Comparative evaluation of [(99m)tc]tilmanocept for sentinel lymph node mapping in breast cancer patients: results of two phase 3 trials

Abstract

Background: Sentinel lymph node (SLN) surgery is used worldwide for staging breast cancer patients and helps limit axillary lymph node dissection. [(99m)Tc]Tilmanocept is a novel receptor-targeted radiopharmaceutical evaluated in 2 open-label, nonrandomized, within-patient, phase 3 trials designed to assess the lymphatic mapping performance.

Methods: A total of 13 centers contributed 148 patients with breast cancer. Each patient received [(99m)Tc]tilmanocept and vital blue dye (VBD). Lymph nodes identified intraoperatively as radioactive and/or blue stained were excised and histologically examined. The primary endpoint, concordance (lower boundary set point at 90 %), was the proportion of nodes detected by VBD and [(99m)Tc]tilmanocept.

Results: A total of 13 centers contributed 148 patients who were injected with both agents. Intraoperatively, 207 of 209 nodes detected by VBD were also detected by [(99m)Tc]tilmanocept for a concordance rate of 99.04 % (p < 0.0001). [(99m)Tc]tilmanocept detected a total of 320 nodes, of which 207 (64.7 %) were detected by VBD. [(99m)Tc]Tilmanocept detected at least 1 SLN in more patients (146) than did VBD (131, p < 0.0001). In 129 of 131 patients with ≥1 blue node, all blue nodes were radioactive. Of 33 pathology-positive nodes (18.2 % patient pathology rate), [(99m)Tc]tilmanocept detected 31 of 33, whereas VBD detected only 25 of 33 (p = 0.0312). No pathology-positive SLNs were detected exclusively by VBD. No serious adverse events were attributed to [(99m)Tc]tilmanocept.

Conclusion: [(99m)Tc]Tilmanocept demonstrated success in detecting a SLN while meeting the primary endpoint. Interestingly, [(99m)Tc]tilmanocept was additionally noted to identify more SLNs in more patients. This localization represented a higher number of metastatic breast cancer lymph nodes than that of VBD.

Fig. 1

[^99mTc]Tilmanocept is composed of a dextran backbone (black) to which are attached multiple units of mannose (green) and DTPA (blue). The mannose units provide a molecular mechanism by which [^99mTc]tilmanocept avidly binds to a receptor specific to recticuloendothelial cells (CD206), and the DTPA units provide a highly stable means to radiolabel tilmanocept with technetium-99m (red). The molecular weight of [^99mTc]tilmanocept is approximately 17,000 grams per mole; the molecular diameter is 7.1 nm

Fig. 2

Lymphoscintigraphy of a 35-year-old woman with carcinoma in situ of the left breast showing 2 intense foci of noted [^99mTc]tilmanocept localization within the left axilla. An intradermal injection (0.4 mL, 0.5 mCi, 3.0 nmol) of [^99mTc]tilmanocept was administered to the upper left quadrant of the left breast. The SPECT/CT image is a fused sagittal cross section acquired 1 h postinjection, which visualizes a sentinel lymph node (arrow) and the injection site. At 5 h after injection, 3 blue and hot lymph nodes (6,724 cps, 1,477 cps, 167 cps) were detected at surgery and excised. Pathologic examination revealed 1 histologically positive lymph node (blue with 6,700 cps, 1.7 × 1.3 × 0.7 cm) and 2 negative lymph nodes