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10.1245/s10434-006-9099-4
Annals of Surgical Oncology 14:913-921 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Lymphoseek: A Molecular Imaging Agent for Melanoma Sentinel Lymph Node Mapping

Anne M. Wallace, MD, FACS1,2, Carl K. Hoh, MD2,3, Scott J. Ellner, DO1,2, Denise D. Darrah, RN2, Gery Schulteis, PhD4 and David R. Vera, PhD2,3

1 Department of Surgery, University of California, San Diego, 200 West Arbor Drive, San Diego, California 92103, USA
2 Moores UCSD Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, La Jolla, California 92093, USA
3 Division of Nuclear Medicine, University of California, San Diego, 200 West Arbor Drive, San Diego, California 92103, USA
4 Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA

Correspondence: Address correspondence and reprint requests to: Anne M. Wallace, MD, FACS; E-mail: amwallace{at}ucsd.edu


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Background: Lymphoseek is a molecular imaging agent specifically designed for sentinel lymph node mapping. We conducted a phase I clinical trial in which Lymphoseek was compared with filtered [99mTc]sulfur colloid (fTcSC) for melanoma sentinel lymph node detection.

Methods: Twenty-four patients (33–81 years) with melanoma participated in this study. Four groups of six patients received an intradermal administration (.5 mCi) of 1.0, 5.0, or 10.0 nmol of 99mTc-labeled Lymphoseek or filtered [99mTc]sulfur colloid. The injection site clearance was monitored by nuclear imaging for 3 hours. Lymph nodes obtained by gamma-guided biopsy (4.0–8.7 hours after injection) were assayed for radioactivity. Clinical chemistry values were monitored (before injection, before surgery, and 4 and 24 hours), and whole-body scans were acquired at 1 and 12 hours after injection.

Results: Lymphoseek exhibited a significantly (P < .001) faster injection site clearance at all dose levels. The mean Lymphoseek clearance half-time was 2.17 ± .96 hours (n = 18) compared with 14.7 ± 6.3 hours for fTcSC (n = 6). The mean sentinel lymph node uptakes of Lymphoseek (.73% ± .94%) and fTcSC (.85% ± 1.19%) were statistically equivalent (P = .68). Lymphoseek exhibited a lower mean number of sentinel lymph nodes per basin (1.6) than fTcSC (1.9). No adverse events were observed, nor were any clinically significant alterations in laboratory parameters. Radiation absorbed doses were lower than filtered [99mTc]sulfur colloid.

Conclusions: The molecular imaging agent Lymphoseek demonstrated faster injection site clearance and equivalent primary sentinel node uptake when compared with filtered [99mTc]sulfur colloid.

Key Words: Sentinel lymph node biopsy • Radiopharmaceutical • [99mTc]DTPA-mannosyl-dextran • Lymphoseek • Molecular imaging • Melanoma


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Lymphoseek (Neoprobe Corp., Dublin, OH) is a molecular imaging agent that accumulates in lymphatic tissues by binding to a macrophage-specific receptor. The receptor, mannose-binding protein,1 recognizes and binds macromolecules that carry multiple carbohydrate side chains that terminate with mannose. Lymphoseek, also known as 99mTc-diethylenetriamine pentaacetic acid–mannosyl-dextran,2 is composed of a dextran backbone to which multiple units of mannose and diethylenetriamine pentaacetic acid (DTPA) are synthetically attached. The mannose units serve as substrates for receptor recognition and binding, and the DTPA serves as attachment sites for labeling the macromolecule with 99mTc. Lymphoseek was designed to exhibit two features: rapid clearance from the administration site and sustained sentinel lymph node uptake without distal lymph node accumulation.

Previous preclinical studies demonstrated the properties required for sentinel lymph node imaging. Lymphoseek exhibited high receptor affinity. In rabbits, Lymphoseek demonstrated significantly faster injection site clearance and significantly lower distal lymph node uptake than filtered [99mTc]sulfur colloid (fTcSC).2 Submucosal administration into pig colon and stomach resulted in lymph node accumulation within 10 minutes,3,4 which persisted for 3 hours.5 Rapid sentinel lymph node uptake was also observed after direct injection into the porcine prostate gland.6

The first phase I clinical trial of Lymphoseek was a comparison with fTcSC in women with breast cancer. A dose of 1 nmol of Lymphoseek demonstrated significantly faster clearance from the injection site and equivalent sentinel lymph node accumulation.7 No adverse events or clinically significant changes in clinical and laboratory values were observed. These findings were also demonstrated at the 5-nmol dose level.8

