tbuckley/cabot-search huggingface dataset:
Postoperative complications following neoadjuvant therapy and surgery in a phase 2 borderline resectable pancreatic cancer clinical trial (Alliance A021501).
Authors: Rebecca A Snyder, Tyler J. Zemla, Qian Shi, Diana I. Segovia, Syed Ahmad, Eileen Mary O'Reilly, Joseph M. Herman, Matthew H. G. Katz
Journal: Journal of Clinical Oncology (2024)

664 Background: Postoperative complications in patients with borderline resectable pancreatic cancer treated with neoadjuvant therapy and pancreatectomy in the national cooperative group setting have not been previously characterized. Further, the impact of preoperative hypofractionated radiotherapy on postoperative outcomes is largely unknown. We sought to quantify perioperative morbidity among patients with pancreatic cancer who received neoadjuvant modified FOLFIRINOX chemotherapy with or without hypofractionated radiotherapy on a multicenter clinical trial. Methods: The A021501 phase 2 trial randomized patients with borderline resectable pancreatic ductal adenocarcinoma to 8 doses of mFOLFIRINOX (Arm 1) or 7 doses of mFOLFIRINOX then hypofractionated radiotherapy (Arm 2), followed by pancreatectomy (Dec 31, 2016-Jan 1, 2019). Patients underwent resection according to defined operative standards at enrolling centers without specific requirements for either surgeon or hospital volume. Surgical complications and adverse events were assessed and captured at a single time point of 90 days after surgery and compared between treatment arms. Results: Of 126 enrolled patients, 51 (40%) underwent pancreatectomy (n=32, Arm 1; n=19, Arm 2) at 28 institutions. Vascular resection was performed in 19 patients (37%). One patient in Arm 2 died within 90 days after surgery. Rates of any surgical complication were 19% (n=6) in Arm 1 and 42% (n=8) in Arm 2 (p=0.07). Median length of stay was 7 days (range 5-38 days). Five (10%) patients required reoperation within 90 days. Readmission rates were higher in Arm 2 than Arm 1 (16% vs. 42%, p=0.04) but there were no differences in rates of reoperation, pancreatic fistula or abscess requiring drainage, or wound infection between study arms. 54% of patients (n=26/48) experienced a grade 3 or higher adverse event, with no difference between treatment arms (47% versus 67%, p=0.7). Rates of initiation of adjuvant therapy did not differ between treatment arms (66% vs. 68%, p=0.4). Pancreatic fistula and abscess were associated with adjuvant therapy (p&lt;0.01). No difference in overall survival was observed based on occurrence of surgical complications (HR 1.1; 95% CI 0.5-2.6). Conclusions: In this national cooperative group study of patients with borderline resectable pancreatic cancer,postoperative complications following neoadjuvant chemotherapy, radiation, and surgical resection were consistent with rates previously reported by high-volume institutions and using large datasets. Multimodality trials of preoperative therapy for locoregionally advanced pancreatic cancer may be safely performed in the cooperative group setting. Clinical trial information: NCT02839343 .
Adjuvant chemoradiotherapy (CRT) plus pembrolizumab for locally advanced esophageal squamous cell carcinoma (ESCC) with high risk of recurrence after neoadjuvant CRT plus surgery: A single-arm phase II study.
