Citations

e15599 Background: Screening and removal of pre-malignant adenomas has reduced CRC incidence in adults older than 50 years (later onset CRC [LOCRC]), but EOCRC incidence has increased by 1-2% annually since the 1990s. The liver is the commonest site of CRC metastasis, and EOCRC presents with more advanced stage compared with LOCRC. Oligometastasis (OM) refers to potentially resectable CRC, and complete resection of CRC primary and OM is associated with improved survival and potential cure. Here, we examined treatment outcomes of EOCRC with synchronous liver oligometastases (sLiOM) at our institution. Methods: We performed a retrospective review of institutional electronic health records and identified 160 EOCRC patients with sLiOM treated with curative intent in the last decade. Demographics, treatment, and follow up data were recorded, and analysis for survival outcomes performed. The study protocol was exempt after review by Mayo Clinic institutional review board. Results: Of 160 patients, median age at diagnosis was 43 years. Primary tumor was in the left colorectum in 73% and right colon in 26% of patients. Metastasis was limited to the liver only in 64%, and liver metastasis was solitary in 14% of patients (table 1). Fluoropyrimidine doublet backbone (81%) was more commonly used compared to triplet (19%), with doublet + bevacizumab (41%) as the most common regimen. Hepatectomy only (59%), combined hepatectomy with ablation (32%), ablation only (5%), transarterial radioembolization (2%), and trans arterial embolization (1%) were the modalities employed for sLiOM. Of the 148 patients who underwent hepatectomy, R0 resection was achieved in 51%. After a median follow-up of 37 months, progression-free survival was 11.6 mos (95% CI 9-14mos) and median overall was 83.6 mos (95% CI 62-105mos). The median time to liver progression was 16 mos (95% CI 12-20 mos). At data cut off, 41 patients (26%) were alive and disease-free, and 60 patients (38%) were alive and disease free in the liver only. Conclusions: This multi-site, retrospective analysis of EOCRC patients demonstrates excellent survival outcomes with localized treatment of sLiOM. Median OS in this cohort compares favorably to previously reported mOS of 36 months in EOCRC patients (Arhin et al, 2021). Cure is not often achieved even after treatment of sLiOM in this cohort, suggesting aggressive disease biology and the need for improved patient selection. [Table: see text]

Abstract Introduction: The development of hepatocellular carcinoma (HCC) is associated with underlying chronic liver disease from viral hepatitis or nonviral etiologies, such as nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease. An area of current research interest is the relationship between etiology of chronic liver disease in HCC patients and the response to specific treatment modalities. The purpose of this study is to identify prognostic indicators and compare survival outcomes among HCC patients within an Appalachian patient population. Methods: A single-institution, retrospective chart review was conducted for all patients diagnosed with HCC between August 2009 and March 2017 at West Virginia University Hospital. Patient demographics, tumor characteristics, laboratory data and treatment information were obtained from the electronic medical record (EMR). Survival analyses were performed using Kaplan-Meier method and multivariable Cox regression analysis. Results: The study sample (n=100) had a mean age of 62 years and was comprised of 82% males and 18% females. Nonviral etiologies of chronic liver disease were predominant (55%) over chronic viral hepatitis (45%). Significant adverse prognostic indicators of overall survival (OS) were Child-Pugh class C and tumor size >5 cm at diagnosis (p<0.0001, log-rank test). Patients who received liver-directed therapy (LDT) or liver resection had greater OS compared to those not treated with either modality (15.5 vs. 2.0 months, p<0.0001). Liver ablation or resection as initial modes of treatment had greater OS compared to those who initially received transarterial chemoembolization (TACE) or transarterial radioembolization (TARE) (17.2 vs 14.9 months, p<0.05). Patients who received TACE or TARE (n=60) as initial treatment had characteristics of advanced disease, with 45% having a tumor greater than 5 cm in size and 77% having multifocal unilobar or bilobar tumors. Among all patients who received LDT or resection, post-treatment albumin-bilirubin grade (ALBI) of 1 or 2 correlated with greater OS than grade 3 (22.5 vs 6.2 months, p<0.0001). In the multivariate Cox analysis, tumor size, Child-Pugh class and mode of initial treatment (resection/ablation vs. TACE/TARE) were independent predictors of OS (p<0.05). Conclusions: Treatment with LDT or liver resection correlated with greater overall survival in this predominantly nonviral cohort of HCC patients. Post-treatment ALBI grade correlated with overall survival and may have prognostic value in guiding clinical management. Mode of initial treatment was a predictor of overall survival, but further studies are needed to compare tumor characteristics between groups. Research is ongoing to evaluate the relationship between chronic liver disease etiology and survival among HCC patients treated with LDT, immunotherapy or a combination of both. Citation Format: Michelle Hartzell, Gary Monroe, Jon Shakesprere, Sijin Wen, J. Wallis Marsh, Jacob Fuqua, Robert Grammer, Beau Toskich, Midhun Malla. Prognostic indicators and outcomes of hepatocellular carcinoma (HCC) in an Appalachian population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6745.

