ML18033B017

Advisory Committee on the Medical Uses of Isotopes (ACMUI) February 15, 2018 Teleconference Meeting Ebinder

ML18033B017
Person / Time
Issue date:	02/01/2018
From:	Dilsizian V, Mettler D, Palestro C, Zanzonico P Advisory Committee on the Medical Uses of Isotopes
To:
Holiday, Sophie
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Download: ML18033B017 (34)

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Advisory Committee on the Medical Uses of Isotopes TELECONFERENCE AGENDA Thursday, February 15, 2018 9:00 AM - 11:00 AM (ET)

OPEN SESSION 9:00 - 10:00 am Discuss the Revised Draft Report of the ACMUI Nursing Mother Guidelines for the Medical Administration of Radioactive Materials 10:00 - 11:00 am Discuss the Revised Draft Report of the ACMUI Physical Presence Requirements for the Leksell Gamma Knife Icon'

Advisory Committee on Medical Uses of Isotopes (ACMUI)

Sub-Committee on Nursing Mother Guidelines for the Medical Administration of Radioactive Materials Subcommittee Members:

Vasken Dilsizian, M.D., Darlene Metter, M.D. (Chair), Christopher Palestro, M.D.,

Pat Zanzonico, Ph.D.

Date: February 1, 2018 Introduction Nursing or breast-feeding is the feeding of an infant from the female breast. Lactation is the process of milk production. Shortly after delivery and along with the initiation of supply and demand, the maintenance of lactation becomes relatively constant with a daily production of about 800 mL1.

Milk production is influenced by many hormones, the most important being prolactin. The release of prolactin is dependent on the removal of milk from the breasts. Milk removal occurs with nursing and stimulates feedback mechanisms promoting the release of prolactin, and thus further milk production. When milk ceases to be removed from the breast, prolactin levels fall with a concomitant rise in Feedback Inhibitor of Lactation, a protein which inhibits milk production. Complete cessation of milk production generally occurs about six weeks after the last breast-feeding.

At times, it is necessary to administer diagnostic or therapeutic radiopharmaceuticals to the nursing mother. Many of these agents appear in breast milk. 2 Therefore, the use of radiopharmaceuticals during nursing raises radiation exposure concerns for both the nursing infant and mother. For the nursing infant, this exposure comes internally, from the ingested radioactive milk, and externally, from exposure to the mother who is a radiation source in close proximity to the infant during nursing and child care. Consequently, the charge of this subcommittee is To review the radiation exposure from diagnostic and therapeutic radiopharmaceuticals, including brachytherapy, to the nursing mother and child.

Current Guidance Breast-feeding is not regulated. A nursing mother who has received unsealed byproduct material can be released by a licensee if the total effective dose equivalent to any other individual, 1 of 26

including her nursing child, is projected to not exceed 5 mSv (0.5 rem). If a nursing mother continues to breast-feed after receiving a radiopharmaceutical and the nursing childs radiation exposure could exceed an effective dose equivalent of 1 mSv (0.1 rem), written instructions must be given to the mother regarding the potential adverse consequences if breast-feeding is not interrupted or ceased as well as guidance on the discontinuation of breast-feeding (10CFR 35.75) 3.

Radiation Safety The ALARA (As Low As (is) Reasonably Achievable) principle is the Nuclear Regulatory Commissions (NRC) guidance on radiation safety (10 CFR 20.1003). ALARA directs the licensee and individuals to take every reasonable effort to decrease ionizing radiation exposure as far below regulatory dose limits as practically possible. These instructions should be individualized to include the consideration of available resources and their value in achieving this radiation exposure goal. Many nuclear medicine procedures are elective, and for the nursing mother it may be possible to delay these exams to allow for the interruption or, in some cases, the cessation of breast-feeding 4.

Before radioiodine therapy, oral and written radiation precaution instructions must be provided to the nursing mother and, as needed, to the appropriate family and/or caretakers. All patient, family or caretaker therapy concerns and questions should also be addressed. This information must be given in a sufficient individualized time frame to allow for appropriate radiation safety preparation, and should be provided at least six weeks prior to the anticipated radioiodine procedure, thereby allowing the necessary time for the cessation of lactation.

Radiopharmaceuticals Radiopharmaceuticals consist of two components: the radioisotope and the non-radioactive carrier targeted for a specific molecule or metabolic pathway.

Once administered, these agents circulate and undergo both radioactive decay of the radioisotope and biologic elimination of the carrier component. The elimination half-time associated with the combined physical decay and pharmacokinetic clearance is termed the effective half-life.

The physical decay or half-life is the time required for a given quantity of radioactivity to decrease to one half of its original activity solely as a result of radioactive decay. For a radionuclide, ten physical half-lives will account for 99.999% of its radioactive decay5.

The biological half-life is the time required to reduce the amount of a given substance in an internal organ or the whole body to one half of its original value solely as a result of biological elimination. Five biological half-lives of most drugs account for 97% of a drugs clearance, and 2 of 26

presumably this clearance also applies to the radiopharmaceutical carrier component in breast milk 6.

Lactation and Breast-feeding Cessation When a radiopharmaceutical is administered to a nursing mother who temporarily stops breast-feeding, it is advisable for her to breast pump during this interruption period. The ongoing removal of breast milk from the breast will ensure that lactation will continue. Expression of milk will also facilitate the radiopharmaceuticals biologic elimination from the breast and therefore, an overall potential reduction in the radiation exposure to the maternal breasts.

During this interruption period, the mother may express and store her milk to be used after the milk is no longer radioactive, which is typically 10 physical half-lives of the radiopharmaceutical (i.e., 99mTc physical half-life is 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br />, equating ten half-lives to 60 hours6.944444e-4 days <br />0.0167 hours <br />9.920635e-5 weeks <br />2.283e-5 months <br />). Breast milk can also be expressed prior to radiopharmaceutical administration and used to feed the nursing child until breast-feeding can be resumed 7. Alternatively, the nursing mother may choose to discard the expressed radioactive milk.

Nursing mothers should inform their healthcare provider of their breast-feeding status so that if a medical procedure involving radioactive material is contemplated, decisions can be made to maximize patient outcomes while minimizing the overall radiation risk to the nursing mother and infant 8.

Appropriate signage should also be posted in the nuclear medicine clinic/waiting room alerting women to notify the nuclear medicine staff before their procedure if they are breast-feeding.

Breast Milk and Drugs When substances enter the maternal circulation, this vascular delivery allows for transfer of material from the glandular breast alveoli into maternal milk. Many factors control the regulation of this transfer and include the dramatic increase in blood flow to the lactating breast.

Shortly after child delivery, a brief period of greater alveolar diffusion occurs which permits a higher level of antibodies, antibacterial factors and other substances to concentrate in breast milk. These diffusion factors are facilitated by low molecular weight, low protein binding and high lipid solubility of these substances 9.

Although the exact mechanism of radiopharmaceutical uptake into breast milk is unknown 10, a drugs concentration in the maternal circulation is generally proportional to its concentration in breast milk. In other words, higher serum levels generally result in a higher drug level in breast milk.

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Radiopharmaceutical uptake by the breast is fairly rapid with peak concentrations at 3-4 hours after administration. It is of interest that studies on breast milk uptake have been highly variable for a given radiopharmaceutical and at different times within the same patient. The biological half-life however, appears less variable 11.

Radiation Exposure to the Maternal Lactating Breast from Diagnostic and Therapeutic Radiopharmaceuticals Systemically administered radiopharmaceuticals will localize in variable amounts to all body tissues, including the breasts. In lactating breasts, enhanced uptake and secretion into breast milk may occur with certain radiopharmaceuticals and possibly their radioactive metabolites 12 13 14 15 16 17 18 19 20 21 22 23 24

. This greater uptake would result in an increased radiation dose to the lactating relative to the non-lactating breast. Due to the relatively high sensitivity of the female breast to radiation carcinogenesis 25, the enhanced radiation dose to the lactating breast warrants consideration. This section therefore addresses the radiation dose to lactating breasts and provides absorbed dose estimates for commonly used radiopharmaceuticals (Table 1).

