The AEC/NRC 30 mCi Rule: Regulatory Origins and Clinical Consequences for 131 I Remnant Ablative Doses

Abstract

Background:

Clinical and historical uncertainty exists surrounding the regulations of the Atomic Energy Commission/Nuclear Regulatory Commission (AEC/NRC) requiring patient hospitalization when ¹³¹I activities exceed 30 mCi. This review investigates the sometimes disturbing regulatory and clinical origins and consequences of the use of this low, 30 mCi dose as a prescription for thyroid remnant ablation.

Summary:

As early as in the 1940s, activities of ¹³¹I between 30 and 200 mCi, often fractionated, were employed. The AEC deliberated from 1947 to the early 1960s before imposing as a license condition the requirement of hospitalizing patients until they contained <30 mCi of any byproduct material. The written AEC record throughout these years contains no supportive data to suggest safety issues requiring hospitalization at this activity level of ¹³¹I. Yet the techniques for making the necessary calculations for determining radiation safety were available at this time. Declarations on the subject by nongovernmental bodies were misinterpreted as confirming such hospitalization as a legal requirement. The 30 mCi license condition was codified into NRC regulations in 1987 and was subsequently removed in 1997. Without any data, these U.S. regulatory agencies caused significant expense, inconvenience, and fear, affecting thyroid cancer patients and their families. This 30 mCi regulatory activity limit morphed, by a fortunate coincidence, into an acceptable ablative activity before there were solid confirmatory data. Studies on this 30 mCi ablative dose indicate that this activity was never associated with radiation health and safety issues, and was never more effective than higher ablative doses but led slightly more often to the need for a second ¹³¹I dose. Nevertheless, the available data generally support the American Thyroid Association and Society of Nuclear Medicine and Molecular Imaging Guidelines, which indicate, without a treatment activity preference, that 30–100 mCi of ¹³¹I provide adequate ablation. Follow-up data on the rates of recurrences, deaths, and second primary malignancies within this range of doses are unavailable.

Conclusions:

This history of unjustified governmental action and blind acceptance must remind the medical/radiation safety community to require solid data before ever again adopting baseless requirements. The 30 mCi dose should have never been employed as a requirement for hospitalization.

Introduction

¹³¹Ihas been employed in therapeutic approaches for thyroid cancer patients since 1943. In the early 1960s, the Atomic Energy Commission (AEC) mandated, without any supporting radiation safety data, that patients treated with ¹³¹I must be hospitalized until their body burden was <30 mCi or 1110 MBq (since the latter Système Internationale units were not employed in the United States until much later, the traditional unit of millicuries (mCi) will be used throughout this manuscript). This so-called 30 mCi rule, which caused a financial burden for both the hospital and the patient, and emotional distress for the isolated patient and his/her family, remained in force until the Nuclear Regulatory Commission (NRC), successor to the AEC, removed this regulatory requirement in 1997, more than 30 years later. Another unintended consequence of the 30 mCi rule has been the use of a clinically acceptable 30 mCi ablative dose of ¹³¹I.

This study has two goals: to investigate the origins of the AEC/NRC 30 mCi rule, and to critique the existing data on ¹³¹I ablation of thyroid remnants post-thyroidectomy employing 30 mCi of ¹³¹I, asking why this activity was believed to be therapeutically efficacious but requiring patient isolation in a hospital. In the early literature on ¹³¹I treatment of thyroid cancer, pioneering therapists did not always distinguish between ¹³¹I for ablation, as adjuvant therapy, or for metastatic disease. We have tried to make clear the usage of ¹³¹I wherever possible. The concept of ablation was first employed to denote destruction of the thyroid gland surgically or with radioiodine in order for radioiodine to be effective in treating functioning metastatic disease, rather than to indicate, as we do in this paper, destruction of remnants of the normal thyroid gland post-thyroidectomy.

