The first study demonstrating the use of radioactive seeds for the preoperative localization and surgical guidance in the excision of non-palpable breast lesions was reported in 2001 (Gray et al. 2001). This study concluded that radioactive seed localization (RSL) was as effective as the standard wire localization (WL) technique. It also demonstrated a reduced incidence of positive margins and reoperative rates, and since the procedure allows for the seed to be implanted prior to the scheduled surgery date it eliminates scheduling conflicts between radiology and surgery. As the RSL procedure appeared in more publications, demonstrating additional benefits over WL, such as less pain and discomfort for the patient and improved surgical approach with better cosmetic outcomes, more institutions, primarily tertiary care medical centers operating under a broad scope radioactive materials license, implemented this new technique (Jakub et al. 2010 ; McGhan et al. 2011 ; Dauer et al. 2013). RSL uses the same radioactive seed (125I) as those used for manual brachytherapy. However, the U.S. Nuclear Regulatory Commission (U.S. NRC) recognized that this application of radioactive seeds did not conform to the current requirements in medical use category 35.400 (Use of Sources for Manual Brachytherapy). It also did not fall under 35.500 (Use of Sealed Sources for Diagnosis) because, at the time, the sources were not approved for diagnostic use under a sealed source and device registry. Therefore, the use of radioactive seeds for localization was placed under 35.1000 (Other Medical Uses), and the NRC issued its initial licensing guidance entitled “I-125 and Pd-103 Low Dose Rate Brachytherapy Seeds Used for Localization of Non-palpable Lesions” in 2006 (U.S. NRC 2006). Because this procedure used the same seed as that for manual brachytherapy, although at somewhat lower activities, the guidance established many of the same requirements as in 35.400.
As the number of publications and presentations showing the advantages of RSL increased, more institutions became interested in adopting the procedure. By 2012, several institutions (Mayo Clinic, University of Pittsburgh Medical Center) offered workshops on how to implement an RSL program. Feedback at these workshops indicated that limited scope medical licensees were having difficulty in amending their license to add RSL due to the regulatory requirements to comply with the NRC licensing guidance document. Some of these requirements included: 1) Only an Authorized User (AU) may perform seed implants; 2) Requiring supervised work experience under the supervision of a 35.490 AU and preceptor; 3) The AU must have work experience in surgical removal of a seed; 4) Verification of seed activity by direct measurement by the licensee; and 5) Limiting use of instrumentation for performing surveys to a thin crystal sodium iodide (NaI) probe. Because Type A medical broad scope licensees are exempt from submitting an amendment for 35.1000 uses under 35.15(a), they were permitted to develop their own procedures for RSL. It became apparent that the current RSL licensing guidance was somewhat burdensome and should be revised to more accurately reflect the safety and training issues associated with the procedure.
There was a presentation from the user community at the March 2015 Advisory Committee on the Medical Use of Isotopes (ACMUI) Meeting recommending certain modifications to the licensing guidance document to make it more relevant to how RSL is performed (U.S. NRC 2015a). The ACMUI formed a subcommittee to review the guidance and it submitted their final report at the October 2015 ACMUI meeting (U.S. NRC 2015b). Concurrently, the U.S. NRC had formed a Working Group in early 2015 to review the RSL guidance document. The Working Group’s draft guidance was submitted to the ACMUI subcommittee for their review, and the subcommittee’s response was presented at the 2016 ACMUI meeting (U.S. NRC 2016a). The U.S. NRC issued its revised RSL licensing guidance titled “Low Activity Radioactive Seeds Used for Localization of Non-Palpable Lesions and Lymph Nodes” in October 2016 (U.S. NRC 2016b). It is interesting to note that RSL is the only non-therapy procedure covered under 35.1000.
AUTHORIZED USER TRAINING AND EXPERIENCE REQUIREMENTS
The original NRC licensing guidance required an AU for RSL to meet the criteria in either 35.490 (manual brachytherapy) or 35.290 (unsealed sources for imaging and localization) plus have supervised work experience under the supervision of a 35.490 AU and preceptor. This was problematic in that while radiation oncologists routinely perform manual brachytherapy using 125I seeds, they are not likely to implant seeds for localization (nor are they likely to be credentialed for the procedure), as this is a specialty performed by radiologists. Radiologists by training routinely implant clips to mark biopsy sites and wires to localize lesions for surgery using needles under mammographic or ultrasonic guidance. Implanting a radioactive seed with a needle is an equivalent procedure. However, a radiologist was required to have supervised work experience for three patient cases under a radiation oncologist 35.490 approved AU in order for them to initially become qualified as an AU for RSL. Also, most radiologists practicing in breast imaging may not also be practicing in nuclear medicine, and therefore would not meet the requirements in 35.290. These two training and experience requirements made it difficult for a radiologist specializing in breast imaging to become an AU for RSL.
