Estimating Tumor Boundaries in Cancer Surgery With Fluorescence Lifetime Imaging

Gary Boas

Cancer is the second leading cause of death in the United States, with an estimated 1,762,450 new cases diagnosed and 606,880 deaths in 2019 alone. While important advances have been made in the development of treatments for cancer, including surgery, a number of challenges remain. Not least: surgeons still lack tools that can clearly delineate tumors from normal tissue during tumor resection. In current practice, surgeons estimate tumor boundaries using palpation and visual inspection, but this approach often results in incomplete removal, leading to disease recurrence and repeat surgeries.

Now, the Martinos Center’s Rahul Pal and Anand T.N. Kumar and colleagues have developed an optical imaging method that can address this challenge using fluorescence lifetime-based tumor contrast enhancement. They reported the method in a Clinical Cancer Research paper recently published online.

Establishing tumor boundaries during resection is a major area of interest. In recent years, researchers have been exploring ways to label tumors with fluorescent molecules so they can better highlight the boundaries. One of the approaches they have devised is to target specific ‘receptors’ – called EGFR receptors – on the cancer cells. EGFR is overexpressed in many cancers and thus offers a means to distinguish between tumors and surrounding healthy tissue using fluorescence imaging techniques. But any gains with this approach are mitigated by the fact that EGFR is also expressed in the healthy tissue, creating background fluorescence and thereby reducing the overall contrast between the two.

The Martinos-based team tackled this problem by visualizing the ‘fluorescence lifetimes’ of the molecules: that is, the average time it takes for the molecules to return to a normal state (typically in the range of nanoseconds) following excitation with pulses of laser light. The conventional optical imaging methods used in previous studies rely on continuous-wave excitation – essentially a beam of light with constant amplitude and frequency – and consequently do not have access to this information.

The advantages of using fluorescence lifetimes for better delineation of tumor boundaries were made manifest in the Clinical Cancer Research study. Not only did the researchers demonstrate, for the first time, that EGFR-overexpressing tumors exhibit a unique fluorescence lifetime, they also showed that the fluorescence lifetimes of tumors labeled with EGFR antibodies are considerably longer than those of muscle tissue and liver with nonspecific uptake of the probe. This greater distinction between the two offers a unique opportunity for cancer surgery, namely because it “provides dramatic improvement in the accuracy of tumor detection using existing cancer-targeted dyes that are in clinical trials, while also potentially offering an absolute measure of tumor vs normal tissue that can help in standardization across multiple image-guided surgery systems,” says Kumar, Director of the Optical Imaging Laboratory at the Martinos Center and senior author of the Clinical Cancer Research paper.

Having demonstrated the potential of the approach, the researchers are now developing it further for clinical use. To this end, they are pursuing two clinical studies to apply the technology for cancer surgery. In the first, they are exploring its use for comprehensive margin assessment in specimens resected from patients undergoing surgery: an important unmet need, especially as pathology is slow and not always comprehensive in establishing tumor boundaries. If this study proves successful, they will build intraoperative image guidance systems capable of exploiting lifetime contrast of targeted probes in tumors. Once validated for intraoperative imaging, these systems will provide a tool for better estimating tumor boundaries and thus could help in improving outcomes in cancer surgery.