The time-integrated activity (also known as the cumulated activity or residence time) in the lactating breast results from radiopharmaceutical secretion into breast milk and was estimated by Stabin and Breitz 26. These investigators assumed a linear filling of milk into the breast to a milk volume of 142 ml over 4 hours4.62963e-5 days <br />0.00111 hours <br />6.613757e-6 weeks <br />1.522e-6 months <br /> and then instantaneous emptying at feeding or pumping. The breast absorbed dose was calculated by using the breast-to-breast S values for the Reference Adult female anatomic model of Stabin et al 27. No attempt was made to model the effect of a temporary interruption of breast-feeding since the mother would likely express/pump milk from her breasts at regular intervals, and the net effect would be comparable to actual breast-feeding.

The 2- to 5-fold increase in breast mass that occurs during pregnancy and lactation was also considered. Due to individual variability, these changes were difficult to model with certainty.

However, the overall effect of a larger lactating breast would be a decrease in the absorbed breast dose, since the radioactivity will be deposited over a larger mass. Stabin and Breitz used a standard breast mass (400 g for both breasts) which produced a conservative upper-limit breast dose estimate for most women and a reasonable though less conservative estimate for smaller breasts.

For 18F-FDG , the individual breast activity, expressed as the standard uptake value (SUV), was measured by Hicks et al 28 in a series of oncology patients at one hour after 18F-FDG injection.

Since the biokinetics of FDG are well known, the one-hour SUV was assumed to reflect the maximum breast activity. Conservatively, the kinetics of FDG breast uptake were ignored (i.e.,

uptake was considered instantaneous) and elimination of activity was assumed to occur only by physical decay (i.e., ignoring the effect of actual breast feeding or pumping). Given the short physical half-life of 18F (1.2 hours2.314815e-5 days <br />5.555556e-4 hours <br />3.306878e-6 weeks <br />7.61e-7 months <br />), the latter assumption is likely not overly conservative. The 4 of 26

18 F-FDG breast-to breast absorbed dose was calculated using the OLINDA computer program 29, again assuming breast-to-breast S values for the Reference Adult Female model 30. The absorbed-dose estimates for the lactating breast thus corresponds to self-irradiation (i.e., breast-to-breast) values.

For the majority of radiopharmaceuticals, once in the maternal circulation, there is less than 10% excretion into breast milk, with most estimates at 0.3 to 5% of the administered activity31.

Several authors have reported higher radiopharmaceutical concentrations and cumulative excretions in patients with greater milk production. Cumulative excretions greater than 10%

have been reported only for 67Ga-citrate and 131I-NaI 32. Consequently, except for 67Ga-citrate and 131I-NaI, the highest absorbed dose estimates to the lactating breasts for typical diagnostic administered activities are usually well under 1 rad (0.01 Gy). 67Ga-citrate and 131I-NaI are both actively secreted into breast milk, and result in notably higher absorbed doses to the lactating breast: 1.1 rad (0.011 Gy) for an administered activity of 5 mCi (185 MBq) of 67Ga-citrate and 200 rad (2 Gy) for a therapeutic administered activity of 150 mCi (5,550 MBq) of 131I-NaI. The exceptionally high 131I-NaI dose to the lactating breasts is worrisome, and has led to recommendations for lactating women for whom radioiodine therapy is planned to discontinue breast-feeding six weeks prior to therapy33 34. This recommendation ensures the complete cessation of lactation, which minimizes radioiodine concentration in the maternal breast, and thus, the absorbed maternal breast dose.

Radiation Exposure: Nursing Child from Nursing Mother The dosimetric analyses in this section assume that there is no interruption of breast-feeding following administration of the radiopharmaceutical to the mother.

(a) External Maternal Radiation to the Nursing Child The most obvious mode of radiation exposure to a nursing child from radiopharmaceutical administration to the childs mother is ingestion of maternal milk containing radioactivity. In addition, the nursing child will be exposed externally from radioactivity in the mother, and this exposure may be significant given the close proximity of the mother and child during nursing and child care. Given the general lack of pertinent data in the literature, the external absorbed dose to the nursing child has been estimated by the following model calculations:

Dnursing childlext = Dnursing childmaternal breastlext + Dnursing childmaternal remlext (1) where Dnursing childmaternal breastlext = the external absorbed dose to the nursing child from activity in the maternal breast 5 of 26

and Dnursing childmaternal remlext = the external absorbed dose to the nursing child from activity in the maternal remainder of body (assumed to be equivalent to the maternal torso).

The external absorbed dose to the nursing child from activity in the maternal breast, Dnursing l

childmaternal breast ext, and in theremainder of the mothers body, Dnursing childmaternal remlext, can be calculated by Equations (2) and (3), respectively:

1 Dnursing childmaternal breastlext = maternal breast

• A * *

• CFpoint-to-linelbreast

• rbreast-to-child2 0.5 * [1-(breast-to-breast)]

• Enursing (2) and 1

Dnursing childmaternal remlext = maternal rem

• A * *

• CFpoint-to-linelmaternal rem

• rmaternal rem-to-child2 0.5 * [1-(maternal WBmaternal WB)]

• Enursing (3) where maternal breast = the radionuclide residence time in the maternal breast (in h),

maternal rem = the radionuclide residence time in the maternal remainder of body (in h),

A = the administered activity (in µCi),

= the radionuclide specific gamma-ray constant (in R-cm2/µCi-h),

rbreast-to-child = the maternal breast-to-child distance (in cm), that is, the distance from the mid-line of the maternal breast to the mid-line of the nursing child, rmaternal rem-to-child = the maternal remainder of body-to-child distance (in cm), that is, the distance from the mid-line of the mothers torso to the mid-line of the nursing child, CFpoint-to-linelbreast = the point source-to-line source conversion factor for the breast, CFpoint-to-linelmaternal rem = the point source-to-line source conversion factor for the maternal remainder of body (corresponding to the maternal torso),

(breast-to-breast) = the breast-to-breast photon absorbed fraction, (maternal WB-to-maternal WB)

= the maternal whole body (WB)-to-maternal whole body (WB) photon absorbed fraction, 6 of 26

and Enursing = the occupancy factor for nursing.

The radionuclide residence times in the breast milk, maternal breast, and in the maternal remainder of body, maternal rem, can be calculated by Equations (4) and (5), respectively:

n breast milk = 1.44

• Fbreast milk

• filbreast milk * (Te)ilbreast milk (4) i=1 n

and maternal rem = 1.44

• Fmaternal rem

• filmaternal rem * (Te)ilmaternal rem (5) i=1 where Fbreast milk = the cumulative fraction of the administered activity in breast milk, filbreast milk = the fraction corresponding to component i of the exponential function describing the time-activity data for breast milk, (Te)ilbreast milk = the effective half-time of component i of the exponential function describing the time-activity data for breast milk, Fmaternal rem = the fraction of the administered activity in maternal remainder of body, filmaternal rem = the fraction corresponding to component i of the exponential function describing the time-activity data for the maternal remainder of body, and (Te)ilbreast milk = the effective half-time of component i of the exponential function describing the time-activity data for the maternal remainder of body.

Implicit in equations (2) and (3) is the assumption that the beta-particle contribution to the external dose from the mother to the nursing child is negligible; given the very short range of beta particles in tissue, this is a reasonable assumption. The factor, 0.5, in Equations (2) and (3) reflects the fact that radiations emitted from within the mother have an equal probability of traveling either towards or away from the nursing child. Furthermore, rather than modeling the maternal breast and torso as point sources, they have been modeled as line sources as described by Siegel et al 35. This provides a more accurate approach to estimating the distance-dependence of the mother-to-child doses than the conventional point-source model.

