Multimodal CEA-targeted fluorescence and radioguided cytoreductive surgery for peritoneal metastases of colorectal origin

Abstract

In patients with colorectal peritoneal metastases scheduled for cytoreductive surgery, accurate preoperative estimation of tumor burden and subsequent intraoperative detection of all tumor deposits remains challenging. In this study (ClinicalTrials.gov NCT03699332) we describe the results of a phase I clinical trial evaluating [¹¹¹In]In-DOTA-labetuzumab-IRDye800CW, a dual-labeled anti-carcinoembryonic antigen (anti-CEA) antibody conjugate that enables both preoperative imaging and intraoperative radioguidance and fluorescence imaging. Primary study outcomes are safety and feasibility of this multimodal imaging approach. Secondary outcomes are determination of the optimal dose, correlation between tracer uptake and histopathology and effects on clinical strategy. Administration of [¹¹¹In]In-DOTA-labetuzumab-IRDye800CW is well-tolerated and enables sensitive pre- and intraoperative imaging in patients who receive 10 or 50 mg of the tracer. Preoperative imaging revealed previously undetected lymph node metastases in one patient, and intraoperative fluorescence imaging revealed four previously undetected metastases in two patients. Alteration of clinical strategy based on multimodal imaging occurred in three patients. Thus, multimodal image-guided surgery after administration of this dual-labeled tracer is a promising approach that may aid in decision making before and during cytoreductive surgical procedures.

Fig. 1. Multi-modal imaging of previously undetected colorectal lymph node metastases.

a (patient #7) Coronal section of preoperative CEA-targeted SPECT/CT images show accumulation of [¹¹¹In]In-DOTA-labetuzumab-IRDye800CW in retroperitoneal para-aortocaval (blue arrow) and left supraclavicular lymph nodes (green arrow). b Transversal section of retroperitoneal lymph nodes (blue arrow). c Intraoperative bright field, d NIR-fluorescence and e NIR-fluorescence overlay view of corresponding retroperitoneal lymph nodes show clear uptake of the tracer, corresponding with preoperative SPECT/CT imaging.

Fig. 2. In-vivo fluorescence imaging of peritoneal metastases and a primary tumor.

a Small fluorescent hotspots in the pouch of Douglas of patient #9. b Intraoperative imaging after resection of suspected tissue reveals fluorescence signal in a small residual lesion of patient #6. c Fluorescence signal from a primary sigmoid tumor of patient #14. All fluorescent lesions were confirmed to contain CEA-expressing colorectal cancer cells on histopathological analysis.

Fig. 3. Ex-vivo radiosignal and NIR-fluorescence based tumor to background ratios.

a Ex-vivo radiosignal tumor to background ratios; radiosignal based tumor-to-background ratios based on back table gamma probe measurements is shown at all 3 dose levels. b Ex-vivo fluorescence tumor to background ratios, the NIR-fluorescence tumor to background ratios based on micropscopic NIR-fluorescence measurements of tissue sections is shown. The panels have also been described in the results section under the header: Back table and pathological analysis. Dose level 2 mg n = 4 subjects, 10 mg n = 5 subjects and 50 mg n = 5 subjects. Differences between TBR were not significant for both the radiosignal (p = 0.2) and the fluorescent signal (p = 0.1) (one-way ANOVA testing with post-hoc Bonferroni correction). Source data are provided as a Source Data file.

Fig. 4. Intraoperative fluorescence detection of previously undetected peritoneal metastases.

(patient #15): Top row: Intraoperative NIR-fluorescence imaging of the right abdominal wall after cytoreductive surgery reveals two fluorescent lesions (b, c) not visible during standard visual inspection (a). Bottom row: pathological assessment of one of these lesions shows a CEA-expressing submillimeter tumor deposit on H&E (c) and CEA (d) immunohistochemistry that correlates with a strong fluorescence signal (f). Correlation between NIR-fluorescence and immunohistochemistry was performed on 2 or more different tissue sections for each independent case.