Review

Seidlin et al. in 1946 announced the first successful treatment of a patient with a widely metastatic thyroid cancer, based on the use of fractionated doses of ¹³⁰I (total 110 mCi) and ¹³¹I (total 156 mCi) administered from 1943 to 1945 (1). Among the many insights gained from this remarkable case of thyroid cancer were the need to remove most of the thyroid gland of the patient before radioiodine could effectively treat the cancer, and the use of injected bovine thyrotropin (TSH) to stimulate radioiodine uptake by the tumor (2,3). The need for ablation in the therapy of papillary and follicular thyroid cancer has been frequently documented over the last six decades, based on the level of tumor risk to the patient (4). The exact dose of ¹³¹I required for ablation of thyroid remnants has remained controversial over this same time period, theoretically requiring individual thyroid gland remnant dosimetry.

Beginning in January 1947, only five months after the AEC's Oak Ridge National Laboratories began to produce ¹³¹I for general distribution, large single doses of 100–200 mCi were being employed post-thyroidectomy (Table 1), without a known precedent, in the early years of ¹³¹I ablative therapy (5 –12), possibly to deliver a larger amount of radioactivity more efficiently as a single dose, rather than the fractionated dosing scheme used by Seidlin et al. (1). This use of multiple doses of ¹³¹I must not be confused with the concept of fractionated radiation doses from external beam radiotherapy where the purpose of the fractionation is to kill tumor cells more optimally while minimizing the damage to normal tissue. It is not known which dosing scheme was favored by the majority of early therapists who used ¹³¹I, as there was insufficient published evidence supporting one dose method over the other. Nevertheless, this historical record indicates that neither cost nor availability of ¹³¹I from the AEC hindered the use of large treatment doses of this radioisotope.

Table 1.

Early Attempts at Ablation Therapy (1947–1975)

Ablative activity in MBq (mCi)	Institution(s)	Years covered	Reference
1295 (35) every 2 wks, 6 months	Univ. Chicago	1947–1953	Clark (1953) (14)
2220 (60) or more	Univ. Texas MD Anderson Hosp	1947–1953	Trunnell (1953) (5)
3700 (100)- “greater than 7400 (200)” for remnant ablation	Univ. Michigan	Jan. 1947–Jun 1983	Beierwaltes et al. (1984) (6)
3700–5550 (100–150)	UCLA	1949–1964	Blahd et al. (1964) (7)
2479–3700 (67–100) to ablate “the normal thyroid” instead of surgical thyroidectomy	Memorial Center, NY	1949–1961	Benua et al. (1962) (8)
1850–3700 (50–100) in place of surgery for ablation	Hammersmith Hospital, London	1950–1956	Goolden (1958) (9)
2960 (80)	University College Hospital, London	1950–1970	Pochin (1971) (10)
1850–3700 (50–150) for ablation	Ohio State Univ., Univ. Texas, Univ. Florence	1950–1975	Wong et al. (1990) (11)
3700–7400 (100–200) for ablation and mets, not textually separated	Univ. Cincinnati	1950–1964	Saenger (1964) (12)

A single dose of 25–50 mCi, which could be repeated in four to eight weeks, was in use in Chicago before 1957 (13), and the minutes of AEC's Advisory Subcommittee on Human Applications during the 1950s also confirm the use of ablative doses in this range. Seidlin et al. had fractionated the treatment doses of their first patient in this range, and this could have provided a precedent for the relatively low ablative doses employed (1). Clark, also working in Chicago, inferred from his histopathology studies that the activity of cancers appeared to occur in “shifts,” that is, he felt that thyroid cancer cells in individual neoplastic follicles concentrated iodine variably over time. Therefore, beginning in 1947, Clark administered 35 mCi of ¹³¹I every two weeks for six months (totaling 400–450 mCi) as ablative therapy to reduce the risk of recurrent thyroid carcinoma (14). Tumor uptake of ¹³¹I at this time was stimulated in several ways by individual investigators: thyrotropin injection, thiouracil, or following a delay post-thyroidectomy to allow the serum TSH to rise. Trunnell of the University of Texas MD Anderson Hospital wrote about this confusing situation in 1953: “In considering our subject, there are perhaps a half dozen different approaches, each of which must ultimately be tested” (5).

