Lymphoseek (TM) is a registered trademark of Navidea Biopharmaceuticals, Inc and is a (technetium Tc 99m tilmanocept) injection.

Note: last updated before 2017

Background

1. [99mTc]tilmanocept (TcTM) is a receptor targeted radiopharmaceutical targetted to SLN's (sentinel lymph nodes) (Baker et al 2015)
   1. Tilmanocpet is a small synthetic molecule that accumulates in lymphatic tissue by binding receptors expressed on reticuloendothelial cells in lymph nodes
   2. The small size of this molecule permits more rapid clearance from its injection site compared to radiolabelled sulfur colloid
   3. The specific binding to lymphatic tissue allows for sustained SLN uptake in first echelon nodes
   4. TcTM received FDA approval in May 2013
2. "Trials comparing (99m)Tc-tilmanocept with other (99m) Tc-based agents are required before it can be routinely used in the clinical setting" (Tausch et al. 2014)
   1. The mannose moieties of tilanocept facilitate binding to mannose receptors (CD206) in the RES in SLN's with this binding preventing transit to second-echelon lymph nodes
   2. SLN concept based on the orderly spread of tumor cells from a primary to a defined lymph node in the relevant nodal basin
   3. Lymphatic mapping has two major objectives:
      1. reduce morbidity associated with lymph node assessment
      2. improve the accuracy of nodal involvement
   4. A new radiation-free technique has been recently introduced (SentiMag® - Endomagnetics, Cambridge, UK) 
      1. Consists of magnetometer and magnetic tracer that can be visualized through he skin by its brown color
      2. Favorable initial report (Douek M et al 2014)
3. Multi center trial of 101 patients with T1-4 N0M0 SCC of the head and neck including skin/oral cavity (Agrawal et al 2015)
   1. Difference in injection based on timing of surgery
      1. 50ug of (99m)Tc-tilmanoceopt radiolabelled with either 0.5 mCi (same day) or 2.0 mCi (next day), followed by lymphoscintigraphy, SLNB and END
      2. Identified one or more SLN's in 81/83 patients (97.6%)
      3. False negative rate of 2.6% (one patient with tumor positive non-SLN with all SLN's negative)
      4. Negative predictive value of 97.8%; overall accuracy of 98.8%
      5. No significant differences between one day and two day procedures
      6. The timing of injection: preferred the day-before-surgery injection for floor of mouth tumors to reduce the 'shine-through'
      7. Hand held gamma detector - initial survey of entire cervical lymph node basin at risk
         1. 'SLN was defined as a lymph node with a mean invite count>3 square roots of the mean normal tissue background count (3 standard deviation) added to the mean normal tissue background out ('3σ rule')
         2. SLN biopsy considered complete when on further hot nodes were detected.
      8. "The present study supports that the SLN detection rate and FNR for nodal metastases were not significantly affected by the day of surgery relative to timing of [99mTc]tilmanocept injection. This attribute portends that the use of [99mTc]tilmanocept provides substantial leeway and scheduling flexibility with regard to time of injection and subsequent lymphoscintigraphy and SLNB procedures (i.e. next-day surgery) without compromising the reliability of results."

According to the highlights of prescribing information attached to the lymphoseek website (ref 1):

1.  Indications and usage: Lymphoseek is a radioactive diagnostic agent indicated with or without scintigraphic imaging for:
   1. Lymphatic mapping using a handheld gamma counter to locate lymph nodes draining a primary tumor site in patients with solid tumors for which this procedure is a component of intraoperative management
   2. Guiding sentinel lymph node biopsy using a handheld gamma counter in patients with clinically node negative squamous cell carcinoma of the oral cavity, breast cancer or melanoma
2. Dosage and administration
   1. Supplied as a Kit - prepared by radiolabeling with Tc 99m and diluting prior to use
   2. Recommended dose of lymphoseek is 18.5 MBq (0.5 mCi) administered at least 15 minutes before initiating intraoperative lymphatic mapping or SLN bx - with need to complete these procedures within 15 hours of injection
   3. Use lymphoseek within 6 hours of its preparation (other sites within this website say 8 hours)
3. Kit for preparation contains
   1. five Tilmanocept Powder vials - each with 250 mcg tilmanocept
   2. five DILUENT for Lymphoseek vials containing 4.5 cc of sterile buffered saline
4. Warning about Hypersensitivity if previous reaction to dextran or modified forms of dextran
5. Noted that concomitant administration of local anesthetics with Lymphoseek is not recommended and may impair the lymph nodal mapping
6. Citing three studies
   1. Lymphoscintigraphy evaluated the agreement in location of lymph nodes identified by scintigraphic imaging and the handheld gamma counter -
      1. at least one scintigraphic 'hot spot' identified in 95% of patients imaged
      2. overall an 84% agreement on nodal level between location of preoperative scintigraphic imaging hot spots and the intraoperative lymph node findings
         1. 43 hots spots without corresponding hot nodes
      3. 31 hot nodes without corresponding hot spots

Other peer reviewed information (note TcTM = technetium tilmanocept; TcSC = technetium sulfur colloid):

1. Baker et al (2015): Comparison of patients on clinical trials with SLN biopsy at UCSD for breast cancer using TcTM (and VBD = vital blue dye) with a cohort of patients using TcSC (and VBD) during the 1-yr period succeeding conclusion of the later trial (3/11 to 3/12)
   1. Conclusion: SLN with TcTM required fewer SLN's to identify the same rate of node-positive patients compared with TcSC in breast cancer patients with similar risk of axillary metazoic disease. Suggests molecularly targeted mechanism of SLN identification may reduce the total number of nodes necessary for accurate axillary staging.

References

Prescribing information linked to Lymphoseek website http://lymphoseek.com/assets/pdfs/Lymphoseek%20Package%20Insert%20-%20Oc... 6-09-2015 hath

Baker JL, Pu M, Tokin CA, Hoh CK, Vera DR, Messer K, Wallace A: Comparison of (99m)Tctilmanocept and filtered (99m)Tcsulfur colloid for identification of SLNs in breast cancer patients. Ann Surg Oncol. 2015 Jan;22(1):40-5

Douek M, Klaase J, Monypenny I, et al Sentinel node biopsy using a magnetic tracer versus standard technique: the SentiMAG multicentre trial. Ann Surg Oncol. 2014;21(4):1237-1245

Sondak VK, King DW, Zager JS, et al. Combined analysis of phase III trials evaluating [99mTc]tilmanocept and vital blue dye for identification of sentinel lymph nodes in clinically node-negative cutaneous melanoma. Ann Surg Oncol. 2013;20(2):680–688

Tausch C, Baege A, Rageth C: Mapping lymph nodes in cancer management - role of (99m)Tc-tilmanocept injection Onco Targets There. 2014 Jun 24;7:1151-8

Agrawal Amit, Civantos, FJ, Brumund KT, Chepeha DB, Hall NC, Carrol WR, Smith RB, Zitsch RP, Lee WT, Shnayder Y, Cognetti DM, Pitman KT, King DW, Christman LA and Lai SY: [^99mTc]Tilmanocept Accurately Detects Sentinel Lymph Nodes and Predicts Node Pathology Status in Patiens with Oral Squamous Cell Carcinoma of the Head and Neck: Results of a Phase III Multi-institutional Trial. Annals of Surgical Oncology 2014