(b) Internal Radiation Dose to the Nursing Child from Ingestion of Radioactive Milk The second major pathway of radiation exposure to a nursing child resulting from radiopharmaceutical administration to the childs mother is the ingestion of radioactive maternal 7 of 26

milk. As already noted, generallyless than 10% of an administered radiopharmaceutical activity is excreted into breast milk; typical estimates range from 0.3% to 5% of the initial administered activity36. Higher cumulative excretions been reported only with 67Ga-citrate and 131I-NaI up to

~10 and ~25%, respectively37. Based on the cumulative fraction of the administered activity in breast milk and the half-time(s) of clearance from breast milk (Table 3), radiopharmaceutical residence times can be calculated using equation (4).

Assuming complete ingestion of the 142 mL (Stabin and Breitz26) of radioactive milk by the nursing child and ignoring the subsequent kinetics of absorption and clearance from the child, the whole-body residence time of the radiopharmaceutical in the child can be equated with its residence time in the breast milk, breast milk. An upper limit of the whole-body absorbed dose to the nursing child (specifically, for the Reference Newborn anatomic model) from ingestion of radioactive milk, Dnursing childlint, can then be derived using equation (6):

Dnursing childlint = breast milk

• DF(WBWB)newborn (6) where DF(WBWB)newborn = the whole body-to-whole body dose factor (in rad/mCi-h) for the Reference Newborn anatomic model.

Implicit in the dose estimates shown in Table 3 is that breast-feeding was not interrupted following administration of the radiopharmaceutical to the nursing mother.

(c) Total Radiation Dose to the Nursing Child The total radiation doses to a nursing child for various radiopharmaceuticals administered to the mother, calculated by summing the respective external and internal radiation doses, are presented in Table 4; these represent the mean whole-body absorbed doses to the child. The calculated absorbed doses to the nursing child if breast-feeding were not interrupted uniformly exceed 0.1 rad (= 100 mrad), and thus the 100-mrem (1-mSv) maximum recommended dose limit for a nursing child.

Despite the conservative assumptions implicit in estimating the doses for 18F-FDG and 99mTc-labeled radiopharmaceuticals, these doses only slightly exceed the 100-mrem dose limit. 67Ga-citrate and 131I-NaI doses, however, exceed the 100-mrem dose limit by more than an order of magnitude and with 131I-NaI therapy by several orders of magnitude. Therefore, with the exception of 131I-NaI and several other radiopharmaceuticals (See Precautions for Nursing Mothers: Recommendations and Rationale and Table 5 below), a brief temporary discontinuation of breast-feeding following maternal radiopharmaceutical administration is sufficient to maintain the nursing childs radiation dose below the 100-mrem (1-mSv) dose limit.

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The magnitude of the radiation dose to the nursing child for 131I-NaI, especially for therapy, reinforces the need for permanent discontinuation of breast-feeding for the current child following 131I-NaI administration to the nursing mother. Breast feeding, however, is allowed for future pregnancies. The radiation dose to the nursing childs thyroid will be considerably higher than that to the whole-body (with the potential for damage to the childs thyroid), further reinforcing the need to cease breast-feeding for any 131I administration.

For 67Ga-citrate, the dose to the nursing mothers breast and the whole-body dose to the nursing child will be significant as well if breast-feeding is not discontinued (see Tables 2, 3 and 4).

However, based on the dose estimates to the maternal breast (Table 1), and in contrast to the recommendation for a therapeutic administration of 131I, discontinuation of breast-feeding prior to the administration of 67Ga-citrate is not required. Following administration of 67Ga-citrate, discontinuation of breast-feeding for a period of 4 weeks is recommended, which is consistent with the most conservative recommendation in the literature.

Radiation Exposure to the Nursing Child from Implanted Sources: Brachytherapy and Radioactive Seed Localization Brachytherapy is used to treat breast cancer, especially in breast conservation surgery for early-stage cancer 38 39 40. The purpose of brachytherapy is to deliver a localized boost dose to the lumpectomy bed after whole-breast radiation. Several brachytherapy treatments are usually required. After each treatment, the radioactive seed is removed and no radioactivity remains in the breast. Accordingly, except for suspending breast-feeding while the sources are in place, brachytherapy does not present any restrictions on breast-feeding.

Radioembolic therapy using ytrrium-90 (90Y)-labeled microspheres (SirSpheres',

TheraSperes') is used for treating unresectable liver tumors 41 42. Under fluoroscopic guidance the radiolabeled microspheres are infused intra-arterially to selectively treat tumors, thereby relatively sparing normal tissue. The 90Y microsphere system is considered a medical device (i.e., a brachytherapy device) and is licensed under 10CFR35.1000 (Other medical uses of byproduct material or radiation from byproduct material). As a pure beta emitter, 90Y does not cause a significant external radiation hazard from the resulting bremsstrahlung, which produces only a negligible external dose 43. For lactating mothers who receive 90Y -microspheres breast-feeding does not need to be interrupted, as the 90Y does not enter the systemic circulation, breast tissue or breast milk. As noted, there is no significant external dose to the child (as only the potential source of external radiation from 90Y is the very low-yield emission of bremsstrahlung).

The purpose of radioactive seed localization (RSL) is to preoperatively localize suspicious non-palpable breast lesions for surgical excision 44 45. RSL is an alternative to the traditional needle-9 of 26

wire preoperative localization, wherein a non-radioactive percutaneous wire is placed into the breast to guide surgical excision of suspicious tissue.

The RSL seed(s) may be removed intra-operatively from the tissue specimen or more commonly, the tissue specimen containing the seed(s) is sent to Pathology for seed removal, analysis and documentation. Breast-feeding should be suspended while the seeds are in place. No radioactivity remains in the breast once all seeds have been removed and accounted for. Breast-feeding can be continued up to seed implantation and resumed immediately after seed removal.

Precautions for Nursing Mothers: Recommendations and Rationale Existing recommendations for nursing mothers promulgated by the NRC 46, the International Commission on Radiological Protection (ICRP) 47, and others 48 are based on a maximum dose (i.e., dose equivalent) to the nursing child of 100 mrem (0.1 rem). As summarized in Table 5, the extant recommended precautions for nursing mothers are somewhat variable in terms of both the radiopharmaceutical and the time interval for breast feeding interruption following radiopharmaceutical administration to the nursing mother. The cited NRC and ICRP recommendations are the most current and up-to-date.

In formulating the current recommendations - listed in the last column in Table 5 - our Sub-Committee generally selected the most conservative existing recommendation, which was usually the longest interruption period for each radiopharmaceutical. To the extent that it is practical, expressed radioactive milk can be held for decay in storage for the same length of time as the recommended interruption period and then used for feeding the child. The Sub-Committees recommended interruption periods apply not only to breast-feeding but also to the close physical proximity of the nursing mother to the nursing child (i.e., caressing or holding the child with a similar distance to the mother as for breast-feeding).

Specific Sub-Committee recommendations for the nursing mother include the following:

1. For 99mTc-labeled radiopharmaceuticals, rather than a radiopharmaceutical-specific interruption period, a single interruption period of 24-hours is recommended. Although this time interval may be longer than absolutely necessary for some 99mTc-labeled radiopharmaceuticals, it is compliant with the 100-mrem dose limit and simplifies the guidance, thereby avoiding confusion and reducing the likelihood of error.

2. For 18F-FDG, all other 18F-labeled and all gallium-68 (68Ga)-labeled radiopharmaceuticals, a 12-hour interruption period is recommended. This conservative recommendation is cautious and simplifies safety instructions for patients and medical professionals. A 12-hour interruption period is recommended for 68Ga for the following reasons: (a) a physical half-life comparable to that of 18F, (b) the propensity of free 10 of 26

radiogallium to accumulate in breast milk and (c) the lack of relevant data on 68Ga-labeled agents in nursing mothers.

3. For very-short-lived positron-emitting radionuclides used in imaging, carbon-11 (11C)

(physical half-life: 20.4 min), nitrogen-13 (13N) (9.97 min), and oxygen-15 (15O) (2.04 min), and generator-produced rubidium-82 (82Rb) (1.27 min), no interruption in breast-feeding is recommended, since there is no significant activity remaining in the mother after the procedure is completed.