An earlier investigative document by Siegel has attempted to uncover the mystery of the 30 mCi regulatory limit for patient discharge (15). Additional facts regarding the history of this rule have been uncovered, which shed further light on its questionable use to force the needless hospitalization of patients. In 1947, a 12-member Subcommittee on Human Applications of the Committee on Isotope Distribution was named to advise the AEC. A leading member was Dr. Paul Aebersold, Chief of the Isotopes Division at the AEC in Oak Ridge. During the first meeting of this Subcommittee, in March 1948, in summarizing a discussion of the safety of administering ¹³¹I for thyroid cancer treatments, the minutes of the meeting noted that “In many clinical uses of allocated material, the treatment is so experimental that it may be advisable to require hospitalization of the patient for the purpose of obtaining satisfactory clinical data. Some clinical uses have become rather routine and may not require such extensive clinical observations as to require hospitalization. Some recommendations should be made concerning requirement of hospitalization in connection with specific types of treatment.” Here, treatment and ablation are conflated as one concept. During the Subcommittee's second annual meeting in March 1949, clarification of policy on hospitalization and supervision of patients receiving radioisotopes was again discussed. The Subcommittee agreed that the thyrotoxic patient could appropriately be treated with radioiodine without hospitalization, but that it was an overstatement to say that these patients did not require supervision. The issue of thyroid cancer treatment was not discussed, as there were no systematic data available on which to build definitive statements concerning radiation safety precautions. In February 1954, a staff memorandum submitted to the AEC proposed that radioisotope distribution regulations be amended by the addition of general radiological health and safety standards applicable to users of AEC-distributed radioisotopes. The staff's proposed amendment of Part 30 (Part 30.85 General Radiological Health-Safety Standards) stated “Patients receiving high dosage radioisotope therapy shall be hospitalized or suitably confined until the total body content of administered radioactive material has been reduced to a maximum of 50 millicuries.” Note the use of 50, not 30 mCi. The AEC Commissioners apparently did not agree with this staff proposal, since no action was taken related to it. At this time, the AEC had no regulations regarding general radiological health and safety standards, which had been left up to the user physician, who was only required to have “adequate training.”

The minutes of the AEC Subcommittee on Human Applications meeting of March 1954 reflected the trend regarding dose in applications for ¹³¹I therapy of thyroid cancer. A significant number of applications indicated the proposed utilization of single or multiple doses of 25–30 mCi. At this meeting, the AEC asked the Advisory Subcommittee to consider whether this represented a true therapeutic dose or an attempt to avoid hospitalization of the patient to be treated. It is noteworthy that up until this point in time, the AEC had not required the 30 mCi limit or even consistently recommended this limit for outpatient therapy, yet apparently many physicians incorrectly believed that such a recommendation or requirement had been instituted. In these minutes, one reads, “Dr. Aebersold stated that the Commission cannot set forth as a requirement the hospitalization of patients containing 30 millicuries of radioisotopes since this level is not provided for in the Federal Register. He stated that no doubt circumstances will arise where hospitalization of thyroid cancer patients will be indicated but that this should be dependent upon medical considerations and not upon radioactivity content of the patient.” Remarkably, while the scientific basis and necessary techniques for calculating the likely the exposures to others from radioactive patients had been established by this time (with the exception of the use of the occupancy factor), we find no evidence of AEC use of any such methodology (15). Dr. Richard Chamberlain, another member of the Subcommittee stated “that some groups are following the fractional dose techniques using iodine-131 in the treatment of thyroid cancer. A single dose of around 30 millicuries repeated at intervals to provide a total dose of 100 to 200 millicuries may be satisfactory.” The Subcommittee then concluded “that the use of 30 millicuries of most radioisotopes in patients does not present a significant external hazard. It was recommended that the dosage level of between 30–50 millicuries of a gamma emitting radioisotope be used as a guide for recommending hospitalization.” After this meeting, no clarification came forth from the AEC as to whether there was a 30 or 50 mCi recommendation for hospitalization and whether this was now a requirement of the Commission.

