Image-guided cancer surgery using near-infrared fluorescence

Abstract

Paradigm shifts in surgery arise when surgeons are empowered to perform surgery faster, better and less expensively than current standards. Optical imaging that exploits invisible near-infrared (NIR) fluorescent light (700-900 nm) has the potential to improve cancer surgery outcomes, minimize the time patients are under anaesthesia and lower health-care costs largely by way of its improved contrast and depth of tissue penetration relative to visible light. Accordingly, the past few years have witnessed an explosion of proof-of-concept clinical trials in the field. In this Review, we introduce the concept of NIR fluorescence imaging for cancer surgery, examine the clinical trial literature to date and outline the key issues pertaining to imaging system and contrast agent optimization. Although NIR seems to be superior to many traditional imaging techniques, its incorporation into routine care of patients with cancer depends on rigorous clinical trials and validation studies.

Conflict of interest statement

Financial Declaration

FLARE™ technology is owned by Beth Israel Deaconess Medical Center, a teaching hospital of Harvard Medical School. It has been licensed to the FLARE Foundation, a non-profit organization focused on promoting the dissemination of medical imaging technology for research and clinical use. Dr. Frangioni is the founder and chairman of the FLARE™ Foundation. The Beth Israel Deaconess Medical Center will receive royalties for sale of FLARE™ Technology. Dr. Frangioni has elected to surrender post-market royalties to which he would otherwise be entitled as inventor, and has elected to donate pre-market proceeds to the FLARE Foundation. Dr. Frangioni has started three for-profit companies, Curadel, Curadel ResVet Imaging, and Curadel Surgical Innovations, which may someday be non-exclusive sub-licensees of FLARE™ technology.

Figures

Figure 1. The mechanics of NIR fluorescence imaging

A NIR fluorescent contrast agent is administered intravenously, topically, or intraparenchymally. During surgery, the agent is visualized using a NIR fluorescence imaging system of the desired form factor, i.e., above the surgical field for open surgery or encased within a fiberscope for minimally-invasive and robotic surgery (open surgery form factor shown). All systems must have adequate NIR excitation light, collection optics and filtration, and a camera sensitive to NIR fluorescence emission light. An optimal imaging system includes simultaneous visible (i.e., white) light illumination of the surgical field, which can be merged with NIR fluorescence images. The surgeon display can be one of several forms factors including a standard computer monitor, goggles, or a wall projector (monitor form factor shown). Current imaging systems operate at a sufficient working distance that enables the surgeon to operate and illuminates a sizable surgical field.

Figure 2. Examples of intraoperative NIR fluorescence imaging

a. Example of SLN mapping using NIR fluorescence imaging in a patient with cutaneous melanoma. Displayed are the color images (left), NIR fluorescence images (middle), and pseudocolored (NIR fluorescence in lime green) merges of the two (right). The lymphatic channel (arrowhead) and SLNs (arrows) can be clearly identified percutaneously and in real-time (top panel). Identification of a SLN (bottom panel) is demonstrated using 800 nm NIR fluorescence imaging 15 min after injection of 1.6 mL of 1000 μM ICG admixed with human serum albumin around the tumor. All images were acquired in real time using the mini-FLARE imaging system. NIR excitation fluence rate was approximately 8 mW/cm2 and camera exposure time was 10 ms. Scale bars represent 1 cm. Reproduced with permission. b. Example of NIR fluorescence imaging of the ureter during lower abdominal surgery in a patient with ovarian carcinoma. Intraoperative imaging of the ureter (arrow), 45 min after administration of 1 mg/kg methylene blue. Displayed are the color images (left), 700 nm NIR fluorescence images (middle), and a pseudocolored (NIR fluorescence in lime green) merge of the two (right) acquired with the mini-FLARE imaging system. NIR excitation fluence rate was approximately 1 mW/cm2 and camera exposure time was 150 ms. Scale bars represent 1 cm. Reproduced with permission. c. Example of fluorescence imaging in brain surgery during resection of a glioblastoma multiforme (+) using oral 5-ALA-induced PpIX. White light image (left), visible fluorescence (middle) and quantitative fluorescence images overlayed onto white light images (right) are displayed. Reproduced with permission.

Figure 3. Administration, Biodistribution, and Clearance of a NIR fluorescent contrast agent

Schematic (top row) and clinical example (middle row) of the four key phases of NIR fluorescence imaging after intravenous administration of a NIR fluorophore. Top-row: Shown from left-to-right are the different phases over time: first, a NIR fluorescent probe is administered. After intravenous administration, for example, NIR fluorescence signal is visualized in the vasculature (second panel). Then, the contrast agent is distributed to all tissues in the body (third panel) but the target remains obscured. After adequate clearance time (right panel), adequate contrast between target and surrounding tissue is achieved. Bottom-row: Left: administration of NIR fluorescent contrast agent. Second panel: ICG fluorescence as observed in the vasculature of an abdominal tissue flap to be used for breast reconstructive surgery. Third panel: ICG fluorescence distribution in the liver. Right panel: ICG clearance from the liver over time, revealing a metastatic colon cancer metastasis (arrow). Shown in all panels are pseudocolored (lime green) merges of NIR fluorescence and color video acquired using the mini-FLARE imaging system. Scale bars represent 1 cm. Bottom row: schematic of the four key phases of NIR fluorescence imaging after administration of 5-ALA. Shown from left to-right are the different phases over time: first, the non-fluorescent 5-ALA is orally administered (first panel). After uptake in the bloodstream via the gastrointestinal tract, the substance accumulates in tumor cells (second panel), where it is metabolized to the fluorescent protoporphyrin IX (third panel). After metabolism, tumor demarcation can be visualized using the inherent fluorescent properties of protoporphyrin IX (fourth panel).

Figure 4. NIR fluorescence imaging alone or in combination with other imaging modalities

Left panel: In this example, two superficially located targets, up to 5–8 mm deep, can be located using NIR fluorescence imaging. However, a deeper target at 25 mm would be invisible using by NIR fluorescence imaging alone. Middle panel: Combining NIR fluorescence imaging with radioscintigraphy enables visualization of all three targets. However, spatial and temporal resolution of radioscintigraphy is poor. Once overlying tissue is removed, as guided by radioscintigraphy, NIR fluorescence can be used for more precise image guidance (see also Figure 2). Right panel: Intraoperative ultrasound can visualize targets that are located deeper within tissue, but fails to find superficially located targets because of high acoustic reflectance. These superficial targets, though, can be visualized by NIR fluorescence thereby complementing intraoperative ultrasound. Of note, the ultrasound probe must be in direct contact with the tissue being imaged, thus precluding simultaneous imaging with NIR fluorescence.