Intraoperative Near-Infrared Imaging of Surgical Wounds after Tumor Resections Can Detect Residual Disease

Abstract

Background Surgical resection remains the most effective therapy for solid tumors worldwide. The most important prognostic indicator for cure following cancer surgery is a complete resection with no residual disease. However, intraoperative detection of retained cancer cells after surgery is challenging, and residual disease continues to be the most common cause of local failure. We hypothesized visual enhancement of tumors using near-infrared imaging could potentially identify tumor deposits in the wound after resection. Methods A small animal model of surgery and retained disease was developed. Residual tumor deposits in the wound were targeted using an FDA approved imaging agent, indocyanine green, by the enhanced permeability and retention (EPR) effect. A novel hand-held spectrometer was used to optically visualize retained disease after surgery. Results We found residual disease using near-infrared imaging during surgery that was not visible to the naked eye or microCT. Furthermore, examination of tumor nodules was remarkably precise in delineating margins from normal surrounding tissues. This approach was most successful for tumors with increased neovasculature. Conclusions The results suggest that near-infrared examination of the surgical wound after curative resection can potentially enable the surgeon to locate residual disease. The data in this study is the basis of an ongoing Phase I/II clinical trial in patients who undergo resection for lung and breast cancer.

Intraoperative near-infrared fluorescence imaging and spectroscopy identifies residual tumor cells in wounds

“…The numbers we chose were based on preclinical studies, which suggest doses upward of 3 to 5 mg∕kg provide superior tissue contrast. 6 Third, the dynamic range of our measurements was compromised due to saturation of the NIR fluorescence intensity; this effect was especially significant when probing tissues from the tumor core. These saturation effects prevented accurate characterization of the decay of the fluorescence signal from the core to the tumor margins, and they likely led to an underestimation of tumor contrast in the margins.…”

“…4 To ameliorate these issues, we and others have surmised that image guided surgery using intraoperative NIR imaging and spectroscopy of tumor cells could play a major role identifying cancer in the surgical margins. 1,5,6 NIR optical imaging and spectroscopy have the potential to image tumors intraoperatively using both endogenous (oxy-and deoxyhemoglobin, blood flow) and exogenous [indocyanine green (ICG), quantum dots] contrast. NIR methods have several advantages over traditional techniques: they employ relatively simple instrumentation which is portable [compared to magnetic resonance imaging (MRI)/positron emission tomography (PET)]; they do not require ionizing radiation (compared to radiographs); they can have good sensitivity by employing readily available optical contrast agents; and they are cost effective.…”

“…The long-range goal of the present investigation is to improve detection of residual cancer cells in the wound bed "after surgical resection" of tumors 1,6 by providing quantitative visualization of microscopic disease that is easily missed by the eye. A secondary long-term goal of this research is to use NIR fluorescence imaging to discern the tumor margin and hence identify a surgical margin.…”

“…Although tumor ICG uptake is nonspecific, the dosages and time-from-injection provided excellent tumor-to-background contrast due to enhanced permeability and retention effects. 6 Tumor and surgical margins were derived using NIR fluorescence contrast, and after standard-of-care sarcoma resection, NIR fluorescence contrast helped to detect residual tumor cells in the surgical bed that would have been missed.…”

Intraoperative molecular imaging to identify lung adenocarcinomas

“…We demonstrated in pre-clinical studies in mice and canines that fluorescent NIR imaging with ICG is effective at identifying residual disease in a surgical wound that is not visible to the naked eye and that delineation of tumor margins is very precise using this technology (26). In our first experiment, an experienced independent surgeon examined the wound bed of mice status post incomplete resections of flank tumors by visual inspection and finger palpation.…”