantly different (FDR P=1). The IFG score (Fold Change FC: 1.1, FDR P=0.01) and TIS (FC:17.3, FDR P=0.03) were significantly higher in aoCCA vs eoCCA. On GSEA, angiogenesis was enriched in eoCCA (normalized enrichment score NES=1.51, FDR P=0.16) while IFG (NES= -1.58, FDR P =0.06) and inflammatory response (NES= -1.46, FDR P=0.18) were enriched in aoCCA. Median OS was longer in eoCCA (16.5 vs 13.3 months, Hazard Ratio (HR) 0.86, 95%CI 0.78-0.95, P=0.004). Among patients treated with immunotherapy, median OS was longer in patients with eoCCA (19.2 months, n=19) vs aoCCA (7.6 months, n=150) - HR 0.52, 95%CI 0.28-0.94, p=0.03. No survival difference was identified in patients on chemotherapy (HR 0.91, 95%CI 0.76-1.08, P=0.28). Conclusions: In the largest age-stratified analysis of molecular characteristics of CCA, we identified crucial differences, including higher prevalence of FGFR2 fusions and significant differences in immunotherapy-related markers, angiogenesis enrichment, and inflammatory response. Patients with eoCCA experienced better outcomes with immunotherapy even though immune-oncology-relevant markers favored aoCCA. Our findings, especially higher FGFR2 fusion prevalence in eoCCA, underscore the need for NGS testing and the potential for age-tailored therapeutic strategies. [Table: see text]