4. For iodine-123 in the form of NaI (123I-NaI), an interruption period of 7 days is recommended. This is in marked contrast to the past, where complete cessation of breast-feeding for the current child was recommended. This older, more stringent 123I-NaI recommendation was largely based on contamination (up to 2.5% of the total activity) with long-lived iodine-125 (125I) (physical half-life: 60 days) that occurred with older methods of 123I production 49. Such contamination of 123I with 125I no longer occurs.

Therefore, the restrictions on breast-feeding following 123I-NaI administration to the nursing mother may be justifiably relaxed to an interruption period of 7 days.

5. For gallium-67 (67Ga)-gallium-citrate, an interruption period of 28 days is recommended, which is consistent with the most conservative recommendations for 67Ga in the literature. For indium-111 (111In) labeled white cells an interruption period of 7 days and for thallium-201 (201Tl-chloride) an interruption period of 14 days are recommended.

These recommendations mirror that of the NRC in the Consolidated Guidance About Materials Licenses: Program-Specific Guidance About Medical Use Licenses, NUREG-1556, Vol 9, Rev 1, Appendix U, 2005.

6. For zirconium-89 (89Zr), a 28-day (i.e., 4-week) interruption period was set equal to the maximum recommended interruption period for 67Ga. The rationale for this recommendation are the comparable physical half-lives of 89Zr (3.27 days) and 67Ga (3.26 days), both 89Zr and 67Ga are radiometals and may share some common chemical properties, and lastly, there is a lack of relevant data on 89Zr-labeled agents in nursing mothers.

For lutecium-177 (177Lu), based on the foregoing 89Zr rationale and a longer physical half-life (6.65 days), an interruption period of 35-days (i.e., 5 weeks) is recommended for 177 Lu-labeled radiopharmaceuticals used diagnostically. For 177Lu-labeled radiopharmaceuticals used therapeutically, much higher activities are administered, and thus, permanent cessation of breast-feeding for the current child is recommended.

7. For radium-223 (223Ra) and all other alpha particle-emitting radionuclides, permanent discontinuation of breast-feeding for the current child is recommended. Alpha particles are densely ionizing, have high-linear energy transfer (LET) radiations that potentially incur far more significant biological effects than beta-particles, and are of particular concern in the young child in whom rapid growth and development are occurring. In the absence of relevant data and out of an abundance of caution, permanent discontinuation of breast-feeding for the current child is therefore recommended.

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Subcommittee Recommendations for the Nursing Mother Radiopharmaceutical Breast Feeding Cessation 11 C, 13N, 15O, 82Rb None 18 F-labeled 12-hours 68 Ga-labeled 12-hours 99m Tc-labeled 24-hours 123 I-NaI 7 days 111 In-leukocytes 7 days 201 Tl-chloride 14 days 67 Ga and 89Zr 28 days 177 Lu, diagnostic 35 days 131 I-NaI Stop breast feeding 177 Lu, therapeutic Stop breast feeding 223 Ra and all alpha emitters Stop breast feeding Patient Information: Departmental Signage for Nursing Mothers Nursing mothers undergoing a nuclear medicine or nuclear cardiology procedure may not be aware of the potential dosimetric impact of such procedures on themselves and their nursing child. It is important that nuclear medicine and nuclear cardiology facilities therefore alert nursing mothers that certain radiation safety precautions with respect to breast-feeding may be required before and after they receive a radiopharmaceutical. Analogous to the signage used to alert pregnant and potentially pregnant patients to possible hazards of nuclear medicine and radiological procedures, the following or equivalent signage should be prominently displayed in all patient areas of a nuclear medicine or nuclear cardiology facility: If you are currently breast-feeding or plan to begin breast-feeding in the near future, inform the technologist, nurse or doctor immediately. Depending on the patient demographics in a particular facility, posting such signage in various foreign languages as well as in English should be considered.

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Table 1 Radiopharmaceutical Absorbed Doses to the Lactating Breast Breast Absorbed Dose 50 51 Administered Activity Lowest Estimate Highest Estimate Radiopharmaceutical mCi MBq Rad Gy rad Gy 18 F-FDG 10 370 1.2E-01 1.2E-03 2.0E-01 2.0E-03 51 Cr-EDTA 0.05 1.85 4.2E-07 4.2E-09 2.5E-06 2.5E-08 67 Ga-citrate 5 185 2.2E-02 2.2E-04 1.1E+00 1.1E-02 99m Tc-DTPA 20 740 6.1E-04 6.1E-06 1.2E-02 1.2E-04 99m Tc-DTPA aerosol 1 37 1.2E-05 1.2E-07 2.5E-04 2.5E-06 99m Tc-DISIDA 8 296 2.0E-03 2.0E-05 6.0E-03 6.0E-05 99m Tc-glucoheptonate 20 740 3.6E-03 3.6E-05 7.4E-03 7.4E-05 99m Tc-HAM 8 296 8.5E-03 8.5E-05 2.3E-02 2.3E-04 99m Tc-MAG3 5 185 3.0E-04 3.0E-06 6.0E-03 6.0E-05 99m Tc-MAA 4 148 1.6E-03 1.6E-05 1.2E-01 1.2E-03 99m Tc-MDP 20 740 2.7E-03 2.7E-05 3.8E-03 3.8E-05 99m Tc-MIBI 30 1110 5.5E-04 5.5E-06 5.1E-03 5.1E-05 99m Tc-PYP 20 740 4.2E-03 4.2E-05 2.2E-02 2.2E-04 13 of 26

99m Tc-RBCs - in vitro labeling 20 740 9.3E-04 9.3E-06 1.6E-03 1.6E-05 99m Tc-RBCs - in vivo labeling 20 740 2.5E-04 2.5E-06 1.1E-01 1.1E-03 99m Tc-pertechnetate 30 1110 1.9E-03 1.9E-05 2.5E-01 2.5E-03 99m Tc-sulfur colloid 12 444 3.2E-03 3.2E-05 4.6E-02 4.6E-04 99m Tc-WBCs 10 370 1.1E-02 1.1E-04 1.5E+00 1.5E-02 111 In-WBCs 0.5 18.5 5.0E-04 5.0E-06 2.5E-03 2.5E-05 123 I-MIBG 10 370 - - 2.7E-02 2.7E-04 123 I-NaI 0.4 15 - - 4.7E-02 4.7E-04 123 I-OIH 2 74 5.5E-03 5.5E-05 5.8E-02 5.8E-04 125 I-OIH 0.01 0.37 - - 8.5E-05 8.5E-07 131 I-OIH 0.3 11 5.0E-03 5.0E-05 3.2E-02 3.2E-04 131 I-NaI 150 5,550 - - 2.0E+02 2.0E+00 201 Tl-chloride 3 111 2.4E-03 2.4E-05 4.1E-03 4.1E-05 14 of 26

Table 2 Estimation of the External Radiation Dose from the Mother to the Nursing Child Assuming No Interruption of Breast-feeding:

Model Parameters 18 F-FDG 67 Ga-citrate 99m Tc 131 I-NaI "Worst case" Photon energy (keV) 511 93, 185, 300 140 364 Physical half-life (h) 1.2 78.2 6.04 193 Specific Gamma-ray Constant, G (R-cm2/mCi-h) 52 0.0057 0.00080 0.00060 0.0022 Administered Activity (mCi), A - Assumed 10 5 30 5 (imaging), 150 (therapy)

Cumulative fraction of activity in breast milk, fbreast milk 0.040 53 0.10 54 0.05 55 0.25 56 Fraction of activity in remainder of body, fmaternal rem 57 0.96 0.90 0.95 0.75 Maternal whole body-to-whole body photon absorbed fraction, f(maternal WB¬maternal WB) 58 0.34 0.31 0.31 0.31 Maternal breast-to-breast photon absorbed fraction, f(Br¬Br) 59 0 0 0 0 Effective half-time of activity in breast, (Te)breast milk (h) 60 1.2 78.2 6.02 10.4 (99%)

81.8 (1%)