In this article, we present the results a second phase I clinical study designed to measure the injection site clearance and sentinel lymph node uptake of patients with melanoma. Six subjects received fTcSC, and 18 subjects received 1 of 3 different doses (1, 5, or 10 nmol) of Lymphoseek.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 
Institutional Review
A phase I clinical trial of Lymphoseek was conducted at the Thornton Hospital of the University of California, San Diego Medical Center, La Jolla. The protocol received the consent of the Division of Medical Imaging and Radiopharmaceutical Drug Products of the US Food and Drug Administration as a Physician-Sponsored Investigational New Drug. The protocol and the informed consent form were approved by the University of California, San Diego, Office for Human Research Protection, the UC San Diego Cancer Center Protocol Review Monitoring Committee, the UC San Diego Human Exposure Review Committee, and the UC San Diego Radioactive Drug Research Committee.

Patient Enrollment
Nine female and 15 male patients with melanoma who would normally be offered sentinel lymph node biopsy as per University of California, San Diego guidelines participated in this study. The need to have follow-through node dissection was determined by the pathologic outcome of the sentinel node and did not affect this study. Twelve qualifying and consenting subjects were randomly selected to receive one of the two imaging agents: Lymphoseek using a dose of 1.0 nmol or fTcSC. After this phase of the study was completed, 12 additional consenting subjects were randomly assigned to 1 of 2 groups to receive either 5 or 10 nmol of Lymphoseek. Pregnant and lactating women, patients with known metastatic disease, and patients currently enrolled in another protocol were excluded from this study. The subjects ranged in age from 33 to 81 years (Table 1Go). Lesion size ranged from .44 to >10 mm; the Clark level9 ranged from II to IV. Six sentinel lymph nodes from four subjects were positive on frozen section. One subject had a Merkel cell carcinoma.


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  		TABLE 1. Subject and radiopharmaceutical summary
 
Agent Preparation
Lymphoseek was synthesized2 and radiolabeled10 as previously described. This study used the same Lymphoseek preparation as our phase I breast cancer trial.7,8 The mean molecular diameter was 7.0 nm, and the average molecular weight was 28,200 g/mol. The average DTPA and mannose densities were 2.1 and 42 mol/mol of dextran, respectively. The Lymphoseek radiochemical purity ranged from 96% to 99%. The radiopharmaceutical was administered within 1 hour of radiolabeling. Filtered TcSC (CIS-US, Bedford, MA) was prepared7 and administered within 1 hour of filtration. The radiochemical purity ranged from 91% to 99% (Table 1Go).

Nuclear Imaging
Each patient received four .1-mL, .125-mCi injections of either Lymphoseek (1, 5, or 10 nmol) or fTcSC at the 3-, 6-, 9-, and 12-o’clock positions surrounding the lesion by using an intradermal technique. Each subject was monitored for any sign of an allergic reaction, such as a rash, hives, edema, or other cutaneous manifestations.

Nuclear imaging of the Lymphoseek and fTcSC studies used the same imaging protocol. Images of the injection site were acquired immediately after the injection and at 15-minute intervals for 1 hour. An imaging standard of a known dilution of injectate was placed within the field of view. All images were acquired (256 x 256 x 16) for 3 minutes and stored on an image-processing computer. Whole-body scans (anterior and posterior views) were performed at 1 and 12 hours after injection. The injection site clearance rate constant (kc) and half-life (Tc) of Lymphoseek and fTcSC were calculated by using decay-corrected counts obtained from the nuclear images of the injection site.7 The percentage of injected dose (%IDIS) in the site of administration at the time of mapping was calculated by extrapolating the exponential clearance defined by each subject’s clearance rate constant.

Sentinel Lymph Node Detection and Measurement
Sentinel lymph node biopsy was performed by using standard technique. At the start of the surgical procedure, isosulfan blue (Lymphazurin 1%; US Surgical Corp., Norwalk, CT) was injected in the same manner as the radiopharmaceutical. The administration site was massaged for several minutes. Also during this time, a handheld gamma probe (Neoprobe 2000; Neoprobe) was used to scan the skin surface to localize the sentinel lymph node. Scintigrams were used to guide the search. After the skin was marked at the site of the highest count rate, the patient was prepared for surgery, and an incision was made at the marked location. With the aid of the gamma probe, the dissection was performed to the hot lymph node and/or to the lymphatic with blue dye accumulation. The lymph node was isolated, removed, and placed on the tip of the gamma probe for counting. The count rate of the excised lymph node was defined as the target activity. A background measurement was made by placing the tip of the gamma probe on the skin surface at least 20 cm from the administration site. Finally, the gamma probe was placed back within the nodal basin to ensure that no significant residual radioactivity remained. Verification that the node contained radioactivity at least 10 times the background was performed before it was sent to pathology. Frozen-section analysis was then performed to identify metastases. Sentinel lymph nodes were defined by having a node:background ratio of at least 10:1. If the sentinel node was histologically positive, then the lymph node dissection was completed.

