Storming the Gates: Sentinel Lymph Node Targeting & Assessment

Intraoperative lymphatic mapping provides surgeons, oncologists and referring physicians with vital information about potential malignancy in the lymphatic system, especially that of sentinel lymph nodes—usually the first check point for the diasporas of metastatic cancer cells that drain from primary tumors. Patients have a better chance of avoiding the increased morbidity associated with extensive nodal dissection by undergoing a biopsy of the sentinel lymph nodes most likely to contain metastatic disease.

Modern lymphoscintigraphy involves lymph-node specific targeting for best-binding and clearance from injection site to the sentinel nodes. Research shows potential for use with fluorescence and other optical imaging techniques, which would eradicate the radiation dose associated with conventional radiopharmaceuticals. New agents seem to present a triple threat and better zero in on targets, accelerate injection clearance time and may reduce costs.

“During the last few years, the technical developments in the field of sentinel lymph node imaging have especially focused on the improvement of the imaging modalities by adding SPECT/CT, laparoscopic gamma probes, portable gamma cameras, navigation and fluorescence,” explains Fijs W.B. Van Leeuwen, PhD, associate professor of radiology at Leiden University Medical Center in Leiden, The Netherlands. “Lately, we have been focusing on the use of multimodal radiopharmaceuticals that allow for the integrated use of these complementary imaging modalities.”

Breaking with tradition

The long-standing mode of lymphatic mapping in the U.S. has been single or dual use of Tc-99m sulfur colloid and isosulfan blue dye, says Anne M. Wallace, MD, professor of clinical surgery and chief of plastic surgery at the University of California, San Diego (UCSD). Wallace is also team lead for the UCSD Moores Cancer Center’s breast cancer program.

“The majority of us use blue dye and radioactivity with technetium sulfur colloid,” she says. “An hour or an hour and a half later it still sits in the injection bed and doesn’t drain well.” After clearance of the radiopharmaceutical, clinicians often inject blue dye prior to surgical guidance so there is both “something hot and something blue,” she adds.

Newcomer Tc-99m tilmanocept, commonly referred to as Lymphoseek (Navidea), was approved by the FDA in March. Wallace has been instrumental in major U.S. clinical trials related to Lymphoseek, which has not yet been approved in Europe. Another lymph node targeting agent, Tc-99m nanocolloid, is the European gold standard of radiopharmaceuticals used to infiltrate and bind to lymph nodes.

Watch out for wash out

Radiopharmaceuticals like nanocolloid and Lymphoseek may be superior for lymph-node specific targeting because they don’t pass through networks of lymph nodes like a babbling brook, which can happen and lead to excessive dissection of cancer-free lymph nodes.

“In general, radiopharmaceuticals for lymph-node identification have been designed not to wash through the lymph nodes; their size makes it so that they accumulate in the node,” explains Van Leeuwen. “Wash through is, however, common for the ‘small’ blue dyes that are used to provide optical identification during surgery. From one of our recent comparative studies of 200 patients, we can conclude that the amount of sentinel nodes that contain the radiopharmaceutical can be more than twice as high as the amount of sentinel nodes stained by the blue dye. Both were used in the same patient.”

Regions of interest

Lymphoseek is approved in the U.S. for use in metastases of the breast and in cases of melanoma. FDA approval was based on two clinical trials involving 332 patients with either breast cancer or melanoma. Imaging studies compared Lymphoseek and blue dye for uptake and relative ability to detect lymph nodes. Those that were detected were surgically dissected for pathohistology. Trial findings indicated that both methods detected most lymph nodes, with Lymphoseek localizing more than blue dye.

Research in prostate cancer is promising as well, especially in the realm of fluorescence imaging. However, while lymphoscintigraphy-guided biopsy is possible for primary prostate cancers that have spread to nearby sentinel nodes, this procedure is not as common in clinical practice, notes Van Leeuwen.

“Accurate staging of the lymph nodes via sentinel node biopsy potentially circumvents the need for regional lymph node dissection, which for prostate cancer is still the standard of care,” Van Leeuwen says. “Currently, the sentinel node biopsy technique is more disseminated to other tumor sites.”

Wallace expounds on research at her institution indicating that Lymphoseek could be better at binding to sentinel nodes that are positive for cancer. “We have data out of UCSD that show it does a little bit better job actually binding to positive nodes and that may be because there are more sentinel nodes that are positive. It should become the standard agent for lymphatic mapping and sentinel node imaging in breast cancer and melanoma.”

The study, published in March in the Annals of Surgical Oncology, showed that Lymphoseek detected 94 percent of known lymph nodes in 148 breast cancer patients. A total of 33 nodes later tested positive for cancer. Of these, Lymphoseek identified 31. In contrast, blue dye detected 25.

New biomarker on the block

David R. Vera, PhD, professor of radiology and surgery and co-director of the molecular imaging program at UCSD, one of five National Cancer Institute-funded molecular imaging centers in the country, is the principal developer of Lymphoseek, which, according to the FDA, is the first lymph node mapping imaging agent to hit the U.S. market for clinical use in more than 30 years. 

Lymphoseek was approved by the FDA for radiolabeling with Tc-99m, but the small molecule also could be conjugated with Indium-111 or Gallium-68, says Vera. The agent’s primary mechanism for lymph node targeting is a natural affinity for the CD206 mannose receptor, which is specific to lymph node anatomy.