Effective half-life of activity in maternal remainder of body, (Te)maternal rem (h) 61 1.2 78.2 6.02 38.4 Distance from mother's breast to nursing child, rbreast-to-child (cm) 62 7.5 Point source-to-line source conversion factor for maternal breast-to-child exposure, CFpoint-to-linelbreast 63 0.32 Distance from mother's torso to nursing child, rmaternal rem-to-child (cm) 64 15 Point source-to-line source conversion factor for maternal torso-to-child exposure, CFpoint-to-linelmaternal rem 65 0.54 Occupancy factor for nursing, Enursing 66 0.33 15 of 26

Table 3 Internal Radiation Dose to the Nursing Child from Ingestion of Radioactive Milk Assuming No Interruption of Breast-feeding:

Model and Kinetic Parameters and Radiation Dose Estimates Reference Newborn Newborn Whole-Body Absorbed Cumulative Residence Time Whole Body-to- Doses, Dnursing childlint Assumed Effective Half-Fraction Excreted in Breast Whole Body Dose Administered Time in Breast Radiopharmaceutical in Breast Milk, Milk tbreast milk 67 Factor Activity (mCi) Milk, (Te)i 1 hours1.157407e-5 days <br />2.777778e-4 hours <br />1.653439e-6 weeks <br />3.805e-7 months <br /> (fbreast milk) (µCi-h/µCi) (DF(WB¬WB)newborn 68rad/µCi-h) rad/mCi rad/Administered Activity 18F-FDG 10 0.04 69 1.2 70 0.048 2.44E-04 0.012 0.12 67Ga-citrate 5 0.10 71 78.2 72 7.8 3.68E-05 0.29 1.4 99mTc, "Worst case" 30 0.05 73 6.02 74 0.30 2.16E-05 0.0065 0.19 131I-NaI 5 (imaging), 0.25 75 10.4 (99%) 76 2.78 1.53E-04 0.43 2.2, 65 150 (therapy) 81.8 (1%)

16 of 26

Table 4 Total Radiation Dose to the Nursing Child Assuming No Interruption of Breast-feeding 17 of 26

Table 5 Recommendations for Cessation of Breast-feeding in Nursing Mothers Undergoing Nuclear Medicine Procedures 28 d 18 of 26

19 of 26 References 1

Fahey F, Zanzonico P, Radiation Safety for Nursing Mothers Undergoing Nuclear Medicine Procedures, presentation, 49th Annual Conference of Radiation Control Program Directors, May 8-11, 2017.

2 Kelly Mom Parenting Breastfeeding website 3

US Nuclear Regulatory Commission Regulatory Guide 8.39: Release of Patients Administered Radioactive Materialsm, April 1997.

4 Royal HD, Schwarz SW, Seigel BA: Case 17: Radiopharmaceutical Misadministration. In:

Nuclear Radiology (Fifth Series) Test And Syllabus (Keyes JW, Brown ML, Miller TR, eds.),

American College of Radiology, Reston, VA, 1998 pp 177-191.

5 Chandra R Introductory Physics of Nuclear Medicine, 3rd edition. Philadelphia. 1990 p.34-37.

6 Anderson PO Radiopharmaceuticals LactMed Update. Breastfeeding Medicine Vol 11(5):2016.

Page 216-217.

7 Ibid 8

Ibid 9

Anderson PO Radiopharmaceuticals LactMed Update. Breastfeeding Medicine Vol 11(5):2016.

Page 216-217.

10 Stabin MG, Breitz HB. Breast Milk Excretion of Radiopharmaceuticals: Mechanisms, Findings and Radiation Dosimetry. J Nucl Med 2000; 41:863-873.

11 Ibid 12 Ibid 13 Hedrick WR, Di Simone RN, and Keen RL: Radiation dosimetry from breast milk excretion of radioiodine and pertechnetate. J Nucl Med. 27:1569-71, 1986.

14 Mountford PJ and Coakley AJ: Breast milk radioactivity following injection of 99Tcm-pertechnetate and 99Tcm-glucoheptonate. Nucl Med Commun. 8:839-45., 1987 15 Mountford PJ and Coakley AJ: A review of the secretion of radioactivity in human breast milk: data, quantitative analysis and recommendations. Nucl Med Commun. 10:15-27, 1989.

16 Mountford PJ, Coakley AJ, and Hall FM: Excretion of radioactivity in breast milk following injection of 99Tcm- DTPA. Nucl Med Commun. 6:341-5, 1985.

20 of 26

17 Ogunleye OT: Assessment of radiation dose to infants from breast milk following the administration of 99mTc pertechnetate to nursing mothers. Health Phys. 45:149-51, 1983.

18 Robinson PS, Barker P, Campbell A, et al.: Iodine-131 in breast milk following therapy for thyroid carcinoma [see comments]. J Nucl Med. 35:1797-801, 1994.

19 Rubow S, Klopper J, Wasserman H, et al.: The excretion of radiopharmaceuticals in human breast milk: additional data and dosimetry [see comments]. Eur J Nucl Med. 21:144-53, 1994.

20 Rumble WF, Aamodt RL, Jones AE, et al.: Accidental ingestion of Tc-99m in breast milk by a 10-week-old child. J Nucl Med. 19:913-5, 1978.

21 Sharma SC, Osborne RP, Jose B, et al.: Dose estimation to the infant from breast milk following intraperitoneal administration of chromic phosphate 32P for the treatment of early ovarian cancer. Health Phys. 47:452-4, 1984.

22 Siddiqui AR: Accidental ingestion of Tc-99m in breast milk by a 10-week-old child [letter]. J Nucl Med. 20:799, 1979.

23 Simon SL, Luckyanov N, Bouville A, et al.: Transfer of 131I into human breast milk and transfer coefficients for radiological dose assessments. Health Phys. 82:796-806, 2002.

24 Castronovo FP, Jr., Stone H, and Ulanski J: Radioactivity in breast milk following 111In-octreotide. Nucl Med Commun. 21:695-9, 2000.

25 BEIR, Health Effects of Exposure to Low Levels of Ionizing Radiation (BEIR VII).

Biological Effects of Ionizing Radiation (BEIR) Committee, National Research Council. 2006, Washington, DC: National Academies Press.

26 Stabin MG, Breitz HB. Breast Milk Excretion of Radiopharmaceuticals: Mechanisms, Findings and Radiation Dosimetry. J Nucl Med 2000; 41:863-873.

27 Stabin M, Watson E, Cristy M, et al., Mathematical Models and Specific Absorbed Fractions of Photon Energy in the Nonpregnant Adult Female and at the End of Each Trimester of Pregnancy. 1995, Oak Ridge National Laboratoies: Oak Ridge, TN 28 Hicks RJ, Binns D, and Stabin MG: Pattern of uptake and excretion of (18)F-FDG in the lactating breast. J Nucl Med. 42:1238-42, 2001.

29 Stabin MG, Sparks RB, and Crowe E: OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med. 46:1023-7, 2005.

21 of 26

30 Cristy M and Eckerman K, Specific absorbed fractions of energy at various ages from internal photon sources (I-VII). Oak Ridge National Laboratory Report ORNL/TM-8381/V1-7. 1987, Springfield, VA: National Technical Information Service, Dept of Commerce.

31 Stabin MG, Breitz HB. Breast Milk Excretion of Radiopharmaceuticals: Mechanisms, Findings and Radiation Dosimetry. J Nucl Med 2000; 41:863-873.

32 Ibid 33 Luster M, Clarke SE, Dietlein M, et al.: Guidelines for radioiodine therapy of differentiated thyroid cancer. Eur J Nucl Med Mol Imaging. 35:1941-59, 2008.

34 Fact Sheet: Guidelines for Patients Receiving Radioiodine I-131 Treatment. Available from:

http://snmmi.files.cms-plus.com/FileDownloads/Patients/FactSheets/Radio_.pdf.

35 Siegel JA, Marcus CS, and Sparks RB: Calculating the absorbed dose from radioactive patients: the line-source versus point-source model. J Nucl Med. 43:1241-4, 2002.

36 Stabin MG, Breitz HB. Breast Milk Excretion of Radiopharmaceuticals: Mechanisms, Findings and Radiation Dosimetry. J Nucl Med 2000; 41:863-873.