The revised guidance provides the following pathways to become an Authorized User for RSL:
- Individual currently listed on a radioactive materials license as an AU for 35.400 medical use of manual brachytherapy sources, or is certified by a U.S. NRC recognized medical specialty board under 35.490; and has training in the use of the intraoperative gamma probe employed to identify the location of implanted seed(s) for excision;
- Individual currently listed on a radioactive materials license as an AU for 35.200 medical use of byproduct material for imaging and localization studies for which a written directive is not required, or is certified by a U.S. NRC recognized medical specialty board under 35.290; and has the appropriate training and work experience. This supervised training and work experience shall/should include radiation safety procedures and precautions for receiving, preparing, implanting, and removing RSL sources, including performing related radiation surveys after handling of seeds and use of the intraoperative gamma probe. This training and work experience must be under the supervision of an RSL preceptor AU or 35.400 AU, and include participation in at least 3 patient cases; and
- A radiologist that has completed 80 hours of training and experience, including 40 hours of classroom and laboratory training in radionuclide handling technique; and has supervised training and work experience to include radiation safety procedures and precautions for receiving, preparing, implanting, and removing RSL sources, including performing related radiation surveys after all uses of seeds and use of the intraoperative gamma probe. This training and work experience must be under the supervision of an RSL preceptor AU and include participation in at least 3 patient cases. The radiologist must also obtain written attestation from the RSL preceptor AU that he/she has completed the training and experience requirements and is able to independently fulfill the radiation safety related duties as an AU for RSL use.
While radiation oncologists typically do not perform RSL procedures, the U.S. NRC retained an avenue for a radiation oncologist approved under 35.490 to be approved as an AU for RSL. However, they added the requirement for training in the use of instrumentation to identify the location of implanted seed(s) for surgical excision (i.e., intraoperative gamma probe). This training must be provided by an RSL AU or 35.290 AU experienced with sentinel node biopsy procedures.
Supervision of the required RSL training and work experience for an individual who is an AU for 35. 200 can now be under either an RSL preceptor AU or 35.400 AU, where previously it was only permitted under a 35.400 AU. Retaining the 35.400 AU preceptor allows a pathway for an institution initiating a new RSL program (where no one is currently listed on the radioactive materials license as an AU for RSL) to get an individual listed on the license as an AU for 35.200 to be approved for RSL. The requirement for 3 supervised cases still presents the biggest hurdle in establishing a new program where no one is yet approved as an AU for RSL.
Because most radiologists who perform RSL are specializing in breast imaging, they are most likely to take the newly created third pathway to become an AU. The 40 hours of classroom and laboratory training will have been satisfied by their radiology residency training and the additional required work experience can be obtained during their clinical practice, however, this work experience must be under the supervision of an RSL preceptor AU. This pathway also requires a written attestation from the preceptor AU. It is important to have documentation of the individuals training and experience in all of the areas outlined in the revised guidance. Table 1 provides a summary of the AU pathway requirements.
WORKING UNDER SUPERVISION OF AUTHORIZED USER
The RSL procedure involves a multidisciplinary team to perform three separate components: 1) implanting a radioactive seed in a patient under mammographic or ultrasonic guidance by a radiologist; 2) excision of the target lesion/tissue and seed from the patient by a surgeon; and 3) removing the seed from the tissue specimen by a pathologist or pathology assistant.
The previous guidance implied that only an AU may implant seeds, and thus prevented a radiologist, who is not an AU but has the appropriate training and experience, to implant seeds in a patient. This scenario is similar to a radiologist performing a sentinel node injection of 99mTc sulfur colloid under the “supervision” of the Nuclear Medicine AU. The revised guidance acknowledges that multiple steps of the RSL procedure are performed by individuals working under the supervision of the AU in accordance with 35.27. It identifies the specific radiation safety training topics that must be provided for radiologists, surgeons, and pathology personnel to participate in RSL procedures. This training may be provided by either an RSL AU or the Radiation Safety Officer (RSO). It also requires the RSO to have received training in the radiation safety, regulatory issues, and emergency procedures for RSL, and that this training be supervised by an individual (RSO or AU) that is authorized for RSL procedures. It is important to have documentation of the individuals training and experience in all of the areas outlined in the revised guidance.