All lymph nodes and injection standards were assayed for radioactivity by using a dose calibrator located adjacent to the operating room. The %IDSN in each lymph node was calculated as previously described.7

Subject Monitoring
Vital signs and electrocardiograms were obtained before fTcSC and Lymphoseek administration and at 15 and 30 minutes after administration. Blood pressure, heart rate, respiratory rate, temperature, and oxygen saturation were obtained at baseline, immediately after injection, and at .25, .5, 1, 2, and 24 hours after administration. Blood and urine samples were obtained before injection and at 4 and 24 hours after administration. The 4-hour samples occurred before surgery. The laboratory measurements, as previously listed,8 included a hemogram and white blood cell differential, urinalysis, and a 21-component serum chemistry panel. All subjects were subjectively evaluated upon arrival for the study and monitored for a 24-hour period during an overnight hospital stay. Patients were additionally seen 1 week later in clinic follow-up and at 30 days after the procedure were either contacted by phone for a subjective evaluation or seen in the clinic.

An adverse reaction was defined by the Pharmacopeia Committee of the Society of Nuclear Medicine11 or as any of the clinical parameters (hemogram, urinalysis, and 21-component clinical chemistry panel) showing significant variation from preadministration levels and falling outside acceptable clinical norms 24 hours after administration. Toxicity levels were defined by the National Cancer Institute Common Toxicity criteria;12 grades 3 and 4 were considered clinically significant.

Radiation Absorbed Dose
We calculated the radiation absorbed dose13 and the effective dose14 for Lymphoseek at each molar dose level and fTcSC. Values for each group were based on the mean clearance rate constants and %IDs. We used the standard MIR technique of simplified dose calculation by using S factors.15 The S-factors were based on the average reference adult for the 99mTc isotope13 with the breast as the site of administration. We used the same assumptions as the dosimetry calculations for Lymphoseek sentinel lymph node mapping of breast cancer.8

Statistical Methods
For the measures kc, Tc, %IDIS, and %IDSN, statistical significance was evaluated by planned comparisons of each molar dose of Lymphoseek with the fTcSC control group by using the nonpaired Student’s t-test (JMP software; SAS Institute, Cary, NC). As previously described,8 each molar dose of Lymphoseek was also compared with fTcSC standard on a full panel of clinical laboratory tests, and the change from presurgery baseline was taken as the index of comparison. The Wilcoxon rank-sum statistic was used to evaluate each laboratory parameter. A two-tailed P value of < .05 was considered statistically significant, with no correction made for multiple comparisons, because the conservative approach in a phase I trial would be to treat any statistically reliable change in clinical laboratory result as potentially meaningful and worthy of evaluation for clinical significance.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 CONCLUSION
 REFERENCES
 
The Lymphoseek exhibited a significantly faster injection site clearance at all molar doses than fTcSC. The clearance rate constants (Table 2Go) for Lymphoseek ranged from .112 to .636/h and ranged from .026 to .076/h for fTcSC. The mean injection site clearance rate constant kc for Lymphoseek (molar dose levels combined) equaled .319 ± .141/h (Table 3Go), which was almost an order of magnitude higher than the mean fTcSC clearance rate constant of .047 ± .014/h. These values translated to Tc values of 2.17 ± .96 h for Lymphoseek and 14.7 ± 6.3 h for fTcSC. The clearance rate constant did not correlate with the Lymphoseek molar dose; the mean kc values for 1-, 5-, and 10-nmol doses were .338 ± .146/h, .400 ± .143/h, and .226 ± .092/h, respectively. The calculated %ID within the injection site at the time of excision ranged from 2.8% to 62% for Lymphoseek and from 56% to 88% for fTcSC. These values depend on the time of sentinel node excision, which ranged from 4.0 to 8.7 hours after administration (Table 2Go).