TPS622 Background: In patients with early and intermediate hepatocellular carcinoma (HCC) who are ineligible for resection, thermal ablation, or liver transplant, transarterial radioembolization (TARE) with yttrium-90 glass microspheres has shown superior efficacy compared to transarterial chemoembolization; a subset of patients progress despite effective local therapy. Immunotherapy using the single tremelimumab regular interval durvalumab (STRIDE) regimen has demonstrated superior overall survival to sorafenib in advanced HCC. Recent work showed that TARE upregulates both the innate and adaptive immune systems. The possibility for TARE and STRIDE to have additive or synergistic effects when combined is of current scientific and clinical interest. The primary objective of the Phase II ROWAN Study is to assess the objective response rate and durability of local tumor control with TARE followed by STRIDE vs. TARE alone. Methods: ROWAN is a global, open-label, prospective, multicenter randomized controlled trial comparing treatment with TARE using glass microspheres followed by the STRIDE regimen (a single dose of 300 mg tremelimumab combined with 1500 mg monthly dose of durvalumab for 18 months) to TARE alone in HCC. ROWAN will include 150 patients across approximately 20 study sites in North America and Europe. Key inclusion criteria: HCC, diagnosed by radiographic imaging or histology; ineligible for or declined liver resection, thermal ablation, or transplantation; Child-Pugh A; ECOG 0; life expectancy ≥6 months; treatment naïve; unilobar tumor; measurable by mRECIST; tumor volume ≤25% of whole liver volume; and untreated future liver remnant volume ≥30% of whole liver volume. Key exclusion criteria: extrahepatic metastases; shunt fraction with a lung dose of >30 Gy; macrovascular invasion; infiltrative disease not evaluable by mRECIST; history of any organ allograph; autoimmune or inflammatory disorder; current use of immunosuppressive medication; history of malignancy other than HCC within past 3 years; and active infection. Patients will be randomized in a 1:1 ratio to two study arms (TARE followed by STRIDE or TARE alone) using two stratification factors (TARE treatment goal [ablative vs. non-ablative] and alpha fetoprotein level [>400 vs. ≤400 ng/mL]). Tumor and blood samples will be collected for correlative studies. Co-primary efficacy endpoints are objective response rate and duration of response (localized mRECIST). The primary safety endpoint is the number of adverse events (AEs) and serious AEs. Interim statistical analyses will be conducted after 25 patients have been randomized to each arm and completed the second imaging assessment 6 months post-randomization; final analysis will be after the last evaluable patient has completed the 18 months follow-up visit post-randomization or discontinued treatment. Clinical trial information: 05063565 .

TPS629 Background: The anti–PD-L1 antibody ATEZO prevents PD-L1 from interacting with PD-1 and B7.1, thus reinvigorating antitumor T cell activity. Anti-VEGF BEV can increase dendritic cell maturation, enhance T cell infiltration, and reduce myeloid-derived suppressor cells and regulatory T-cells in tumors. This combination has been FDA approved for first-line treatment of advanced HCC based on the IMbrave150 study. On the other hand, locoregional radiotherapy (e.g., Y90 TARE) enhances the diversity of the intratumoral T cell receptor repertoire. It is the standard of care for pts with intermediate-stage HCC (iHCC). Based on preclinical and clinical data, we hypothesize that the combination of Y90 TARE, BEV, and ATEZO induces synergistic tumor-killing. Methods: This is an open-label, multicenter, randomized phase II study of Y90 TARE and BEV plus ATEZO compared with Y90 TARE alone in pts with unresectable IHCC (NCT04541173). The primary study objective is to assess and compare the progression-free survival (PFS) (per mRECIST 1.1) of pts in each arm. The main secondary objective is to determine the safety and tolerability (CTCAE v5) of TARE combined with ATEZO and BEV in pts with HCC. Exploratory objectives are to assess the role of the immunoscore and PD-L1 expression levels in the prediction of improved clinical outcome in pts receiving Y-90 TARE and BEV plus ATEZO; the composition of tumor-infiltrating immune cell subtypes in predicting response to a chosen therapy; how Y90 therapy affects the proportion of antigen-presenting cells in the tumor; and symptoms experienced by pts receiving TARE and BEV plus ATEZO treatment, using patient-reported outcomes. Eligible pts have either HCC that is not amenable to surgical resection, confirmed by pathology review, or at least BCLC stage B HCC outside of downstaging criteria. Other standard eligibility criteria apply. Pts must have a pretreatment liver biopsy taken and then be randomized 1:1 to TARE (Arm A) or TARE followed by ATEZO and BEV (Arm B). Pts will have TARE mapping during week (wk) 1 and TARE treatment during wk 2. In Arm B, pts will start BEV plus ATEZO 4 wks (±1 wk) after TARE treatment. Pts will have abdominal MRI or CT scans every 12 weeks, CT scans of the chest every 24 wks. Disease progression will be captured by both RECIST 1.1 and mRECIST. We plan to assess the safety of TARE with BEV and ATEZO in the first 10 pts randomized to Arm B for two cycles. If there are no Grade ≥ 3 unexpected toxicities possibly, probably or definitely related to combined TARE plus BEV plus ATEZO, the study will continue to accrue 128 pts in total. Pts will continue study treatment (Arm B) for a total of 24 months from initiation of TARE or until intolerable toxicity or disease progression occur, whichever is earlier. Clinical trial information: NCT04541173 .