Authors: Jhe-Cyuan Guo, Ta-Chen Huang, Hung-Yang Kuo, Chia-Chi Lin, Feng-Ming Hsu, Jason C. Cheng, Yen-Lin Huang, Min-Shu Hsieh, Pei-Ming Huang, Jang-Ming Lee, Shu-Ling Wu, Chih-Hung Hsu
Journal: Journal of Clinical Oncology (2024)

320 Background: Adjuvant anti-PD-1 therapy with nivolumab has shown efficacy in reducing recurrence rates in patients with locoregional esophageal cancer including squamous cell carcinoma who achieved R0 resection but harboring pathologic residual disease following neoadjuvant CRT. However, the efficacy of adjuvant anti-PD-1 therapy in improving outcomes for patients at higher risk of recurrence, especially those with involved or close resection margin (≤1 mm), remains unclear. Methods: We conducted a phase II trial of adjuvant cisplatin (30mg/m2 IV every week for 2 cycles)-based CRT (180-200cGy per fraction for 10-13 fractions) followed by pembrolizumab (200mg IV every 3 weeks for 18 cycles) in patients with locally advanced ESCC who had high-risk recurrence features in esophagectomy tumor tissues, including involved or close margin (≤1 mm), extranodal extension (ENE) of involved lymph node, and ypN2-3, following neoadjuvant CRT (ClinicalTrials.gov Identiﬁer: NCT03322267). Primary endpoint was 1-year relapse-free survival (RFS) rate in comparison with a historical control of 32%. 1 Secondary endpoints included RFS, overall survival (OS), and toxicity. Results: Between Nov 2018 and Dec 2022, we enrolled a total of 25 patients with high risk recurrence features, including margin ≤1 mm (18 patients), ENE of involved lymph node (9), and ypN2-3 (9). Majority of patients were male (88%) and current smokers (84%). The median follow-up duration was 16.5 months (95% CI 10.6-27.1). One-year RFS rate was 63.3% (95% CI 44.5-79.8). Median RFS and OS were 15.3 months (95% CI 10.2-20.4) and 38.3 months (95% CI 10.2-66.3), respectively. Any grade treatment emergent adverse events (TEAEs) occurred in 56% and 75% of patients during cisplatin-based CRT and pembrolizumab treatment, respectively. Grade 3 TEAEs were infrequent, including leukopenia (4%), pancreatitis (4%), infection (8%), and colitis (4%). There was no grade 4 TRAE. Conclusions: Adjuvant cisplatin-based CRT followed by 1-year treatment of pembrolizumab was well-tolerated, and was associated with an improved 1-year RFS rate in patients with pathologic residual disease and high risk for recurrence following trimodality therapy for locally advanced ESCC. 1. Guo JC et al: J Thorac Oncol 2015;10:1481-9. Clinical trial information: NCT03322267 .
Comparison of the treatment effect between lenvatinib and atezolizumab plus bevacizumab for unresectable hepatocellular carcinoma in pathologically diagnosed metabolic dysfunction–associated steatotic liver disease.
Authors: Hirokazu Takahashi, Yuichi Koshiyama, Yasuhide Mitsumoto, Takashi Kobayashi, Hideki Hayashi, Taeang Arai, Koji Sawada, Michihiro Nonaka, Takashi Nakahara, Kengo Tomita, Takanori Ito, Kazuo Notsumata, Yuya Seko, Hideki Fujii, Shinichi Aishima, Masato Yoneda, Hidenori Toyoda, Yoshio Sumida, Atsushi Nakajima, Takeshi Okanoue
Journal: Journal of Clinical Oncology (2024)

493 Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the leading etiologies of HCC. Recent evidence indicates that MASLD might affect the response to immune checkpoint inhibitors and multi-receptor tyrosine kinase inhibitors in the treatment for unresectable hepatocellular carcinoma (HCC), yet real-world data with accurate pathological diagnosis of MASLD has not been confirmed. Methods: Patients with unresectable HCC who had been pathologically diagnosed with MASLD by liver biopsy and/or hepatectomy and later received treatment with lenvatinib (LEN) or atezolizumab plus bevacizumab (ATZ/Bev) as first-line systemic treatment for HCC were included. Outcomes of treatment with LEN or ATZ/Bev were compared. Results: A total of 48 patients who received LEN (n=26) and ATZ/Bev (n=22) were included. The mean time from pathological diagnosis to the initiation of treatment was not different (LEN 1,542 days, ATZ/Bev 1,260 days; p=0.48). The degree of steatosis, inflammation, ballooning hepatocytes and fibrosis did not differ between LEN and ATZ/Bev. At the initiation of treatment, BCLC stage, albumin–bilirubin grade, and Child–Pugh grade did not differ between LEN and ATZ/Bev. The overall response rate and disease control rate evaluated with modified RECIST criteria were not different between LEN and ATZ/Bev (26.1% and 77.2% for LEN, and 22.7% and 70.8% for ATZ/Bev). Median progression-free survival (PFS) was not different between LEN and ATZ/Bev (266 days vs 287 days, p=0.278). Median overall survival (OS) of LEN tended to be longer than that of ATZ/Bev (1364 days vs 663 days, p=0.081). The potential advantage of LEN in OS was statistically significant in the patients with Child-Pugh score = 5 (P=0.0443). A total of 17 patients received both LEN and ATZ/Bev treatment and order of the treatment did not associate with PFS and OS. Conclusions: Outcomes of LEN and ATZ/Bev treatment for advanced HCC were not different in pathologically confirmed MASLD. Longer OS of LEN than ATZ/Bev was observed in the patients with relatively better liver function, suggesting that LEN might be a suitable first-line treatment for HCC with compensated liver function in the patients with pathologically confirmed MASLD.