“It also is found in reticular endothelial system in the liver and a few other places,” explains Wallace. “This agent, when injected into the skin or the breast, drains and binds nicely to the lymph node and doesn’t move around. This particular agent was designed for lymphatic mapping.”

Compared to blue dye and sulfur colloid, Lymphoseek could quicken the pace of surgery. A 2009 study published in Nuclear Medicine and Biology evaluated Tc-99m sulfur colloid in contrast with Lymphoseek for lymphatic mapping in breast cancer patients and found that the mean injection site clearance half-time of Lymphoseek was approximately two hours, plus or minus an hour, vs. unfiltered sulfur colloid’s 57.5 hours, give or take almost 93 hours, for clearance to lymph nodes. Uptake was found to be statistically comparable in both agents.

“Within minutes of injection, Lymphoseek is in the lymph node, because this is a small molecule that drains very quickly,” says Wallace. “Its clearance is very fast.”

The agent was documented in the same study to remain detectable in lymph nodes by gamma counter for up to 24 hours after injection. “Once it lands in the lymph node, it binds and stays there,” explains Vera. “It doesn’t pass through the lymph node. It’s a very high affinity interaction. We also were able to image lymph nodes up to 36 hours later using fluorescence.”

Sulfur colloid was never specifically designed for lymphatic mapping, according to Vera. The FDA has not approved filtered sulfur colloid for lymphoscintigraphy, but radiopharmacists regularly alter the compound, stripping it of a size-stabilizing component, resulting in a filtered compound comprised of little bits of sulfur and technetium that are just passing through. “Lymphoseek is highly defined. It is not a particle, but a small macromolecule of well-defined dimensions and its interactions are highly characterized, both biochemically and in its distribution.”

Stand-off of the sentinel-specific agents

Lymphoseek’s developer Vera indicates the agent will soon be up for European regulatory approval and could potentially overtake, and eventually even replace, Tc-99m Nanocolloid in European markets, and describes the albumin-based imaging agent as a “dead end.”

Nanocolloid is currently not approved for clinical use in the U.S., but it is the most widely used radiopharmaceutical for lymphatic mapping throughout Europe. Van Leeuwen is more conservative in his estimation of how Lymphoseek will compare in head-to-head clinical trials, which he says are still lacking.

“One of the reasons provided for the specific lymph node accumulation of this radiopharmaceutical is the recognition and accumulation of these colloidal particles by the immune cells residing in the lymph nodes,” says Van Leeuwen. “Prior to a broad clinical implementation of Lymphoseek, randomized multicenter trials will be required—including groups that have extensive experience in the use of Tc-99m nanocolloid—to demonstrate an added value over conventional radiopharmaceuticals.”

Blue dye: Ousted at last?

All three researchers referred to studies presenting targeted radiopharmaceuticals as superior lymph node mapping agents compared to blue dye, which has inherent issues related to cost and a potential for allergic reaction.

“[Lymphoseek] may allow us to eventually stop using blue dye, which is very expensive and has a significant allergic reaction rate,” says Wallace. She believes that Lymphoseek will trump blue dye and become the imaging standard not only in the U.S., but also in Europe.

One major challenge faced by modern intraoperative lymph node mapping is that while these agents may be lymph-node specific, they are not yet cancer specific.

“It is important to realize that the sentinel lymph node procedure as a whole is not tumor specific; via lymphatic drainage patterns, the procedure identifies the tumor draining lymph nodes, which are considered most likely to contain metastatic cancer,” says Van Leeuwen. “Hence, the biggest clinical challenge is the actual visualization of metastatic tumor cells. Such an approach requires tumor-biomarker specific radiopharmaceuticals, rather than lymph-node-biomarker specific radiopharmaceuticals. The biggest challenge will be the visualization/identification of micrometastases (0.2-2mm in diameter) in the lymph nodes as these will be within the detection limit of the currently available camera systems.”

Mapping the future

Vera and Wallace characterize Lymphoseek as a platform for future cancer-targeting agents. This could be possible, because the compound is not limited by an affinity for mannose receptors.

“The take off of this eventually will be finding dendritic cells in tumors and lymph nodes and trying to specifically image for cancer cells, not just draining to lymph nodes,” says Wallace. “The concept of molecular targeting is to find singular or a few cells that might be meaningful and to even tag drugs to those cancer cells. This is very new and will probably take off in the next decade, but there isn’t anything like it on the shelf right now.”

Navidea is in the process of completing phase III trials for lymph node mapping using Lymphoseek for imaging metastatic cancers of the head and neck. A new drug application is expected to be filed by the end of the year.

Progress is underway on other fronts as well. Optical imaging presents a promising next step for both Lymphoseek and Tc-99m nanocolloid, which have both been shown to strongly target lymph nodes. A study published in the March issue of the Journal of Nuclear Medicine found that a combination of optical near-infrared imaging with indocyanine green dye and Tc-99m nanocolloid SPECT was optimal for lymphatic mapping.

In addition to sentinel node targeting in breast cancer and melanoma, Lymphoseek may be ideal for both prostate and colon cancer, according to Wallace. As additional research confirms its efficacy, fluorescence imaging with the Lymphoseek compound could enter clinical practice, offering a more accurate, streamlined and economical process. Stay tuned.