Objective Compression of the left renal vein by the superior mesenteric artery, known as nutcracker phenomenon (NCP), can cause retrograde flow and congestion in communicating venous systems. It has recently been speculated that NCP can result in retrograde flow and congestion of the lumbar veins and epidural venous plexus (EVP), thereby affecting the central nervous system. This study describes the novel use of time-resolved magnetic resonance angiography (trMRA) to evaluate for retrograde left second lumbar vein (L2LV) flow and early EVP enhancement in patients with chronic daily headache (CDH) with and without NCP. Methods A retrospective analysis was performed of 31 patients with CDH (27 females and 4 males; median age, 38 years [range, 18–63 years]) who underwent trMRA centered over the L2LV to evaluate the direction of blood flow and presence of early EVP enhancement from May 2020 to March 2022. Descriptive statistics were performed, and anatomic associations were analyzed in patients with and without retrograde L2LV flow and early EVP enhancement. The accuracy of magnetic resonance imaging findings in detecting these flow patterns was also assessed. Results Patients with NCP who demonstrated narrowing of the left renal vein, a positive beak sign (P = 0.052), decreased aortomesenteric distance (P = 0.038), and decreased SMA angle demonstrated increased rates of retrograde L2LV flow and early EVP enhancement. A positive beak sign was 83% specific, and an aortomesenteric distance of ≤6.5 mm was 61% sensitive and 83% specific for identifying retrograde L2LV flow with early regional EVP enhancement in patients with CDH. Conclusions Retrograde L2LV flow with early EVP enhancement in CDH patients can be effectively evaluated using trMRA and was seen with greater propensity in those patients with NCP.

AbstractObjectiveTo describe the embolization technique and short‐term clinical outcome in dogs undergoing lymphatic embolization (LE) as part of treatment for presumptive idiopathic chylothorax (IC). Additionally, to document findings in computed tomography lymphangiography (CTLa) following embolization.Study designProspective case series.AnimalsEight client‐owned dogs.MethodsDogs underwent CTLa followed by thoracic duct ligation (TDL), pericardiectomy (PC) and LE. A mixture of 3:1 lipiodol: n‐butyl cyanoacrylate embolic solution was injected through a catheterized mesenteric lymphatic vessel via limited abdominal approach using intraoperative fluoroscopy. CTLa was scheduled for 12 weeks postoperatively, and long‐term follow‐up was obtained via telephone contact.ResultsLE was technically successful in six of the eight dogs; and clinically successful in five of the six dogs. In the unsuccessful dog, a diagnosis of lymphangiosarcoma was determined, and the owners elected for euthanasia. Five dogs who underwent successful LE underwent CTLa at 12 weeks. Complete resolution of pleural effusion occurred in three dogs and scant pleural effusion in two dogs. A robust lymphatic embolus preventing antegrade continuation of radiocontrast was documented in all five dogs. Five of the six dogs that underwent LE, were alive and clinically normal at 358–960 days postoperatively.ConclusionsLE is a feasible part of treatment for dogs with IC. Additionally, a robust lymphatic embolus and lack of radiocontrast flow past the embolus was documented at 12 weeks following surgery.Clinical significanceLE has the potential to reduce surgical failure by reducing efferent lymphatic chyle flow, occluding missed lymphatic branches and preventing the development of collateral branches.