The previous guidance required a Written Directive for RSL to have the same documentation requirements as for manual brachytherapy in 35.40(b)(6). The revised guidance recognizes that RSL is a localization procedure using a low activity radioactive seed that does not deliver a therapeutic dose, so it eliminated the requirement for a Written Directive since it did not meet any of the applicable criteria in 35.40. Documentation of the implant is still required and must include the radioisotope, patient’s name or identification number, and measured or manufacturer’s decay corrected activity. While the sources used for RSL are not intended for therapeutic use, they do have the potential to deliver a dose greater than 0.5 Gy to surrounding tissue if left in place for an extended period of time. Typical RSL procedures schedule the explantation of the seed within 5 d following the implantation date. While the seed should be removed as soon as practical to minimize radiation exposure to the patient, there is no time limit set by the U.S. NRC in their guidance document. Licensees are permitted to develop their own procedures that will allow flexibility for patient management in scheduling surgery. Licensees should be cautious in committing to a definite time period for surgical removal of the implanted seed.
MEDICAL EVENT CRITERIA
With RSL the current Medical Event criteria in 35.3045 are not applicable since there is no prescribed dose, and no prescribed implant time. Instead RSL uses an accepted activity range for the seed to be implanted; and a flexible time range that the seed can remain implanted to accommodate a scheduled surgery. The revised guidance lists the following specific criteria that would require Medical Event reporting and notification for RSL:
- Using the wrong radionuclide;
- Implanting a seed in the wrong patient;
- Implanting the wrong number of seeds; or
- Failure to perform the explantation surgery.
The event must also exceed a dose threshold of 0.05 Sv effective dose equivalent or 0.5 Sv to any organ or tissue. However, the guidance states that in situations where the patient failed to return for the scheduled explantation surgery or if a physician determined that removal of the seed would jeopardize the patient’s health, these events would not need to be reported as a Medical Event since they are considered “patient intervention.”
Licensees need to be able to assess the radiation dose to the surrounding tissue for seeds remaining in place for an extended period of time. The dose to tissue at 1 cm from a 200-μCi seed would only be approximately 0.3 Gy if left in place for 5 d. Since several cm of tissue surrounding the seed is removed during surgery, the dose to the remaining tissue would only be approximately 0.02 Gy at a distance of 3 cm from the seed. One method for assessing this dose is to use the tables in the American Association of Physicists in Medicine (AAPM) Report No. 51 titled “Dosimetry of Interstitial Brachytherapy Sources” (AAPM 1995).
The U.S. NRC appropriately excluded wrong implant site from the Medical Event criteria since it would be difficult to judge how far off from the intended target the seed would need to be to meet this criteria, and precise placement of a seed through a needle in soft tissue can be challenging. However, radiologists will often make last-minute decisions to implant more than one seed to bracket a lesion or place another seed closer to the lesion, which may cause confusion with what is intended by “wrong number of seeds,” especially since there is no written directive or prescription specifying the number of seeds to be implanted prior to the procedure. While a very rare occurrence, it is interesting to note that the U.S. NRC did not include implant of a leaking sealed source as one of the Medical Event criteria. A licensee would still be required to report any event resulting from intervention of a patient that results or will result in unintended permanent functional damage to an organ or a physiological system, as determined by a physician, in accordance with 35.3045(b).
RADIATION SURVEYS AND INSTRUMENTATION
There is a commitment to perform radiation surveys and maintain records following implant and explant of the radioactive seed(s) in accordance with 35.404. The original guidance emphasized the use of a portable instrument with a thin crystal sodium iodide (NaI) probe, which is certainly the instrument of choice for trying to locate a lost or missing seed due to its sensitivity for low energy photons. The revised guidance allows the licensee to describe the portable survey instruments and calibrations that will be used to survey for the low activity radioactive seeds in different situations.
A Geiger-Muller (GM) survey meter works well for monitoring the seed implant procedure to confirm that the seed is in the needle prior to the implant, that the seed is in the patient after the implant, and that the seed is no longer inside the needle or loose and free outside of the patient in the implant area.
The intraoperative gamma probe is used for surveying in both the operating room and pathology lab. The surgeon surveys the excised tissue and the surgical site (cavity) where the tissue was removed with the gamma probe to confirm that the seed is located in the specimen and is no longer present in the patient. It is also used by the pathologist to locate the seed in the tissue specimen and confirm its removal. Most gamma probes do not require any routine (annual) calibration. There is only a system check when the instrument is turned on for use.
Most institutions performing RSL will obtain a confirmatory mammographic or ultrasonic image following the implant to visually confirm the presence of the seed, its location, and if it was damaged during insertion. Similarly, a mammographic or ultrasonic image of the specimen is routinely obtained after it has been surgically removed from the patient to confirm the seed location and tissue margins. The U.S. NRC will not permit these images to substitute for the required radiation surveys.
