An open label trial of folate receptor-targeted intraoperative molecular imaging to localize pulmonary squamous cell carcinomas

Abstract

BackgroundClinical applicability of folate receptor-targeted intraoperative molecular imaging (FR-IMI) has been established for surgically resectable pulmonary adenocarcinoma. A role for FR-IMI in other lung cancer histologies has not been studied. In this study, we evaluate feasibility of FR-IMI in patients undergoing pulmonary resection for squamous cell carcinomas (SCCs).MethodsIn a human clinical trial (NCT02602119), twelve subjects with pulmonary SCCs underwent FR-IMI with a near-infrared contrast agent that targets the folate receptor-α (FRα), OTL38. Near-infrared signal from tumors and benign lung was quantified to calculate tumor-to-background ratios (TBR). Folate receptor-alpha expression was characterized, and histopathologic correlative analyses were performed to evaluate patterns of OTL38 accumulation. An exploratory analysis was performed to determine patient and histopathologic variables that predict tumor fluorescence.Results9 of 13 SCCs (in 9 of 12 of subjects) displayed intraoperative fluorescence upon NIR evaluation (median TBR, 3.9). OTL38 accumulated within SCCs in a FRα-dependent manner. FR-IMI was reliable in localizing nodules as small as 1.1 cm, and prevented conversion to thoracotomy for nodule localization in three subjects. Upon evaluation of patient and histopathologic variables, in situ fluorescence was associated with distance from the pleural surface, and was independent of alternative variables including tumor size and metabolic activity.ConclusionsThis work demonstrates that FR-IMI is potentially feasible in 70% of SCC patients, and that molecular imaging can improve localization during minimally invasive pulmonary resection. These findings complement previous data demonstrating that ∼98% of pulmonary adenocarcinomas are localized during FR-IMI and suggest broad applicability for NSCLC patients undergoing resection.

Optimization of Second Window Indocyanine Green for Intraoperative Near-Infrared Imaging of Thoracic Malignancy

“…A TBR≥2.0 was considered positive for fluorescence based on previous studies using this as a cutoff for fluorescence with this imaging system. (16)(17)(18) Background fluorescence from the heart or ribs in situ was defined as any perceptible fluorescent signal from the heart or ribs at the gain that produced optimal contrast between tumor and adjacent normal tissue or 100% gain if there was no tumor fluorescence. The percentages of cases with tumor and background heart or rib fluorescence stratified by histology and ICG dose were compared by the Fisher exact test.…”

Emerging Fluorescent Molecular Tracers to Guide Intra-Operative Surgical Decision-Making

“…Additional clinical studies with both tracers have since been performed in lung, ovarian, and renal cancer. The surgical procedure is generally performed between 2 and 6 h post-injection of either tracer (Hoogstins et al, 2016; Keating et al, 2017; Mahalingam et al, 2018b; Predina et al, 2018).…”

Intraoperative fluorescence imaging in thoracic surgery

“…We hypothesized that fluorescent nonpulmonary adenocarcinoma nodules have low level FRα expression or accumulation of tumor‐associated macrophages, which express folate receptor‐beta . In a follow‐up study of IFI with OTL38 for pulmonary squamous cell carcinomas, approximately 70% (9/13) of nodules accumulated OTL38 . All 9 nodules had FRα expression, albeit at low levels in 4 patients, suggesting that low levels of FRα expression are sufficient for identification with OTL38.…”