37 Ibid 38 Polgar C and Major T: Current status and perspectives of brachytherapy for breast cancer. Int J Clin Oncol. 14:7-24, 2009.

39 Smith BD, Arthur DW, Buchholz TA, et al.: Accelerated partial breast irradiation consensus statement from the American Society for Radiation Oncology (ASTRO). Int J Radiat Oncol Biol Phys. 74:987-1001, 2009.

40 Smith GL, Xu Y, Buchholz TA, et al.: Brachytherapy for accelerated partial-breast irradiation:

a rapidly emerging technology in breast cancer care. J Clin Oncol. 29:157-65, 2011.

41 Thomson W, Mills A, Smith N, et al.: Day and night radiation doses to patients' relatives:

Implications of ICRP 60 (Abstract). Nucl Med Commun. 14:275, 1993 42 Edeline J, Gilabert M, Garin E, et al.: Yttrium-90 microsphere radioembolization for hepatocellular carcinoma. Liver Cancer. 4:16-25, 2015.

43 Zanzonico PB, Binkert BL, and Goldsmith SJ: Bremsstrahlung radiation exposure from pure beta-ray emitters. J Nucl Med. 40:1024-8, 1999.

44 Jakub JW, Gray RJ, Degnim AC, et al.: Current status of radioactive seed for localization of non palpable breast lesions. Am J Surg. 199:522-8, 2010.

22 of 26

45 Gray RJ, Pockaj BA, Karstaedt PJ, et al.: Radioactive seed localization of nonpalpable breast lesions is better than wire localization. Am J Surg. 188:377-80, 2004.

46 NRC, Consolidated Guidance About Materials Licenses Program-Specific Guidance About Medical Use Licenses, Draft Report for Comment, NUREG-1556, Volume 9, Rev. 3, N.R.

Commission, Editor. 2016: Rockville, MD.

47 ICRP: Annex D. Recommendations on Breat-Feeding Interruptions. Radiation Dose to Patients from Radiopharmaceuticals. A Third Amendment to ICRP Publication 53. Annals of the ICRP. 38:163-165, 2008.

48 Center MSKC, Policy and Procedure L1208 - Lactating Mothers Receiving Radiopharmaceuticals. 2017: New York, NY.

49 Johns H and Cunningham J, The Physics of Radiology. 1974, Springfield, IL: Charles C Thomas. pp 276-277.

50 Except for 18F-FDG, the breast absorbed doses are taken from Stabin MG and Breitz HB:

Breast milk excretion of radiopharmaceuticals: mechanisms, findings, and radiation dosimetry. J Nucl Med. 41:863-73, 2000. The 18F-FDG breast absorbed doses were calculated based on the referenced data from Hicks RJ, Binns D, and Stabin MG: Pattern of uptake and excretion of 18F-FDG in the lactating breast. J Nucl Med. 42:1238-42, 2001.

51 For radiopharmaceuticals which only a single breast absorbed dose is available in the literature, the absorbed dose is listed in the "Highest Estimate" column.

52 The specific gamma-ray constant, G, is the photon exposure rate (in R/h) at 1 cm from a 1-mCi point source in air.

53 Hicks RJ, Binns D, and Stabin MG: Pattern of uptake and excretion of (18)F-FDG in the lactating breast. J Nucl Med. 42:1238-42, 2001.

54 Stabin MG and Breitz HB: Breast milk excretion of radiopharmaceuticals: mechanisms, findings, and radiation dosimetry. J Nucl Med. 41:863-73, 2000.

55 Ibid 56 Robinson PS, Barker P, Campbell A, et al.: Iodine-131 in breast milk following therapy for thyroid carcinoma [see comments]. J Nucl Med. 35:1797-801, 1994.

57 The fraction of activity in the maternal remainder of the body, fmaternal rem, equals 1 minus the cumulative fraction of activity in breast milk.

23 of 26

58 Cristy M and Eckerman K, Specific absorbed fractions of energy at various ages from internal photon sources (I-VII). Oak Ridge National Laboratory Report ORNL/TM-8381/V1-7. 1987, Springfield, VA: National Technical Information Service, Dept of Commerce.

59 It is conservatively assumed that the maternal breast does not attenuate any of the photon radiation emitted from the breast.

60 For short-lived 18F and 99mTc, the effective half-time in breast milk, (Te)breast milk, is conservatively equated with the respective physical half-life. For 131I, the bi-exponential time-activity function with the effective half-times listed is referenced in Robinson PS, Barker P, Campbell A, et al.: Iodine-131 in breast milk following therapy for thyroid carcinoma [see comments]. J Nucl Med. 35:1797-801, 1994.

61 For short-lived 18F and 99mTc, the effective half-time in maternal remainder of body, (Te)maternal 131 rem, is conservatively equated with the respective physical half-life. For I, the whole-body biological half-time in a post-thyroidectomy thyroid cancer patient was assumed to be 2 days (or 48 hours5.555556e-4 days <br />0.0133 hours <br />7.936508e-5 weeks <br />1.8264e-5 months <br />).

62 The distance from the mother's breast to the nursing child, rbreast-to-child, corresponds to the assumed approximate distance from the mid-line of the mother's breast (i.e., for the Reference Adult Female anatomic phantom) to the mid-line of the child (i.e., the Reference Newborn anatomic model). This is the sum of the one-half of the "a" parameter value, 1/2

• 5 cm =2.5 cm, tabulated for the Reference Adult Female and the "BT" parameter value, 2.5 cm, for the Reference Newborn referenced in Cristy M and Eckerman K, Specific absorbed fractions of energy at various ages from internal photon sources (I-VII). Oak Ridge National Laboratory Report ORNL/TM-8381/V1-7. 1987, Springfield, VA: National Technical Information Service, Dept of Commerce.

63 In order to model the maternal breast activity as a line source, rather than a point source, a conversion factor is required to appropriately adjust the inverse-square dependence on distance of the point-source dose rate. This conversion factor depends on the length of the line source, which is 5 cm for the breast line source, and the distance from the line source, which is rbreast-to-child = 7.5 cm for the mid-line of the nursing child.

The length of the breast line source is equated with parameter "c" tabulated for the Reference Adult Female anatomic model referenced in Cristy M and Eckerman K, Specific absorbed fractions of energy at various ages from internal photon sources (I-VII). Oak Ridge National Laboratory Report ORNL/TM-8381/V1-7. 1987, Springfield, VA: National Technical Information Service, Dept of Commerce.

24 of 26

The conversion factor is taken from Siegel JA, Marcus CS, and Sparks RB: Calculating the absorbed dose from radioactive patients: the line-source versus point-source model. J Nucl Med.

43:1241-4, 2002, Table 1.

64 The distance from the mother's torso to the nursing child, rmaternal rem-to-child, corresponds to the assumed approximate distance from the mid-line of the mother (i.e., for the Reference Adult Female anatomic phantom) to the mid-line of the child (i.e., the Reference Newborn anatomic model). This is the sum of the "BT" parameter values, 5 and 10 cm res[ectively to include conversion factor referenced in Cristy M and Eckerman K, Specific absorbed fractions of energy at various ages from internal photon sources (I-VII). Oak Ridge National Laboratory Report ORNL/TM-8381/V1-7. 1987, Springfield, VA: National Technical Information Service, Dept of Commerce.

65 See Note 63. For the point source-to-line source conversion factor for the maternal torso-to-child exposure, the length of the line source is 63 cm for the maternal torso and the distance from the line source is rmother-to-child = 15 cm. The length of the maternal torso line source is equated with parameter "CT" tabulated for the Reference Adult Female anatomic model referenced in Cristy M and Eckerman K, Specific absorbed fractions of energy at various ages from internal photon sources (I-VII). Oak Ridge National Laboratory Report ORNL/TM-8381/V1-7. 1987, Springfield, VA: National Technical Information Service, Dept of Commerce.