TPS4177 Background: The anti–PD-L1 antibody atezolizumab (ATEZO) prevents PD-L1 from interacting with PD-1 and B7.1, thus reinvigorating antitumor T cell activity. Anti-VEGF bevacizumab (BEV) increases dendritic cell maturation, enhances T cell infiltration, and reduces myeloid-derived suppressor cells and regulatory T cells in tumors. ATEZO + BEV is FDA approved for first-line treatment of advanced HCC based on the IMbrave 150 study. Locoregional radiotherapy (e.g., Y90 TARE) enhances the diversity of the intratumoral T cell receptor repertoire and increases tumor antigen release. We hypothesize that the Y90 TARE + BEV + ATEZO combination induces synergistic tumor killing and prolongs progression-free survival in patients (pts) receiving Y90 TARE (HR = 0.6 when compared to Y-90 TARE alone). Methods: Eligible pts have HCC that cannot be surgically resected (confirmed by pathology review), is at least BCLC stage B, and is outside Milan criteria. Other requirements include ECOG PS of 0-1 at screening, measurable disease by RECIST 1.1, no prior systemic therapy, and FLR estimated at ≥ 40% post local therapy. Pts must have a pretreatment liver biopsy taken and then be randomized 1:1 to TARE (Arm A) or TARE + ATEZO + BEV (Arm B). Pts will have TARE mapping followed by TARE treatment. In Arm B, pts will begin TARE treatment followed by BEV + ATEZO (4 wks [± 1 wk] later). Pts will have abdominal MRI or CT scans every 12 weeks and CT scans of the chest every 24 wks. The primary study objective is to assess and compare pts' progression-free survival (per mRECIST 1.1) in each study arm. The main secondary objective is to determine the safety and tolerability (CTCAE v5) of pts in Arm B. Exploratory objectives are to define the use of cellular and circulating biomarkers in the prediction of improved clinical outcomes of pts in Arm B. Symptoms experienced by pts in both arms using patient-reported outcomes will be assessed. Disease progression will be captured by both RECIST 1.1 and mRECIST. We plan to assess the safety of Y90 TARE + BEV + ATEZO in the first 10 pts randomized to Arm B for two cycles, and if there are no grade ≥ 3 unexpected toxicities possibly, probably, or definitely related to combined TARE + BEV + ATEZO, continue to accrue 128 pts in total (current enrollment n- = 5). Pts will continue study treatment (Arm B) for a total of 24 months from initiation of TARE or until intolerable toxicity or disease progression occur, whichever is earlier. Enrollment began in September 2020. Clinical trial information: NCT04541173.

e16124 Background: Immune checkpoint inhibitors (ICI) have emerged as a standard treatment option for advanced hepatocellular carcinoma (HCC). Unfortunately, many patients with advanced HCC develop progressive disease on ICI therapy. Furthermore, clinical predictors of response to ICI therapy in HCC are poorly understood. B-catenin mutations are among the most frequent genetic abnormalities in HCC and may provide a mechanism for immune evasion and poor response to ICI (Ruiz de Galarreta, Marina et al. “β-Catenin Activation Promotes Immune Escape and Resistance to Anti-PD-1 Therapy in Hepatocellular Carcinoma.” Cancer discovery 9,8 (2019): 1124-1141. doi:10.1158/2159-8290.CD-19-0074). Methods: We conducted a retrospective cohort study of patients with advanced HCC who were treated with ICI therapy. All patients had ctDNA tumor profiling and were assessed for B-catenin mutation status. Disease status was determined by RECISTv1.1. Median progression-free survival (PFS), 3-month PFS, 6-month PFS, and the disease control rate (DCR) on ICI therapy were compared between B-catenin mutation (BCM) and B-catenin wild-type (BCWT) groups. Results: 15 stage III/IV HCC patients were included in the study. 9 patients harbored BCMs and 6 patients were BCWT. The median PFS in patients with BCM HCC was 4.0 months versus 4.9 months in patients with BCWT HCC. At 3 months, PFS was 56% for BCM HCC compared to 67% for BCWT HCC. Furthermore, the 6-month PFS was 11% for BCM HCC and 50% for BCWT HCC. For best response, 33% of patients with BCM HCC achieved stable disease compared to 67% of patients with BCWT HCC. No patients in our cohort achieved partial or complete response. The DCR for BCM HCC was 33% and the DCR for BCWT HCC was 67%. Conclusions: In patients with advanced HCC, B-catenin mutation status may serve as a potential biomarker of response to ICI therapy. Our data suggests that patients who do not harbor these mutations, have a more durable response to ICI therapy. Further studies are needed to validate these findings.