Risk of relapse after surgical resection of localized appendiceal adenocarcinoma.
Authors: Mohammad Mahdi Fanaeian, Mahmoud M.G. Yousef, Abdelrahman M.G. Yousef, Wai Chin Foo, Melissa Taggart, Karen A. Beaty, Christopher Scally, Paul F. Mansfield, Keith F. Fournier, Beth A Helmink, John Paul Y.C. Shen
Journal: Journal of Clinical Oncology (2024)

58 Background: Appendiceal adenocarcinoma (AA) encompasses a heterogenous mix of histologic subtypes and frequently presents with peritoneal metastases. Data regarding the risk of relapse after surgical resection in patients with localized AA (stages I–III) is limited. More accurate evaluation of features predictive of relapse is critical to counsel patients, determine follow-up, and guide decisions regarding adjuvant therapy. Methods: The Foundry software platform was used to query the MD Anderson Cancer Center (MDA) Electronic Health Record database to identify and extract clinical information from AA patients presented to MDA from 2004 to 2023. Results: We identified 296 patients with localized AA, split into two cohorts: patients who underwent surgery at MDA (n=133) and patients with surgery at an outside institution later referred to MDA (n=163). The most common histologic subtypes were mucinous (n=124, 41.9%) and goblet (n=121, 40.9%) with less frequent colonic-type (n=42, 14.2%) and signet ring cell (SRC, n=9, 3%). With a median follow-up of 47 months, the relapse rate (RR) for the MDA surgical cohort was only 6% (n=8), with a median time to relapse of 24 months (range=8-74). Evaluating all 296 localized AA patients, histologic subtype was significantly associated with risk of relapse, with goblet AAs having lowest risk (6%, n=7), followed by colonic-type (12%, n=5), mucinous (27%, n=33), and SRC (44%, n=4; overall P&lt; 0.001), with a median time of relapse of 26 months (range=3-96). Patients with a positive LN, higher grade, and/or higher T stage showed a higher RR (Table). Use of adjuvant chemotherapy (AC) was not associated with RR in our cohort, with odds ratio trending towards increased risk of relapse (14.4% vs 19.2%, OR=1.4, 95% CI=0.76-2.6; P=0.27). Restricting to only high-risk patients (poorly differentiated, LN-positive, and/or T4, n=205), similar results were observed with 18.4% (n=17) relapsed without AC vs 19.4% (n=22) relapsed with AC (OR=1.06, 95%CI=0.52-2.15; P=0.85). AC was also not associated with improved RFS (HR=1.2, 95%CI=0.63-2.2, P=0.59). Conclusions: Patients with localized AA who undergo surgical resection have a low risk of relapse, especially those with goblet AA. This retrospective analysis did not identify a benefit from adjuvant chemotherapy. Considering the clear histologic and molecular differences between AA and CRC, these data call into question the current practice of applying CRC data to guide AC decisions in AA. Prospective clinical trials of AC in AA, stratified by histologic subtype, are urgently needed. [Table: see text]
Clinical characteristics and the course of hepatobiliary and pancreatic malignant tumors with high microsatellite instability after pembrolizumab administration: A multicenter observational study.
