A Phase I/II Trial of 125I Methylene Blue for One-Stage Sentinel Lymph Node Biopsy

Sentinel lymph node biopsy was initially developed as a technique for the detection of regional lymph node metastasis in patients with melanoma by Morton et al.1 The evolution of the procedure as a means to detect the presence of axillary lymph node metastasis in patients with breast cancer developed shortly thereafter. In less than 10 years following the initial reports utilizing this technique, dozens of studies have appeared in the scientific literature validating use of sentinel node biopsy as an accurate means of detecting metastatic disease in the axillary lymph nodes in patients with breast cancer.2–5 Almost simultaneously, reports appeared in the literature documenting the success of sentinel node localization using either isosulfan blue dye alone or using isosulfan blue dye in conjunction with technetium99m labeled sulfur colloid (99mTcSC). While most authors use a combination of blue dye and 99mTcSC, Guiliano et al continue to report excellent results using isosulfan blue dye alone.6 Conversely, Krag et al report similar excellent results using only radiotracer.2,3 Currently, the majority of breast surgeons prefer to use both dye and radiotracer for their evaluation of sentinel nodes. In recent years, others have published studies suggesting that sentinel node accuracy and yield could be duplicated with the use of methylene blue dye as opposed to isosulfan blue dye.7–9 This change in dye preference has found its way into the practice of a significant population of breast surgeons. Injection of small quantities (0.1–0.5 mL) of methylene blue into the breast during needle/wire breast cancer mammographic localization procedures has been done for years and has been associated with no reported adverse effects.10 In a similar fashion, injection of methylene blue in the web space between the toes has been used widely as a method to detect lymphatic channels for their cannulation for lymphangiograms. With the development of the sentinel node biopsy method of evaluating axillary lymph node status in women with breast cancer came some unanticipated consequences for both surgeon and patient alike. Patients must undergo a separate preoperative injection of radiocolloid prior to their surgery. The radiocolloid injection is commonly performed a minimum of 2 hours preoperatively, often the afternoon prior to surgery or more typically the morning of surgery. Patients uniformly note that the radiocolloid injection is very painful. The injection is painful whether it is injected in small quantities intradermally or in larger quantities around the periphery of a tumor.11,12 With the advent of sentinel lymph node biopsy as an alternative standard of care for breast conservation candidates, there has been an increase in patient and referring-physician demand for this less invasive procedure. Surgeons have often been forced to deal with major delays in their surgical schedules based on the requirement for an additional preoperative procedure that is performed at the discretion of nonoperating room personnel, specifically nuclear medicine physicians and technicians.13 A single, simultaneous injection of blue dye and radiocolloid in the operating room at the time of breast cancer surgery would obviate the need for an additional preoperative procedure for the patients and would prevent delays in the surgical schedule. Unfortunately, 99mTc sulfur colloid has high-energy gamma emissions and a significant amount of activity (1–10 mCi) is commonly injected to ensure adequate node uptake. Much of this activity must clear from the injection site before the hand-held gamma probe can effectively discriminate individual nodes in the axilla from the injection site We have devised a simple, economically feasible way to produce a sterile, pyrogen-free 125I-labeled methylene blue dye. Preliminary animal experimentation showed rapid transit to regional nodes and limited systemic biodistribution.14 When absorbed systemically, the radiolabeled dye is rapidly cleared in the urine. We hypothesized that admixing small quantities of the 125I labeled methylene blue dye (0.1–0.5 mL) in a much larger (4.5–4.9 mL) quantity of unlabeled methylene blue dye should offer the surgeon all the specificity of a 2-stage sentinel lymph node biopsy procedure, enhanced intraoperative 2-point discrimination based on the low energy of 125Iodine's gamma emissions, and potentially offer increased safety based on 125Iodine's low-energy (35 Kev) gamma emissions. More importantly, the use of a 1-step intraoperative procedure would be painless and would obviate the need for a second procedure performed outside of the operating room by nonsurgical personnel.