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  		TABLE 2. Injection site clearance and sentinel lymph node uptake
 

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  		TABLE 3. Injection site clearance and sentinel lymph node uptake of Lymphoseek and filtered [99mTc]sulfur colloid
 
There was little variation from prestudy and electrocardiogram tracings acquired after administration of either agent. Vital signs remained stable for all subjects. Clinical chemistry, hemogram, and urinalysis deviations were those commonly associated with surgery. No adverse events related to the either agent were noted.

Figure 1Go illustrates the clearance of radioactivity from the administration sites of two sentinel node studies. The data represented by diamonds are from a sentinel lymph node study (subject 17) that used a 5-nmol dose (.48 mCi) of Lymphoseek. The subject had a 1.30-mm Clark level III melanoma on the right forearm. Linear regression analysis gave a slope of –.377 ± .074/h. This value is equivalent to a Tc of 1.83 ± .36 hours. Figure 2Go is an image acquired 2 hours after administration. Mapping and sentinel lymph node excision were performed at 4.5 hours after administration. The %ID in the sentinel node as measured by the dose calibrator at 4.5 hours was .42% ± .04%; the gamma probe registered 2400 cps. On the basis of the Tc of 1.83 hours, the injection site at 4.5 hours contained 18% of the dose. The injection site was located on the right forearm and was not in the field-of-view.


Figure 1
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  		FIG. 1. Clearance of radioactivity from the injection site of two sentinel node cases: Lymphoseek (diamonds; subject 17) exhibited a half-life of 1.83 ± .35 hours, and filtered [99mTc]sulfur colloid (triangles; subject 4) exhibited a half-life of 19.7 ± 3.2 hours.

 

Figure 2
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  		FIG. 2. An image acquired 2 hours after a 5-nmol (.48-mCi) injection of Lymphoseek (subject 17). When measured at 4.5 hours, the sentinel node (arrow) accumulated .42% ± .04% of the dose; the gamma probe registered 2,400 cps. On the basis of the clearance half-life of 1.83 hours, the injection site at 4.5 hours contained 18% of the dose. The injection site (not in the field of view) is on the right forearm.

 
The %ID at the injection site at this time, as predicted by the injection site clearance Tc, was 18%. The data represented by triangles are from a study that used fTcSC (subject 4). The linear regression yielded a slope of –.035 ± .005/h, which is equivalent to a Tc of 19.7 ± 3.2 hours. Sentinel node mapping was performed at 7.5 hours; the %ID at the injection site at this time, as predicted by Tc, was 77%. Four lymph nodes were detected with the intraoperative gamma probe, which satisfied the criteria for sentinel lymph node status (Table 2Go). Only two of these four were stained blue. The %ID values were 1.50%, .11%, and .06%. The last sentinel lymph node was not stained blue.

Sentinel lymph node uptake was extremely variable (Table 2Go); the count rate in counts per second (cps) from the intraoperative gamma detector ranged from 53 to 28,000 cps for the receptor-binding agent and 67 to 3,900 cps for the filtered colloid. The mean %ID for all of the Lymphoseek studies was .73% ± .94%. This value was not significantly different (P = .68) from the mean sentinel node uptake of .85% ± 1.19% for fTcSC. If only the hottest (primary) sentinel lymph node in each basin was averaged, the comparison (P = .23) was .73% ± .94% for Lymphoseek and 1.47% ± 1.36% for fTcSC. Sentinel lymph node uptake did not correlate with the Lymphoseek molar dose; the mean %IDSN for the 1-, 5-, and 10-nmol doses was .49% ± .59%, 1.20% ± 1.45%, and .75% ± .74%, respectively (Table 3Go). If only the hottest (primary) sentinel lymph node within each basin was averaged, then the mean %ID was .62% ± .74%, 1.34% ± 1.38%, and .85% ± .82%, respectively.

All of the studies exhibited a sentinel lymph node by gamma probe detection. The mean number of sentinel nodes per basin detected by Lymphoseek at all molar dose levels was 1.6. The average number of sentinel lymph nodes per basin for the 1-, 5-, and 10-nmol doses was 1.6, 1.9, and 1.4, respectively. The mean number of sentinel nodes per basin detected by Lymphazurin was 1.4. The blue dye failed to detect at least 1 sentinel lymph node in 5 of 30 basins; 2 of these failures resulted in no sentinel lymph node detection by the dye. A blue but nonradioactive lymph node was detected during one study; the dose was 10 nmol of Lymphoseek. Concordance of Lymphazurin and Lymphoseek at all molar dose levels was 67%. Concordance between the agents at the 1-, 5-, and 10-nmol Lymphoseek doses was 90%, 39%, and 75%, respectively. The mean number of sentinel lymph nodes per basin detected by fTcSC was 1.9. Concordance of fTcSC and Lymphazurin was 73%.