Authors: Yuta Maruki, Kenji Ikezawa, Mitsuhito Sasaki, Satoshi Kobayashi, Akiko Todaka, Hidetaka Tsumura, Naohiro Okano, Takeshi Terashima, Tatsuya Yamashita, Yasuyuki Kawamoto, Yasushi Kojima, Hiroshi Imaoka, Hiroko Hosoi, Chigusa Morizane, Makoto Ueno, Masafumi Ikeda, Takuji Okusaka
Journal: Journal of Clinical Oncology (2024)

459 Background: The Keynote-158 trial have resulted in an expanded approval for pembrolizumab (Pem) in solid tumors with high microsatellite instability (MSI-H). In the trial, Pem was administered to patients with MSI-H solid tumors, excluding colorectal cancer, and the overall response rate (ORR) was 34%. However, the ORR for pancreatic (PANC) and biliary tract (BT) cancer were 19% (4/22 cases) and 41% (9/22 cases), respectively, suggesting the possibility of varying treatment efficacy by the primary tumor site. In this study, we aimed to clarify the clinical characteristics of patients with MSI-H and the efficacy of Pem administration in hepatobiliary and pancreatic (HBP) cancers. Methods: A multicenter observational study of patients with HBP cancer with MSI-H was conducted from March 2020 to March 2023. This study consists of prospective and retrospective cohorts. We evaluated the efficacy of PEM administration in patients with PANC and BT, respectively. Results: We enrolled 51 patients, including 32 in the prospective cohort; males comprised 51% of the patients. The BT, PANC, and liver were the primary sites in 26, 24, and 1 patients, respectively. MSI-H diagnostic methods were the MSI kit (FALCO) and comprehensive genome profile in 43 (84%) and 8 (16%) patients, respectively. Intrahepatic cholangiocarcinoma (ICC) was the most common cancer in BT tumor; ICC was observed 13 (50%) patients, followed by perihilar, gallbladder, and distal bile duct (including ampullary cancer) cancers in 6, 4, and 3 patients, respectively. Some rare histological types were observed, two patients had neuroendocrine carcinoma and one had hepatoid carcinoma in PANC. One had an undifferentiated carcinoma in BT. Five and six patients with PANC and BT tumors, respectively, had one or more first-degree relatives with lynch syndrome-related disease. Pem was administered to 96% and 88% of the patients with PANC and BT tumors, respectively. The ORR was 30% in PANC and 73% in BT tumors (p=0.003). In BT tumor, three patients demonstrated complete response as follows: two with ICC and one with perihilar cholangiocarcinoma. The median progression-free survival was 3.2 months (95% confidence interval [CI], 1.3–14.4) and 16.3 months (95% CI, 8.7 to not reached) in patients PANC and BT tumors (p=0.08), respectively. Grade 3/4 immune-related adverse events occurred in 13% and 29% of the patients with PANC and BT tumors, respectively. Conclusions: ICC was the most common BT cancer with MSI-H. Pem was significantly more effective in BT tumors than in PANC tumors, with higher ORR. Clinical trial information: UMIN000040591 .
Molecular characterization of small extracellular vesicles in patients with pancreatic cancer treated with neoadjuvant chemotherapy followed by stereotactic body radiation (SBRT).