Both the previous and revised guidance place heavy emphasis on routine monitoring before, during, and after all uses of the seeds. This is to ensure rapid identification and remediation of a broken or leaking seed. Emergency procedures should be developed for responding to source rupture, retrieval of leaking/cut sources, contamination control, and decontamination of the patient and area. There have been several reported cases of a 125I seed being cut by pathology personnel during removal from the tissue specimen, so it is important to have written procedures and appropriate equipment to respond to these types of adverse events. Since the RSL procedure is often performed in conjunction with sentinel node biopsy where the patient is injected with approximately 500 μCi of 99mTc sulfur colloid, the radiation from the 99mTc would make it very difficult to detect any leakage of 125I either during the surgical removal of the lesion/seed from the patient or removal of the seed from the lesion in pathology. Consideration should be given to having instrumentation with gamma spectroscopy capability. If the seed is cut/leaking while implanted in the patient, a radiation dose assessment must be performed and consideration given to blocking the patient’s thyroid gland with stable iodine. The revised guidance also requires written emergency procedures for other types of adverse events such as loss of a seed, inability to locate an implanted seed during surgery, or failure of a patient implanted with a radioactive seed to return for their scheduled explantation surgery.
COMMITMENTS FOR CERTAIN SAFETY PRECAUTIONS AND PROCEDURES
The revised guidance changed or eliminated several commitments to certain safety precautions and procedures, which made strict compliance very burdensome. The activity of the seed may now be verified by using the activity measurement provided by the manufacturer for pre-loaded/pre-packaged needles, where previously it implied a direct measurement by the licensee.
Early use of the 125I seeds for RSL was considered “off-label” as the Sealed Source and Device certificate did not address the physical conditions encountered with this procedure. Limited specific medical use licensees were required to obtain an amendment for the new conditions of use, and broad scope licensees had to perform their own engineering and radiation safety evaluation addressing the different conditions of use. If a licensee uses the pre-loaded/pre-packaged needles that are currently approved by the FDA for localization procedures, a custom evaluation for the conditions of use does not need to be performed.
The revised guidance eliminated the commitment to provide annual training on the topics described in 35.410. This training is for personnel caring for patients who are receiving brachytherapy and cannot be released under 35.75, which is not applicable to RSL procedures where patients implanted with seeds are able to be released under 35.75. The revised guidance also eliminated the requirement for the AU to have work experience in “removing RSL sources safely,” and for the surgeon to have work experience in “preparing and implanting brachytherapy sources,” as neither would be medically credentialed to perform those procedures.
The revised guidance retained the commitment to provide the patient with written instruction prior to implantation and to have the patient agree in writing to return for removal of the radioactive seed. Information about the RSL procedure is typically provided to the patient by the surgeon, with emphasis that the patient must return for the scheduled surgery to remove the radioactive seed. An expedient option to obtain patient’s agreement in writing is to include a statement for returning for the scheduled surgery on the radiology implant consent form. No special instruction to the patient with respect to radiation exposure to others is required since they meet the release criteria in 35.75(b).
SEED INVENTORY, TRACKING, AND WASTE DISPOSAL
The radioactive seeds for RSL must be stored in a secure area to prevent unauthorized access or removal as required by 10 CFR 20.1801. Because it is convenient to have the seeds stored close to the room location where they will be implanted, a lockable cabinet in one of the breast imaging rooms is one option. There is a commitment to maintain constant accountability of the seeds in accordance with 35.406. This requires documentation of the number, activity, time, date, location of use, and individual handling the sources each time they are removed and returned to storage. Because it is also important to maintain information to track the radioactive seed from receipt through implant, explant, and disposal, licensees may want to consider an alternative method by using an electronic spreadsheet, which would contain the essential elements required by 35.406 plus the additional seed tracking information. A physical inventory of all radioactive seeds in possession by the licensee is required every 6 mo in accordance with 35.67(g). The required documentation includes the radionuclide, activity, model number, serial number, location, and name of individual performing inventory. The same electronic spreadsheet can be used to provide the semi-annual inventory. Disposal of the radioactive seeds can be by decay in storage, return to manufacturer, or transfer to a licensed radioactive waste broker. Table 2 provides a sample of the information to include in the spreadsheet for tracking radioactive seeds used for RSL.
The use of radioactive seed localization offers both clinical and patient care advantages over the wire localization technique for guiding the surgical excision of non-palpable lesions and lymph nodes. The revised U.S. NRC licensing guidance document for RSL is more focused on how the procedure is performed, and it has eliminated the requirements in the original guidance that were burdensome and not relevant to the RSL procedure. The revised U.S. NRC guidance will allow increased patient access to RSL while maintaining a high level of safety.
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