Among all comparisons made, five parameters showed a significant change from baseline of dose level or dose level by time. Follow-up comparisons revealed the nature of these five significant effects; none could be considered clinically meaningful or attributed to Lymphoseek administration. The red blood cell count (P = .003), hematocrit (P = .009), and hemoglobin (P = .014) were significantly increased in the 1-nmol condition at 24 hours; these effects were not evident at the two higher doses and were attributed to the surgical procedure. Bicarbonate was significantly decreased in the 1-nmol (P = .025) and 5-nmol (P = .027) conditions at 24 hours, but not at the 10-nmol dose or at any dose level at 4 hours. Also, total protein showed a significant increase (P = .040) at 24 hours when the three dose levels were combined and then compared with fTcSC; none of the individual dose levels showed a significant effect.

The plasma %ID per gram of all three dose levels was highest at 15 minutes after administration; the mean values for the 1-, 5-, and 10-nmol doses were 1.0 ± 1.4 x 10–2%/g, 1.0 ± .9 x 10–2%/g, and .65 ± .82 x 10–2%/g, respectively. The %ID for liver, kidneys, bladder, and head, as calculated from the whole-body scans at 1 and 12 hours, was <4.0%. One hour after the administration of fTcSC, the radioactivity within the urinary bladder was .36% ± .17% of the dose. The Lymphoseek values 1 hour after injection were 2.03% ± 2.12% for the group injected with 1 nmol, 1.22% ± 1.10% for the 5-nmol group, and 1.21% ± .53% for the 10-nmol group.

The absorbed radiation dose rates for Lymphoseek and fTcSC were similar to the values obtained for our phase I breast cancer study.8 If the injection site was the breast, the MIRD calculations predicted a radiation dose rate of 4.8 x 10–3 rad/mCi, 3.7 x 10–2 rad/ mCi, and 4.4 x 10–2 rad/mCi for the 1-, 5-, and 10-nmol Lymphoseek injections, respectively. A .5-mCi administration to the breast of 5 nmol would produce an absorbed radiation dose to the injected breast of 1.9 x 10–2 rad. At all Lymphoseek molar doses, as well as fTcSC, the absorbed radiation dose rate to the testes, ovaries, red marrow, and total body was <7.0 x 10–2 rad/mCi. The effective dose equivalent from Lymphoseek at the 1-, 5-, and 10-nmol dose levels was 4.1 x 10–2 mrem/mCi, 2.6 x 10–2 mrem/ mCi, and 3.3 x 10–2 mrem/mCi, respectively. The radiation dose rate to the injection site from [99mTc]sulfur colloid was 7.4 x 10–2 rad/mCi, and the effective dose equivalent was 3.0 x 10–2 mrem/mCi.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
CONCLUSION
 REFERENCES
 
The goal of a phase I clinical trial is the assessment of safety. Because a radiopharmaceutical emits ionizing radiation, it presents potential physical and biological safety issues. Consequently, a phase I clinical trial of a new radiopharmaceutical16 must assess potential biologic toxicities and radiation dosimetry. Our study design consisted of four dependent variables: three different molar doses of Lymphoseek and a dose of fTcSC. This design permitted us to compare the safety profile of Lymphoseek with that of the current sentinel node agent. More importantly, the three molar doses provided a preliminary assessment of the dose-dependent bio-distribution, as well as biological and physical toxicity issues.

The clearance rate constant of Lymphoseek at any of the three molar dose levels was significantly higher than that of fTcSC. This is an important feature of Lymphoseek. One of our design goals was an agent that rapidly cleared from the administration site. Our purpose was to reduce radiation scatter into an adjacent sentinel lymph node and to reduce the radiation absorbed dose to the subject and surgical team. Although the small molecular diameter of Lymphoseek promotes capillary and lymphatic clearance, our second purpose for a rapid clearance was to achieve faster accumulation by the sentinel lymph node.3,6 Clearance from the injection site is a principal component of the dosimetry calculation for a lymphoscintigraphic agent.17 Because intradermal injections result in more rapid clearance than peritumoral administration, our expectation was an enhanced safety profile for both Lymphoseek and fTcSC compared with our dosimetry calculations for breast sentinel node mapping.7

Extremely high biological variability in sentinel lymph node accumulation makes the comparison between agents difficult to achieve. Although the mean number of sentinel nodes per basin for Lymphoseek was lower than for fTcSC and the %IDSN was highest for fTcSC, the differences were not statistically significant. Extremely wide variations in lymph node uptake and regional variations in cutaneous lymph drainage patterns have been extensively documented.18 Consequently, a test for statistical significance of these parameters will require a sample size larger than this study, which was designed to test differences in injection site clearance rates. Clearance of a radiopharmaceutical from the site of administration, which is usually the blood compartment, is a parameter that significantly influences the radiation absorbed dose profile and is, therefore, always a primary focus of a phase I radiopharmaceutical trial.