Authors: Ravi Kumar Paluri, Yixin Su, Sangeetha Sing, Grant Richard Williams, Olumide B. Gbolahan, Upender Manne, Gagan Deep
Journal: Journal of Clinical Oncology (2024)

685 Background: Currently, pancreatic cancer (PanC) is one of the serious gastrointestinal diseases, and more than 90% of the patients die within five years of diagnosis. Therefore, to improve PanC-related mortality, new therapeutic and diagnostic/prognostic measures are urgently needed. In this substudy, we examined the usefulness of plasma small extracellular vesicles (sEV) to discover molecular biomarkers associated with treatment response and overall survival from the plasma samples collected on a prospective clinical trial assessing the efficacy of SBRT following chemotherapy in pancreatic cancers (NCT03600623). Methods: PanCpatients (n=22) with locally advanced and borderline inoperable disease were recruited at the University of Alabama Comprehensive Cancer Center. They were administered either FOLFIRINOX (5-FU, folinic acid, oxaliplatin, and irinotecan) or paclitaxel (gemcitabine-nab-paclitaxel) for 2 months followed by SBRT (33 Gray in 5 fractions). The primary objective of this single-center pilot study was to evaluate the safety and tolerability of this treatment regimen. Further, blood was collected at baseline and, at the end of chemotherapy and radiotherapy. sEV were isolated from archived plasma samples by an established ultracentrifugation method and characterized for size and concentration by nanoparticle tracking analyses (NTA), shape and size by transmission electron microscope (TEM), and surface expression of exosomal tetraspanin markers (CD63, CD9, and CD81) and a PanC marker (CA19-9) by nano-flow cytometry. Lastly, sEV in longitudinal plasma samples were characterized for the expression of specific PanC-related miRNAs (miR196a-5p, miR155-5, miR194-5p, miR301-3p, miR21-5p, miR1246, and miR34a-5p) by real time-PCR (RT-PCR). Results: Neoadjuvant FOLFIRINOX and gemcitabine-nab-paclitaxel followed by SBRT were safe and well tolerated by most patients. NTA data showed that the ultracentrifugation method yielded highly pure sEV (with average diameter of &lt;200 nm) from archived baseline and longitudinal plasma samples. TEM analysis further confirmed the shape and size of the isolated sEV. Nano-flow cytometry showed the expression of exosomal markers, CD63, CD9, and CD81, as well as PanC marker CA19-9 on the surfaces of sEV. The expression of various PanC-related miRNAs in sEV was heterogenous and correlated with corresponding clinical parameters, including treatment response and overall survival. Conclusions: Neoadjuvant chemotherapy in combination with SBRT is safe and tolerable regimen to treat patients with locally advanced and borderline PanC. Further, sEV in the plasma of PanC patients could serve as useful prognostic and predictive markers.
Real-world (RW) effectiveness of nivolumab plus chemotherapy (NIVO+chemo) in patients (pts) with advanced or metastatic gastric carcinoma, gastroesophageal junction carcinoma, or esophageal adenocarcinoma (GC/GEJC/EAC).
Authors: Ian Chau, Afsaneh Barzi, Ying Zhang, Min You, David Bertwistle, Catherine Davis, Clara Chen
Journal: Journal of Clinical Oncology (2024)

295 Background: In the CheckMate 649 trial, NIVO+chemo demonstrated superior efficacy vs chemo alone in pts with previously untreated, advanced, non-human epidermal growth factor receptor 2 positive GC/GEJC/EAC. Our study was the first to evaluate the RW adoption patterns and effectiveness of NIVO+chemo as a first-line (1L) treatment of advanced GC/GEJC/EAC in the immediate period after NIVO approval in this setting. We report the 18-mo follow-up results. Methods: Pts in the United States ≥ 18 years of age with previously untreated advanced or metastatic GC/GEJC/EAC receiving NIVO+chemo or chemo alone (FOLFOX or CAPEOX) between 04/01/2021 and 12/31/2022 were identified in the Flatiron Health database. Pts were followed from the start of 1L therapy to death, loss of data availability, or the end of data abstraction, whichever occurred first. Results: 528 pts were eligible for the analysis (231 [44%] NIVO+chemo, 297 [56%] chemo). The prevalence of PD-L1 combined positive score (CPS) ≥ 5 before the 1L therapy was 55% for NIVO+chemo and 27% for chemo. Baseline demographic and clinical characteristics were