PURPOSE The EXTEND trial tested the hypothesis that adding comprehensive metastasis-directed therapy (MDT) to chemotherapy would improve progression-free survival (PFS) over chemotherapy alone among ...patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC). METHODS EXTEND (ClinicalTrials.gov identifier: NCT03599765 ) is a multicenter, phase II basket trial randomly assigning patients with ≤five metastases 1:1 to MDT plus systemic therapy versus systemic therapy. Disease progression was defined by radiologic criteria (RECIST v1.1), clinical progression, or death. The primary end point was PFS in the per-protocol population, evaluated after all patients achieved at least 6 months of follow-up. Exploratory end points included systemic immune response measures. RESULTS Between March 19, 2019, and February 13, 2023, 41 patients were randomly assigned and 40 were eligible for the primary analysis of PFS (19 patients in the MDT arm; 21 patients in the control arm). At a median follow-up time of 17 months, the median PFS time was 10.3 months (95% CI, 4.6 to 14.0) in the MDT arm versus 2.5 months (95% CI, 1.7 to 5.1) in the control arm. PFS was significantly improved by the addition of MDT to systemic therapy ( P = .030 for stratified log-rank test) with a hazard ratio of 0.43 (95% CI, 0.20 to 0.94). No grade ≥3 or greater adverse events related to MDT were observed. Systemic immune activation events were associated with MDT and correlated with improved PFS. CONCLUSION This study supports the addition of MDT to systemic therapy for patients with oligometastatic PDAC. Induction of systemic immunity is a possible mechanism of benefit. These results warrant confirmatory trials to refine treatment strategy and provide external validation.
Entamoeba histolytica is an intestinal parasite that causes dysentery and amebic liver abscess. E. histolytica has the capability to invade host tissue by union of virulence factor Gal/GalNAc lectin; ...this molecule induces an adherence-inhibitory antibody response as well as to protect against amebic liver abscess (ALA). The present work showed the effect of the immunization with PEΔIII-LC3-KDEL3 recombinant protein. In vitro, this candidate vaccine inhibited adherence of E. histolytica trophozoites to HepG2 cell monolayer, avoiding the cytolysis, and in a hamster model, we observed a vaccine-induced protection against the damage to tissue liver and the inhibition of uncontrolled inflammation. PEΔIII-LC3-KDEL3 reduced the expression of TNF-α, IL-1β, and NF-κB in all immunized groups at 4- and 7-day postinfection. The levels of IL-10, FOXP3, and IFN-γ were elevated at 7 days. The immunohistochemistry assay confirmed this result, revealing an elevated quantity of +IFN-γ cells in the liver tissue. ALA formation in hamsters immunized was minimal, and few trophozoites were identified. Hence, immunization with PEΔIII-LC3-KDEL3 herein prevented invasive amebiasis, avoided an acute proinflammatory response, and activated a protective response within a short time. Finally, this recombinant protein induced an increase of serum IgG.
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Background: Standard treatment of oligometastatic pancreatic ductal adenocarcinoma (PDAC) consists of multi-agent chemotherapy, although outcomes remain poor. We tested the hypothesis that the ...addition of comprehensive metastasis-directed therapy (MDT) to standard-of-care systemic therapy would improve progression-free survival (PFS) compared with systemic therapy alone. Methods: The External Beam Radiation to Eliminate Nominal Metastatic Disease (EXTEND) trial is a multicenter phase II basket trial randomizing patients with ≤ 5 solid tumor metastases 1:1 to MDT plus systemic therapy versus systemic therapy alone. Each histology-specific basket was pre-specified and independently powered for the primary endpoint of PFS; here we present results of the pancreatic cancer basket. Progression was defined by radiographic criteria (RECIST v1.1), clinical events, or death. Patients were stratified at randomization by number of metastases (1-2 vs 3-5), number of prior lines of systemic therapy (0-1 vs 2+), and cancer antigen 19-9 (CA-19-9) level (<90U/ml vs ≥90U/ml). Exploratory endpoints included systemic immune response measures. The cutoff date for the primary analysis was September 1, 2023. ClinicalTrials.gov registration: NCT03599765. Results: Between March 2019 and February 2023, 41 patients with oligometastatic PDAC were randomized and 40 were eligible for PFS analysis (MDT arm: 19 patients; control arm: 21 patients). Baseline characteristics were well-balanced between arms. Thirty-one patients experienced progression or death; median follow-up time for censored patients was 9.9 months. The MDT arm had significantly longer PFS compared to the systemic therapy arm (median PFS 10.3 versus 2.5 months; log-rank p=0.006). After stratification, the estimated PFS hazard ratio was 0.43 (95% confidence interval: 0.20, 0.94; p=0.03) for MDT compared with systemic therapy. There were no grade 3 or greater adverse events with at least possible attribution to MDT, and only one grade 2 adverse event possibly related to treatment in the MDT arm occurred. Increased systemic T-cell stimulatory cytokines, CD8
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T-cell activation, CD8
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T-cell proliferation, and T-cell receptor clonal expansion following treatment were associated with the MDT arm compared with the control arm (all p<0.05). Conclusions: Among patients with oligometastatic PDAC, the combination of MDT plus systemic therapy was associated with improved PFS compared with systemic therapy alone. Further exploration in phase III trials is warranted, as is investigation into the potential therapeutic implications of systemic immune activation associated with MDT receipt. Clinical trial information: NCT03599765 .
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