We used a widely excepted criterion for assigning a lymph node as "sentinel" based on the count rate measured by the handheld gamma detection probe. This definition requires that the measured lymph node have an ex vivo count rate 10-fold higher then background.19 We did not apply a second criterion, which is to require that any additional lymph node have a count rate greater than 20% of the hottest node.20 If we used this additional criterion, the average number of sentinel lymph nodes per basin for both the Lymphoseek and fTcSC studies would be 1.3.

No serious adverse events occurred over the course of the study. Changes in hemogram values were attributed to hemodilution, anesthesia, and blood loss from the surgical procedure. Changes in chemistry values were attributed to nothing-by-mouth status, diabetic status, anesthesia, postoperative changes, and muscle manipulation related to the surgical procedure. Changes in urinalysis were attributed to collection artifacts, diabetic urine abnormalities, and urinary catheterization.

Lymphoseek demonstrated equivalent radiation dosimetry at each molar dose level. The radiation absorbed dose rate is primarily determined by the injection site clearance rate constant, kc, which did not correlate with increasing molar dose. Such a correlation is not expected because the mechanism for Lymphoseek clearance from the injection site, passive diffusion, is independent of mass. Consequently, the selection of molar dose will not significantly alter the dosimetry of Lymphoseek for sentinel lymph node mapping of breast cancer.

When compared with fTcSC, Lymphoseek has a favorable dosimetry profile. Bergqvist et al.17 reported an effective dose equivalent from [99mTc]antimony sulfide colloid of 19.7 mrem/mCi, which is similar to our calculation of 30 mrem/mCi from a fTcSC dose. Other similarities between studies include the same injection site clearance rate constant of .021/h for [99mTc]antimony sulfide colloid and a very wide dispersion of lymph node uptakes: 30% of lymph nodes with <.001 %ID, 30% between .001 and .01 %ID, 28% between .01 and .1 %ID, and 12% between .1 and 1 %ID.

Lymphoseek will also provide lower radiation exposure to the surgical team. This is also due to the rapid clearance of Lymphoseek from the injection site. Table 3Go can be used to compare the exposure rate between Lymphoseek and fTcSC. The mean injection site activity at the time of mapping for Lymphoseek was 26.7 %ID, compared with 73.1% for fTcSC. If the administered dose was .5 mCi, the radioactivity remaining at the periphery of the melanoma was, on average, .13 mCi with Lymphoseek and .37 mCi with fTcSC. This is almost a 3-fold difference, and although mapping for the sentinel lymph node is typically conducted after excision of the melanoma, this difference is a good quantitative comparison of the radiation exposure to the hands that are in contact with the radioactive tissue that surrounds the tumor.


   CONCLUSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
REFERENCES
 
With intradermal administration for melanoma sentinel lymph node mapping, the molecular imaging agent Lymphoseek demonstrated superior injection site clearance, equivalent sentinel lymph node uptake, and fewer sentinel nodes per basin when compared with fTcSC. These results provide the motivation for a phase II clinical trial.


   ACKNOWLEDGMENTS
 
The authors thank the Neoprobe Corporation (Dublin, OH) for the use of a model 2100 intraoperative radioisotope detector. Supported by the American Cancer Society (grant RSG-01-249-01). Lymphoseek is a registered trademark of the Neoprobe Corporation.

Received for publication April 17, 2006. Accepted for publication June 5, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 CONCLUSION
 REFERENCES
 

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  16. US Food and Drug Administration Guidance for Industry, Developing Medical Imaging Drugs and Biological Products: Part 3. Design, Analysis, and Interpretation of Clinical Studies Rockville, MD: US Department of Health and Human Services; 2004.
  17. Bergqvist L, Strand S-E, Persson BRR, Hafstrom L, Jonsson PE. Dosimetry in lymphoscintigraphy of Tc-99m antimony sulfide colloid. J Nucl Med 1982; 23:698–705.[Abstract/Free Full Text]
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