Overview and Future Perspectives on Tumor-Targeted Positron Emission Tomography and Fluorescence Imaging of Pancreatic Cancer in the Era of Neoadjuvant Therapy

Abstract

Background: Despite recent advances in the multimodal treatment of pancreatic ductal adenocarcinoma (PDAC), overall survival remains poor with a 5-year cumulative survival of approximately 10%. Neoadjuvant (chemo- and/or radio-) therapy is increasingly incorporated in treatment strategies for patients with (borderline) resectable and locally advanced disease. Neoadjuvant therapy aims to improve radical resection rates by reducing tumor mass and (partial) encasement of important vascular structures, as well as eradicating occult micrometastases. Results from recent multicenter clinical trials evaluating this approach demonstrate prolonged survival and increased complete surgical resection rates (R0). Currently, tumor response to neoadjuvant therapy is monitored using computed tomography (CT) following the RECIST 1.1 criteria. Accurate assessment of neoadjuvant treatment response and tumor resectability is considered a major challenge, as current conventional imaging modalities provide limited accuracy and specificity for discrimination between necrosis, fibrosis, and remaining vital tumor tissue. As a consequence, resections with tumor-positive margins and subsequent early locoregional tumor recurrences are observed in a substantial number of patients following surgical resection with curative intent. Of these patients, up to 80% are diagnosed with recurrent disease after a median disease-free interval of merely 8 months. These numbers underline the urgent need to improve imaging modalities for more accurate assessment of therapy response and subsequent re-staging of disease, thereby aiming to optimize individual patient’s treatment strategy. In cases of curative intent resection, additional intra-operative real-time guidance could aid surgeons during complex procedures and potentially reduce the rate of incomplete resections and early (locoregional) tumor recurrences. In recent years intraoperative imaging in cancer has made a shift towards tumor-specific molecular targeting. Several important molecular targets have been identified that show overexpression in PDAC, for example: CA19.9, CEA, EGFR, VEGFR/VEGF-A, uPA/uPAR, and various integrins. Tumor-targeted PET/CT combined with intraoperative fluorescence imaging, could provide valuable information for tumor detection and staging, therapy response evaluation with re-staging of disease and intraoperative guidance during surgical resection of PDAC. Methods: A literature search in the PubMed database and (inter)national trial registers was conducted, focusing on studies published over the last 15 years. Data and information of eligible articles regarding PET/CT as well as fluorescence imaging in PDAC were reviewed. Areas covered: This review covers the current strategies, obstacles, challenges, and developments in targeted tumor imaging, focusing on the feasibility and value of PET/CT and fluorescence imaging for integration in the work-up and treatment of PDAC. An overview is given of identified targets and their characteristics, as well as the available literature of conducted and ongoing clinical and preclinical trials evaluating PDAC-targeted nuclear and fluorescent tracers.

Near-Infrared Fluorescence Imaging of Pancreatic Cancer Using a Fluorescently Labelled Anti-CEA Nanobody Probe: A Preclinical Study

“…It would also be useful to perform nuclear labeling, enabling nuclear imaging using for instance Positron Emission Tomography-Computed Tomography (PET-CT). An advantage of using CEA as a targeting moiety is that the CEA expression in PDAC is minimally affected by neoadjuvant chemoradiotherapy, making this tracer suitable for both intraoperative optical imaging and preoperative staging using PET-CT [ 10 , 29 ]. Patient selection could be performed based on elevated CEA levels as these are correlated to CEA expression profiles [ 30 ].…”

Imaging of pancreatic ductal adenocarcinoma – An update for all stages of patient management

“…Recent developments in molecular imaging provided potential biomarkers for response to neoadjuvant therapy evaluation, as well as improving diagnostic and staging accuracy, with encouraging results [123] . However, these require validation and thus cannot yet be recommended for clinical practice.…”

Molecular imaging of pancreatic ductal adenocarcinoma

“…Although PDAC is considered to be a hypovascular cancer type, angiogenesis is a necessary process to provide adequate nutrients and oxygen. 102 In the past few years, though a variety of antiangiogenic agents have failed in late-stage clinical trials of PDAC, 103 other vascular targeting approaches with the purpose of vascular normalization and tumor immunosensitization have shown promise in preclinical models. 104 ImmunoPET imaging targeting angiogenesis can specifically monitor the early effects of antiangiogenesis therapy.…”