The efficacy of Tilmanocept in sentinel lymph mode mapping and identification in breast cancer patients: A comparative review and meta-analysis of the 99mTc-labeled nanocolloid human serum albumin standard of care
Sentinel lymph node (SLN) mapping is common, however question remains as to what the ideal imaging agent is and how such an agent might provide reliable and stable localization of SLNs. (99m)Tc-labeled nanocolloid human serum albumin (Nanocoll(®)) is the most commonly used radio-labeled colloid in Europe and remains the standard of care (SOC). It is used in conjunction with vital blue dyes (VBDs) which relies on simple lymphatic drainage for localization. Although the exact mechanism of Nanocoll SLN localization is unknown, there is general agreement that Nanocoll exhibits the optimal size distribution and radiolabeling properties of the commercially available radiolabel colloids. [(99m)Tc]Tilmanocept is a novel radiopharmaceutical designed to address these deficiencies. Our aim was to compare [(99m)Tc]Tilmanocept to Nanocoll for SLN mapping in breast cancer. Data from the Phase III clinical trials of [(99m)Tc]Tilmanocept's concordance with VBD was compared to a meta-analysis of a review of the literature to identify a (99m)Tc albumin colloid SOC. The primary endpoints were SLN localization rate and degree of localization. Six studies were used for a meta-analysis to identify the colloid-based SOC. Five studies (6,134 patients) were used to calculate the SOC localization rate of 95.91 % (CI 0.9428-0.9754) and three studies (1,380 patients) were used for the SOC SLN degree of localization of 1.6683 (CI 1.5136-1.8230). The lower bound of the confidence interval was used for comparison to Tilmanocept. Tilmanocept data included 148 patients, and pooled analysis revealed a 99.99 % (CI 0.9977-1.0000) localization rate and degree of localization of 2.16 (CI 1.964-2.3600). Tilmanocept was superior to the Nanocoll SOC for both endpoints (P < 0.0001).
"There is currently only one indirect comparison between 99mTc-tilmanocept and the 99mTc-nanocolloid albumin (Nanocoll®; Nycomed Amersham Sorin SRL, VC, Italy).76 In that study, the authors compared data from the results of Phase III trials of 99mTctilmanocept with historical data from 99mTc-nanocolloid-albumin-based protocols. "
[Show abstract][Hide abstract] ABSTRACT: Two decades ago, lymphatic mapping of sentinel lymph nodes (SLN) was introduced into surgical cancer management and was termed sentinel node navigated surgery. Although this technique is now routinely performed in the management of breast cancer and malignant melanoma, it is still under investigation for use in other cancers. The radioisotope technetium ((99m)Tc) and vital blue dyes are among the most widely used enhancers for SLN mapping, although near-infrared fluorescence imaging of indocyanine green is also becoming more commonly used. (99m)Tc-tilmanocept is a new synthetic radioisotope with a relatively small molecular size that was specifically developed for lymphatic mapping. Because of its small size, (99m)Tc-tilmanocept quickly migrates from its site of injection and rapidly accumulates in the SLN. The mannose moieties of (99m)Tc-tilmanosept facilitate its binding to mannose receptors (CD206) expressed in reticuloendothelial cells of the SLN. This binding prevents transit to second-echelon lymph nodes. In Phase III trials of breast cancer and malignant melanoma, and Phase II trials of other malignancies, (99m)Tc-tilmanocept had superior identification rates and sensitivity compared with blue dye. Trials comparing (99m)Tc-tilmanocept with other (99m)Tc-based agents are required before it can be routinely used in clinical settings.
OncoTargets and Therapy 06/2014; 7:1151-8. DOI:10.2147/OTT.S50394 · 2.31 Impact Factor
"In the current studies, [99mTc]tilmanocept and VBD detected at least 1 lymph node in 98.6 % (146 of 148) and 88.5 % (131 of 148) of patients, respectively. Lastly, we constructed a meta-analysis of these phase 3 trials and contrasted the results against the recently published selected performance data of Nanocoll.25 Tilmanocept had superior SLN localization rate (99.9 vs. 95.1 %) and a higher degree of localization (2.16 vs. 1.66 SLN per study) (p < 0.0001). "
[Show abstract][Hide abstract] ABSTRACT: Background
Sentinel lymph node (SLN) surgery is used worldwide for staging breast cancer patients and helps limit axillary lymph node dissection. [99mTc]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.
A total of 13 centers contributed 148 patients with breast cancer. Each patient received [99mTc]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 [99mTc]tilmanocept.
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 [99mTc]tilmanocept for a concordance rate of 99.04 % (p < 0.0001). [99mTc]tilmanocept detected a total of 320 nodes, of which 207 (64.7 %) were detected by VBD. [99mTc]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), [99mTc]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 [99mTc]tilmanocept.
[99mTc]Tilmanocept demonstrated success in detecting a SLN while meeting the primary endpoint. Interestingly, [99mTc]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.
[Show abstract][Hide abstract] ABSTRACT: Purpose:
To determine the imaging and receptor-binding properties of a multireporter probe designed for sentinel lymph node (SLN) mapping via nuclear and fluorescence detection.
Materials and methods:
The animal experiments were approved by the institutional animal care and use committee. A multireporter probe was synthesized by covalently attaching cyanine 7 (Cy7), a near-infrared cyanine dye, to tilmanocept, a radiopharmaceutical that binds to a receptor specific to recticuloendothelial cells. In vitro binding assays of technetium 99m (99mTc)-labeled Cy7 tilmanocept were conducted at 4°C by using receptor-bearing macrophages. Optical SLN imaging after foot pad administration was performed by using two molar doses of Cy7 tilmanocept. Six mice were injected with 0.11 nmol of 99mTc-labeled Cy7 tilmanocept (low-dose group); an additional six mice were injected with 31 nmol of 99mTc-labeled Cy7 tilmanocept (high-dose group) to saturate the receptor sites within the SLN. After 2.5 hours of imaging, the mice were euthanized, and the sentinel and distal lymph nodes were excised and assayed for radioactivity for calculation of SLN percentage of injected dose and extraction. Four mice were used as controls for autofluorescence. Standard optical imaging software was used to plot integrated fluorescence intensity against time for calculation of the SLN uptake rate constant and scaled peak intensity. Significance was calculated by using the Student t test.
In vitro binding assays showed subnanomolar affinity (mean dissociation constant, 0.25 nmol/L±0.10 [standard deviation]). Fluorescence imaging showed a detection sensitivity of 1.6×10(3) counts·sec(-1)·μW(-1) per picomole of Cy7. All four imaging metrics (percentage of injected dose, SLN extraction, SLN uptake rate constant, and expected peak fluorescence intensity) exhibited higher values (P=.005 to P=.042) in the low-dose group than in the high-dose group; this finding was consistent with receptor-mediated image formation.
The multireporter probe 99mTc-labeled Cy7 tilmanocept exhibits in vitro and in vivo receptor-binding properties for successful receptor-targeted SLN mapping with nuclear and optical imaging.
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