In two studies, Lymphoseek outperformed previous agents in identifying nodes containing metastatic malignancies
With this summer’s release of a new Star Trek movie, a new generation of viewers was exposed to visions of the future — something Star Trek first provided more than 47 years ago. Although most of us will never get our wish for access to a “beam me up, Scotty” device, we have been rewarded with some pretty significant technology in part inspired by this series, such as the cell phone.
In addition to consumer devices, Star Trek has fascinated audiences with visions of medicine in the future. One of the most interesting devices has been the tricorder, a hand-held device that had the ability to diagnose problems deep within the body. Who would have thought it possible in 1966, the year Star Trek was first released, that we would eventually see three-dimensionally within the body with the technology of CAT, PET and MRI scans or the impressive ultrasound devices we now have?
Now another example of Hollywood’s fiction has become a reality. With the approval of a new radiopharmaceutical “dye,” physicians can use a hand-held gamma counter, a device slightly larger than the tricorder, to find hidden lymph nodes in patients diagnosed with breast cancer or melanoma.
Surgeons have long used sentinel lymph node (SLN) mapping to find nodes that drain the area of a newly diagnosed malignancy to determine if they are free of disease or have microscopic pockets of the malignancy. This surgical endeavor is a key part of staging these two deadly cancers and is used to determine future treatment options. The gold standard process for this procedure is to inject a compound, vital blue dye (VBD — literally a blue ink-like substance) into the site of the tumor and follow it downstream to the associated lymph nodes. VBD has been used since most of today’s adults were in diapers.
In conjunction with this, more recently, some physicians used a home-brewed colloidal radiotracer with mixed results, but the VBD is still the gold standard. The overall efficiency of the SLN identification is highly dependent on the specificity and retention of the agents used in the mapping injection.
The ideal radiopharmaceutical agent should be:
Is Lymphoseek what we seek? Obviously the ultimate goal is to identify nodes containing tumor regardless of whether they are stained blue with traditional VBD injections. As mentioned earlier, worldwide there are numerous colloidal preparations that have been used with varying success. Until recently, none were universally accepted, specifically targeted, or FDA-approved.
This has all changed with FDA approval of a new marker named Lymphoseek (technetium Tc-99m tilmanocept) (Navidea Biopharmaceuticals), a targeted radioactive agent “indicated for lymphatic mapping with a hand-held gamma counter to assist in the localization of lymph nodes draining a primary tumor site in patients with breast cancer or melanoma.” It is the first lymph node mapping agent approved in three decades.
Lymphoseek contains a mannose-based ligand that attaches to the CD206 receptor on the macrophages and dendritic dells within the lymphatic tissue. A ligand and receptor is analogous to the two pieces of velcro or a lock and key that must match in order to attach to each other. Tilmanocept contains numerous mannose moieties that allow for easy binding to these receptors.
Thus, the radio-tagged injection accumulates in lymphatic tissue and can be detected by the hand-held probe allowing surgeons to easily find the tissue for biopsy. After an injection of Lymphoseek, the nodes can be detected within 10 minutes as the radioactive agent is actually taken within the cells, where it remains for many hours. There is minimal leakage into distant nodes.
Two almost identical open-label, multicenter, single-arm, phase 3 studies were performed to obtain FDA approval of Lymphoseek. Each enrolled patients with either melanoma or breast cancer. A total of 332 patients were enrolled over a three-year period, roughly half with breast cancer and half with melanoma. After mapping was done with both VBD and Lymphoseek, 685 nodes were removed as part of the combined studies.
Inclusion criteria included:
The radiopharmaceutical agent and the VBD were administered in one of two routes. For melanoma patients both were injected intradermally; for breast cancer patients the injections were given into the subareolar or peritumoral region.
The patients were injected with both the Lymphoseek and the VBD shortly prior to exploratory lymph-node surgery, and intraoperative lymphatic mapping was performed visually, manually and using a hand-held gamma detector probe. Masses found were surgically excised by any of the above methods. All material was sent to the laboratory for histopathology.
A comparison of the number and percentage of resected nodes that contained Lymphoseek and/or the blue dye was made. Lymphoseek was present in 94%–100% of resected nodes as compared with 59%–70% found by blue dye in breast cancer and melanoma patients. Thus, Lymphoseek found more associated nodes.
Lymphoseek found a much greater percentage of metastatic cancer-containing nodes than did VBD. In fact, of malignant nodes found, Lymphoseek alone (and not VBD) was present in 241 removed nodes (29%–41% of nodes) in the combined data. Conversely, VBD alone (with no radioactive agent) was present in only eight nodes in the entire study, none of which contained malignancy.
Of even more interest is that 4 of the 34 metastatic nodes in the melanoma patients were detected by Lymphoseek alone. In the breast cancer patients, metastatic disease was picked up by Lymphoseek in 31 of the 33 positive patients and only 25 of the 33 were found in the VBD group. (Note, some nodes were discovered by palpation or visually with no dye during the open surgery.) In both types of cancer no patient had a malignancy that was found only by VBD.
Proper diagnosis and staging are crucial in the treatment of cancer. The clinical trials associated with FDA approval of Lymphoseek clearly demonstrated the superiority of Lymphoseek over the “blue” standard. This new radiopharmaceutical combined with a gamma probe now offers a more precise staging tool, which has the potential to improve outcomes, a concept that Trekkies will welcome in their continued search for Tomorrow’s Medicine.
The author is a director in the value-based health department at Genentech. He has had no other industry affiliations in the past three years. The views expressed in Tomorrow’s Medicine are the author’s alone.