Lighting Up Surgery and Immunotherapy

Cancer surgery is well over a thousand years old, and surgical techniques have evolved dramatically in the last few decades. Despite many advances in terms of technique and technology, surgery is still in the “Dark Ages” in some respects. Among the more serious limitations is the surgeon’s inability to clearly see the margins or periphery of a tumor. Cancer cells are microscopic, i.e., impossible to see with the naked eye. Tumors send out microscopic tendrils of cancer that are frequently missed in the standard approach to surgery.

Moreover, the inability to remove those wayward cells and tiny tendrils can lead to more serious problems later on. When surgeons cut into the tissue to remove a tumor, the resulting inflammation around the surgical margin can cause these residual cancer cells to proliferate, eventually causing a recurrence that is more aggressive and more difficult to treat than the cancer found in the original diagnosis.

One of the breakthroughs that has yet to be fully integrated into surgical practice is the use of fluorescence. The approach called fluorescence-guided surgery, or FGS, enables the surgeon to more fully visualize the tumor and its tendrils. This, in turn, may not only increase the chances of a more complete removal of the cancer, but also may prevent or minimize damage to normal tissues, which generally do not fluoresce or light up.

In FGS, a fluorescent probe (dye or photosensitizer) is applied and becomes concentrated in the tumor but not in the normal surrounding tissues. An external light source then illuminates the surgical area, and the tumor and its tendrils are revealed through the magic of fluorescence. The cancer literally lights up, enabling the surgeon to accurately see how much tissue to be removed.


Reviewing the Evidence

Surgery researchers from the University of California San Diego (USA) recently reviewed the scientific literature on new strategies for using FGS for the treatment of various cancers. They describe the approach as offering a much better chance for “curative surgery” in which not only the tumor but also nearby metastatic cells are eliminated. In some cases, the methods used to visualize the cancer can also serve to help eliminate the residual cancer cells that lie in the vicinity of the primary tumor. (One such approach, called Photoimmunotherapy, is described below.)

“Techniques in fluorescence-guided surgery are emerging that selectively illuminate cancer cells, enhancing the distinction between tumors and surrounding tissues with the potential for single-cell sensitivity,” the authors write in Expert Reviews in Anticancer Therapy. “FGS enhances tumor detection….and in some cases can be combined with therapeutic techniques to eliminate microscopic disease….The ability of the surgeon to accurately visualize tumor margins and identify metastases is necessary for the success of any cancer operation.”

In their report, the San Diego scientists go on to describe new developments and various applications of FGS that have already been used clinically. For example, they note that surgeons are now routinely using fluorescence for imaging bile ducts during surgeries involving the liver and gall bladder. They’re also using these light-based methods to assess the GI tract during colorectal and esophageal surgeries.

Moreover, several recent clinical studies indicate that FGS may be useful for cancers of the ovaries, lung, and head and neck region. Because of its high sensitivity, low cost, portability and real-time capabilities, FGS has excellent potential to improve the short- and long-range outcomes of cancer surgery.


The Photoimmune Advantage

Another exciting FGS-related advance, as mentioned above, is a technique termed photoimmunotherapy (PIT). As with other approaches described above, PIT has the dual ability to localize tumors and facilitate the surgeon’s ability to navigate around the surgical area, again finding and removing “invisible” tendrils of the tumor.

The ability to selectively eliminate cancer cells far from the tumor is perhaps PIT’s greatest advantage. To accomplish this feat, PIT uses an antibody technique commonly known as monoclonal antibodies. These are immune proteins that specifically bind to known proteins or “markers” that serve as identity cards or passports on tumors. The antibodies also bind to the photosensitizer that has been taken up by the cancer cell.

Upon exposure to near-infrared light, the entire antibody-marker- photosensitizer complex becomes toxic to cancer cells and tumors. This effect of PIT has been shown to result in extensive death of those tumor cells known to express the particular marker.  In one laboratory study, for example, a one-time treatment with PIT resulted in a significant shrinking of pancreatic tumors.

Other studies of aggressive pancreatic tumors have shown significant reductions in recurrences and metastases.   When FGS was combined with PIT, the local recurrence rate for experimental pancreatic cancer dropped from 86% to 29%. These findings were reported in the December 2015 Annals of Surgical Oncology.

“Future studies could use with PIT, which may lower local recurrence even further,” the San Diego scientists note. “Additionally, serial PIT treatments could be studied to establish a more effective regimen.” In other words, with repeated or sequential PIT sessions, even better outcomes can be achieved in terms of lowering recurrences and increasing survival. This is a tremendous advantage of light-based therapies in general—the ability to treat repeatedly without incurring a great deal of treatment-related toxicities.

The ability to define cancer markers or “targets” for PIT continues to evolve. As new techniques emerge, the San Diego researchers say, we seem to be moving ever closer toward the ideal of “personalized surgical therapy.” In the future, FGS will be personally designed for each cancer patient’s specific disease.

“Our ‘one-size-fits-all’ solutions will be replaced with ‘precision medicine,’ tailoring treatments to an individual’s unique disease process,” the authors write. “Fluorescence imaging systems will likely become commonplace in the operating rooms on standard laparoscopic imaging systems or as an adjunct for open surgical cases… Every cancer surgery should be fluorescence-guided in the near future.”



DeLong JC, Hoffman RM, Bouvet M. Current status and future perspectives of fluorescence-guided surgery for cancer. Expert Rev Anticancer Ther. 2016 Jan;16(1):71-81.

Hiroshima Y, Maawy A, Zhang Y, Guzman MG, Heim R, Makings L, Luiken GA, Kobayashi H, Tanaka K, Endo I, Hoffman RM, Bouvet M. Photoimmunotherapy Inhibits Tumor Recurrence After Surgical Resection on a Pancreatic Cancer Patient-Derived Orthotopic Xenograft (PDOX) Nude Mouse Model. Ann Surg Oncol. 2015 Dec;22 Suppl 3:1469-74.

Allison RR. Fluorescence guided resection (FGR): A primer for oncology. Photodiagnosis Photodyn Ther. 2015 Nov 28. [Epub ahead of print]