66 An occupancy factor for nursing, Enursing, of 0.25 conservatively assumes that the child will actually be nursing for 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> out of each day (24 hours2.777778e-4 days <br />0.00667 hours <br />3.968254e-5 weeks <br />9.132e-6 months <br />).

n 67 breast milk = 1.44

• Fbreast milk

• filbreast milk * (Te)ilbreast milk i=1 68 Cristy M and Eckerman K, Specific absorbed fractions of energy at various ages from internal photon sources (I-VII). Oak Ridge National Laboratory Report ORNL/TM-8381/V1-7. 1987, Springfield, VA: National Technical Information Service, Dept of Commerce. Whole body-to-whole body dose factors, DF(WB¬WB)newborn, were taken from the OLINDA computer program in Stabin MG, Sparks RB, and Crowe E: OLINDA/EXM: the second-generation personal computer software for internal dose assessment in nuclear medicine. J Nucl Med.

46:1023-7, 2005.

69 Hicks RJ, Binns D, and Stabin MG: Pattern of uptake and excretion of (18)F-FDG in the lactating breast. J Nucl Med. 42:1238-42, 2001.

70 Ibid 71 Stabin MG and Breitz HB: Breast milk excretion of radiopharmaceuticals: mechanisms, findings, and radiation dosimetry. J Nucl Med. 41:863-73, 2000.

25 of 26

72 Ibid 73 Stabin MG and Breitz HB: Breast milk excretion of radiopharmaceuticals: mechanisms, findings, and radiation dosimetry. J Nucl Med. 41:863-73, 2000.

74 Ibid 75 Robinson PS, Barker P, Campbell A, et al.: Iodine-131 in breast milk following therapy for thyroid carcinoma [see comments]. J Nucl Med. 35:1797-801, 1994.

76 Ibid 26 of 26

Nuclear Regulatory Commission (NRC)

Advisory Committee on the Medical Use of Isotopes (ACMUI)

Subcommittee on Physical Presence Requirements for the Leksell Gamma Knife Icon' February 1, 2018 Subcommittee Members:

Ronald Ennis, M.D.

John Suh, M.D. (Chair)

Laura Weil NRC Staff Resource: Sophie Holiday Charge to subcommittee: To propose the appropriate physical presence requirement for the Leksell Gamma Knife Icon' radiosurgery unit.

Subcommittee Process The subcommittee and its Chair were appointed by ACMUI Chair, Phil Alderson, at the regularly scheduled ACMUI meeting April 26, 2017. This subcommittee was formed after a presentation on April 26, 2017 by Elekta, Inc. requesting emendation of the Title 10 Code of Federal Regulations (10 CFR) 35.1000 licensing guidance for the Leksell Gamma Knife Icon' to allow the authorized user (AU) to be physically present in the department during patient treatment and immediately available to come to the treatment room to respond to an emergency based on the very small number of medical events (MEs) that have occurred with modern Gamma Knife units. The initial report was presented on September 12, 2017 at the ACMUI meeting. This is an updated report based on feedback from the last ACMUI meeting in September 2017.

Summary of Subcommittee Recommendations

• The AU and authorized medical physicist (AMP) need to be physically present during the initiation of all treatments. This allows independent confirmation that the correct plan is being used for treatment and that the correct site is being treated during the initiation of treatment.

• The current physical presence requirements for the AU be modified by allowing the AU to be present in the department during treatment, which is defined for the Icon' as within a two minute walk to the console area, and immediately available to come to the treatment room. An AMP needs to be physically present during the entire treatment.

While we recognize the NRC does not have regulations for nursing or auxiliary staff, we 1 of 7

recommend as a best practice that appropriately trained nursing or auxiliary staff be present at Gamma Knife treatment to respond to any immediate medical needs. It should be the responsibility of the AU to determine the necessary training and experience required of the nursing staff.

• If there is an interruption of treatment secondary to medical or mechanical issues, the AU must return to Gamma Knife Icon' console to evaluate the patient and/or to review any mechanical issues. The AU must be present to ensure the correct site is being treated prior to re-initiation of treatment.

• At the conclusion of treatment, the AU must be present at the Icon' console to discuss and review any treatment or patient issues with the patient, physicist, and nurse.

Introduction Gamma stereotactic radiosurgery is a very effective and well established treatment for patients with various benign and malignant brain tumors, vascular malformations and some functional disorders such as trigeminal neuralgia. The shielded unit utilizes 192 or 201 Cobalt-60 (Co-60) sources that simultaneously converge to a central target in the brain by the use of different sized collimator channels that are positioned around the patients skull. The first Gamma Knife in the United States was installed at the University of Pittsburgh in 1987 (Model U). Over the next 12 years, the model B and model C units were introduced. These three systems, licensed under 10 CFR 35.600, (Models U, B and C) have tungsten collimators that are external to the Co-60 sources and are placed on the treatment unit manually. All these units required frame-based immobilization and have fixed beam geometry to maximize reliability and minimize quality assurance checks.

In 2006, the Perfexion' unit was introduced. Unlike the model U, B, and C units, the collimators are inside the treatment unit with sources that can be shielded while the treatment helmet is being switched to another size collimator, which can decrease treatment times and manual intervention by the treatment team. The Perfexion' also uses five different positions (16 mm, 4 mm, off, 8 mm, and home, which is an off position) to turn the beam on and off. These sectors allow for rapid change (within 1 second) of the collimators of each sector. Along with engineering differences that would not meet the provisions under 10 CFR 35.600, the NRC decided to license the Perfexion' under 10 CFR 35.1000. In 2016, the Icon' system was introduced, which allowed for treatment with a thermoplastic frameless mask unlike the Perfexion' unit. In addition, the Icon' unit has a cone-beam computed tomography (CT) which provides stereotactic reference for patient setup and high definition motion management for mask-based treatments. Since the introduction of the Gamma Knife in 1987 in the United States, the use of gamma stereotactic radiosurgery has greatly increased in the United States.

Based on information from Elekta, there are 77 Perfexion' units and 22 Icon' units.

Worldwide, over 1 million patients have been treated with the Gamma Knife.

Given the many advances in gamma stereotactic radiosurgery, the delivery has become more efficient allowing for treatment of multiple patients each day and treatment of multiple targets in a single session, which have increased the treatment times for some patients. Given the 2 of 7

evolution of the Gamma Knife over the past decade from the Model C to Perfexion' and now Icon', the physical presence requirements were examined by the subcommittee.

Current Physical Presence Requirement In October 2002, the NRC modified the regulations in 10 CFR Part 35 to include a section1 regarding gamma stereotactic radiosurgery to include the requirement that For gamma stereotactic radiosurgery unit require an Authorized User with appropriate training and experience in radiation oncology and Authorized Medical Physicist to be physically present throughout all patient treatments involving the unit. This regulation provided for an appropriate response to an emergency and to ensure that the correct dose of radiation is delivered to the patient. The term2 physically present was defined as within hearing distance of normal voice.

The NRC issued a Regulatory Issue Summary (RIS) to clarify the definition of physically present as a result of an event at one of the Gamma Knife centers. The RIS (RIS-2005-23)3, Clarification of the Physical Presence Requirement During Gamma Stereotactic Radiosurgery Treatment, stated that this meant speaking in a normal conversational tone and not a raised voice. As a result, a distance of 20 feet may not be close enough to adequately hear and respond to an emergent situation. This also ensures the correct dose of radiation was delivered.

Rationale for change The current definition ensures that an emergent situation will be addressed immediately by the AU and that the correct dose is delivered. The AU has the knowledge and appropriate training to ensure the safe and effective delivery of stereotactic radiosurgery. The current physical presence definition is not ambiguous and ensures the AU is present for the all the critical portions of the procedure, able to address any medical issues that may arise during treatment, and verify the correct dose will be delivered to the target(s). The AU will have the competency to recognize and respond to any aberration of treatment and ensure response times within seconds if needed.

Medical issues during the Gamma Knife treatment may include pain from the frame, nausea, vomiting, and seizure. Incorrect dose of radiation may result secondary to system failure which could be software, hardware, or combination of both. As serious medical issues and/or significant aberrations in treatment can result in reportable MEs, rules regulating physician presence exist to ensure patient safety.