comparable between treatment groups in the overall cohort and the CPS subgroups. Median follow-up (interquartile range) was 6.0 (2.4−9.8) mo for NIVO+chemo and 6.1 (2.5−9.7) mo for chemo. There were 87 (37.7%) deaths in the NIVO+chemo cohort and 138 (46.5%) in the chemo cohort. NIVO+chemo demonstrated superior overall survival (OS) in the overall cohort, with a 12-mo OS rate of 53.3% vs 38.1% for chemo and a 2.6-mo improvement in median OS (12.6 [95% confidence interval (CI), 10.2−17.9] mo vs 10.0 [8.9−11.5] mo, P = 0.047). Univariate Cox regression analysis of OS yielded a hazard ratio (HR) of 0.76 (95% CI, 0.58−1.00; P = 0.048) and multivariate Cox regression yielded an HR of 0.74 (95% CI, 0.56−0.98; P = 0.033) for NIVO+chemo vs chemo. There was also a consistent trend toward OS benefit with NIVO+chemo vs chemo in all CPS subgroups (Table). Multivariate analysis in the CPS ≥ 1 subgroup yielded a HR of 0.51 (95% CI, 0.30−0.89) for NIVO+chemo vs chemo but was not feasible in other subgroups due to sample size. Conclusions: NIVO+chemo showed superior OS vs chemo alone in previously untreated pts with advanced GC/GEJC/EAC in the RW setting. A trend toward OS benefit was also observed in all CPS subgroups, which will be further examined in future analyses with larger samples and longer follow-up. Clinical trial information: NCT02872116 . [Table: see text]
Tumor immune microenvironment of KRAS G12C mutated pancreatic cancer as compared to other mutations and non-cancer pancreata.
Authors: Vaibhav Sahai, Valerie Gunchick, Simi Paul, Thomas Enzler, Mark Zalupski, Timothy Frankel
Journal: Journal of Clinical Oncology (2024)

704 Background: KRAS G12C mutation occurs in approximately 1% of pancreatic ductal adenocarcinoma (PDA). KRAS G12C inhibitors have a reported response rate of 21-33% in patients with previously treated advanced PDA. KRAS is a known modulator of the tumor immune microenvironment (TME) and a greater understanding of the TME in KRAS G12C as compared to other mutations is crucial for developing rational therapeutic combination strategies in PDA. Methods: We performed multiplex fluorescent immunohistochemistry (mfIHC) on tissue obtained from patients with histologically confirmed PDA (KRAS G12C n=8; other mutations n=108) and normal pancreas (n=38). Serial staining was performed using antibodies against CD3, CD8, CD163, FoxP3 and PanCK for simple and complex phenotyping as well as spatial analyses in the TME. After tyramide based signal amplification, the slides were imaged at 20x magnification using the Mantra Quantitative Pathology workstation. Images were analyzed using inForm Cell Analysis software (Akoya Biosciences). All statistical analyses were performed using JMP Pro 13.2.0. Differences in phenotype, distances, and engagement were evaluated by 2-tailed Student’s t test or ANOVA. Results: Patients with KRAS G12C mutation had a median age of 70 (45-73) years of which majority (n=5, 62.5%) were men with advanced stage at diagnosis (n=6; 75%). The median overall survival is not yet reached (n=5, alive) after a median follow-up time of 14.4 months through reverse censoring methodology. When examining cellular infiltration, CD8+ cytotoxic T lymphocyte cells were significantly more abundant in the G12C TME compared to the cancer and non-cancer controls (p &lt;0.01). Additionally, the relative frequency of CD4+ and Tregs (CD3+/CD8-/FoxP3+) were also significantly higher in G12C (p&lt;0.01). The percentage of CD163+ antigen presenting cells (APCs) out of all cells was significantly higher in G12C (p&lt;0.01) while the percentage of non-functional APCs (PDL1+/CD163+) of all APCs was significantly higher in G12C than cancer and non-cancer controls (p=0.03). In comparison, the PDL1+ epithelial cells were much lower in G12C TME (p&lt;0.01). The cellular engagement and interaction data from the spatial analysis in the TME will be presented at the meeting. Conclusions: We identified increased infiltration of cytotoxic T lymphocytes and APCs in PDA patients with KRAS G12C mutations relative to other mutations and non-cancerous pancreata. Furthermore, while all PDAs had elevated PD-L1 expression on APCs, KRAS G12C tumors had minimal expression on epithelial cells suggesting a mutation specific impact and a potential role of immune checkpoint inhibitors in combination with G12C inhibitors.