Over the past ten years of NMED, there are 12 reportable events involving the Perfexion'. Of the 12 Perfexion' reportable events, only a minority were identified during treatment. The Icon unit has significant enhancements over the Perfexion' unit. Specifically, three features are important: 1) the option of treatment with a thermoplastic frameless mask rather than a frame, 2) ability to perform integrated stereotactic cone-beam computed tomography (CT) which provides stereotactic reference for patient setup, and 3) high definition motion management for mask-based treatments. These enhancements re-open the question regarding the physical presence requirements of the AU for the entire treatment. A review of the 12 events for Perfexion' reveals that none of these events would have escaped detection on an Icon unit using 3 of 7

the thermoplastic frameless mask and high definition motion management for mask-based treatments even if the AU was not physically at the console and could have been rapidly and effectively addressed as long as the AU was immediately available.

Proposal by Elekta, Inc. on April 26, 2017 for Gamma Knife Icon'

1. We will have an Authorized User and Authorized Medical Physicist physically present during the initiation of all treatments involving the unit.

2. We will have an Authorized Medical Physicist physically present throughout all patient treatments involving the unit.

3. We will have an Authorized User physically present in the department during patient treatment and immediately available to come to the treatment room to respond to an emergency.

Recommendations Based on the extremely low number of MEs with the Perfexion' unit coupled with the modifications with the Icon', the subcommittee recommends modifying the current physical presence requirements for the Icon' unit. The major differences between the Icon' versus the Perfexion' are: 1) treatment with a thermoplastic frameless mask rather than invasive frame for some patients; 2) ability to perform integrated stereotactic cone-beam computed tomography (CT) which provides stereotactic reference for patient setup; and 3) high definition motion management for mask-based treatments which allows for online adaptation. Although we respect the proposal by Elekta, Inc., we believe their proposal needs to be more stringent to ensure safe and accurate delivery of gamma stereotactic radiosurgery. Physical presence would utilize a similar definition used by Section V, Summary of changes of the 2002 revised 10 CFR part 35 in the Federal Register4. The following recommendations remain consistent with federal regulations and requirements governing physician supervision from the Centers for Medicare and Medicaid Services and federal regulations.

1. AU and AMP be physically present during the initiation of all treatments involving the Icon' unit.

This will allow independent confirmation that the correct plan is being used for treatment and that the correct site is being treated at the initiation of treatment. This will also allow the authorized user to be part of the universal timeout, which should help prevent the wrong plan from being delivered or the incorrect side from being treated initially.

2. AMP be physically present throughout all patient treatments involving the unit.

The physical presence of an AMP is essential for the safe and accurate delivery of gamma stereotactic radiosurgery. The addition of a medical physicist would ensure that 4 of 7

any software, hardware, or combination of software/hardware failure be recognized immediately and addressed promptly.

The current physical presence requirements for the AU can be modified by allowing the AU to be close enough to the to the console to respond quickly to any issue that arises which is defined as within a two minute walk to the Icon' console area, and immediately available to come to the treatment room. An AMP needs to be physically present during the entire treatment.

In addition to the AU and AMP, as a matter of good practice, we recommend that appropriately trained nursing or auxiliary staff be present at Icon' treatment to respond to any immediate medical needs. It will be the responsibility of the AU to determine the necessary training and experience required of the nursing staff, who will be present throughout the procedure.

3. If there is an interruption of treatment secondary to medical or mechanical issues, the AU must return to Gamma Knife Icon' console to evaluate the patient and/or to review any mechanical issues. The AU must be present to ensure the correct site is being treated during re-initiation of treatment.

4. At the conclusion of treatment, the AU must be present at the Icon' console to discuss any treatment or patient issues with the patient, physicist, and nurse.

The AU will be physically present close to the console, which is defined in this report as within 2 minutes from the console area, during patient treatment and immediately available to furnish assistance and direction throughout the performance of the procedure. Specifying time rather than presence in the department mitigates any misinterpretation of the regulations which has happened in the past5. This definition would be more stringent than the American Society for Radiation Oncology white paper.6 The subcommittee felt that a time, rather than distance, ought to be used to define physically present in the department. Depending on the configuration of the department, distance may not be easily measured, i.e., the department may be located on multiple floors, not necessarily in close proximity. In addition, the subcommittee believes that physically present in the department can be ambiguous especially if the Gamma Knife center is distant from the radiation oncology department or if the Gamma Knife is not present within the radiation oncology department such as a neurosurgery department or free standing center. Since a medical physicist would be physically present for the duration of treatments, medical and software/hardware incidents could be addressed during the 2 minute interval before the AU would arrive.

Summary:

The subcommittee recommends that for the Leksell Gamma Knife Icon':

• The AU and AMP need to be physically present during the initiation of all treatments.

This allows independent confirmation that the correct site is being treated, confirm that 5 of 7

the correct plan is being used for treatment and particularly important for functional cases, all of which are components of the universal time outs. It also provides an opportunity to visualize the movement of the treatment table to the correct position via treatment room cameras.

• The current physical presence requirements for the AU be modified by allowing the AU to be within a 2 minute walk of the console area and immediately available to come to the treatment room after initiation of treatments. An AMP needs to be physically present by the console area during the entire treatment. (i.e., at the console or within normal hearing voice) of the AU.

• If there is an interruption of treatment secondary to medical or mechanical issues, the AU must return to Gamma Knife Icon' console to evaluate the patient and/or to review any mechanical issues. The AU must be present to ensure the correct site is being treated during re-initiation of treatment.

• At the conclusion of treatment, the AU must be present at the Gamma Knife Icon' console to discuss any treatment or patient issues with the patient, AMP and nurse.

We believe that the recommendations would allow for the safe and effective delivery of gamma stereotactic radiosurgery while allowing the AU more flexibility to be available for other medical issues, other than those requiring personal supervision, in a radiation oncology department if warranted. We also believe that the recommendations will allow the licensee to determine if an ME has occurred, would allow the regulator to inspect and regulate a Gamma Knife center, would not unfavorably encroach on the practice of medicine, and are consistent with regulations governing physician supervision. As a subcommittee, we believe it is inappropriate for the AU to be more than a 2 minute walk from the console under any circumstance as the AU needs to be immediately available and needs to ensure the correct radiation dose is delivered. In addition, we recommend that the AU work with their radiation safety officer to determine how long it will take for the AU to return to the Gamma Knife Icon' console area from another location at which he/she wishes to work. The center will need to determine best method to contact the physician as paging a physician can take time. Since any change can be subject to interpretation, it is important that each Gamma Knife center determine what area would be within 2 minutes of the console. Ultimately, each AU will need to decide if he or she wishes to adopt the revised physical presence proposal or maintain the current physical presence rules, which is more stringent.

Given the proposed change, it is imperative that a culture of safety and quality with checks and balances at every level exists to ensure that the safest and most effective care is delivered to patients while simultaneously protecting the public. Licensees are encouraged to continue to audit and monitor their programs and adopt best practices including a high reliability system approach7 to mitigate MEs.

Respectfully submitted, February 1, 2018 Subcommittee on Physical Presence Requirements for Leksell Gamma Knife Icon',

Advisory Committee on the Medical Uses of Isotopes (ACMUI),

Nuclear Regulatory Commission (NRC) 6 of 7

References

1. 10 CFR 35.615(f)(3).

2.Section V, Summary of changes of 2002 revised part 35 in Federal Register (67 FR 20355)

3. NRC-issued Regulatory Issues Summary (RIS) 2005 October 2005

4. 42 C.F.R. § 410.32

5. Mastroianni A, McCaffrey JF. Target tumors, not yourself: A review of False Claims Act allegations against radiation oncologists. Appl Radiat Oncol 4(2): 14-21, 2015

6. Solberg TD, Balter JM, Benedict SH, et al. Quality and safety considerations in stereotactic radiosurgery and stereotactic body radiation therapy: Executive summary.

Pract Radiat Oncol 2:2-9, 2012.

7. Reason J. Human error: models and management. BMJ 32:768-770, 2000 7 of 7