Thus, when applying for a license in the 1950s, no binding requirement existed for the 30 mCi limit for ¹³¹I. During this time period, the AEC provided instructions for filling out the form required to use byproduct material for human use, AEC Form-313a, stating “Although it is normally desirable to hospitalize patients containing more than 30 millicuries of radioactivity, the AEC does not routinely require such hospitalization.” We could find no justification for the statement “… normally desirable to hospitalize patients containing more than 30 millicuries….” In fact, up to this point, the 50 mCi activity level was more often noted. Furthermore, although the AEC indicated that hospitalization was not “routinely required” at the 30 mCi level, this was exactly what was happening in many nuclear medicine facilities throughout the United States, likely as a direct result of misleading and confusing communications by the AEC. Unfortunately, the AEC did virtually nothing to dispel this misconception, even though there were no data to justify this situation. In the AEC Subcommittee on Human Applications meeting on May 7–8, 1955, the minutes reflected the difficulties the AEC's Allocations Branch was having in reviewing proposals for thyroid carcinoma therapy. The Subcommittee members, Drs. Richard Chamberlain, Leon Jacobson, and Edith Quimby, and other attendees were again asked for guidance to help AEC's Isotopes Division in their review of applications. It was mentioned that the 30 mCi dose stated so frequently on submitted applications was believed by some physicians to be all the AEC would approve. According to Dr. Chamberlain, “In treating thyroid carcinoma with radioiodine, which should be still considered an experimental procedure, one needs to provide the whole regimen of medical knowledge available in institutions.” He stated that “the period of hospitalization was not particularly important but that it was important to have the program viewed as experimental and approached as such.” Dr. Aebersold questioned the basis on which one should maintain a patient in the hospital, and whether or not the actual radiation level at a specified distance from the patient would be a better system than the millicurie content. In the discussion that followed, it was brought out “that it was difficult to generalize because of the wide variety of situations possible and that no exact specifications could be set down,” even though measurements could have been made and/or calculational techniques could have provided some answers. It appears that up until and during 1955, the AEC and its Subcommittee on Human Applications did little to clarify the incorrect belief held by some treating physicians regarding the 30 mCi dose, thereby allowing some licensees to self-impose a (nonexistent) regulatory “license condition” upon themselves erroneously. It is noteworthy that the AEC's Advisory Subcommittee first realized and discussed the need for some recommendations concerning the requirement for hospitalization at their first meeting in 1948, but seven years later, there was still no consistent recommendation, and this brought about much confusion in the regulated community.

A 1957 document entitled “The Medical Use of Radioisotopes,” issued by the Isotopes Branch, Division of Licensing and Regulation, US AEC, represented the recommendations and requirements of the AEC, taking into account the advice of the Subcommittee on Human Applications, for licensing the possession of byproduct material for medical use. It stated that “From the standpoint of radiological safety alone, it is advisable that patients with more than 30 millicuries of byproduct material internally administered be hospitalized. It is strongly recommended that in all cases a patient containing more than 50 millicuries of byproduct material be hospitalized.” In 1958, an early textbook of Nuclear Medicine (16) indicated, without a cited reference, that patients treated with ¹³¹I should be hospitalized if their therapeutic activity exceeded 50 mCi. To add to the confusion, a nonregulatory body, the National Committee on Radiation Protection and Measurements (NCRP), in “Safe Handling of Bodies Containing Radioactive Isotopes,” Handbook 65, published by the National Bureau of Standards in July, 1958, stated that “The Advisory Committee on Isotope Distribution of the U.S. Atomic Energy Commission advises that all patients receiving large doses of radioisotopes be hospitalized until the isotope content is not more than 30 mCi.” No relevant health and safety data existed to justify this statement. Nor had the AEC's Advisory Subcommittee actually recommended such an absolute limit at this time.

Finally, in December 1963, Mr. Eber Price, Assistant Director of the AEC Division of Licensing and Regulation, responding to an inquiry from Eugene L. Saenger, MD, of the University of Cincinnati Medical Center, about the 30 mCi rule, wrote that current hospitalization requirements, in which patients treated with ¹³¹I had to remain hospitalized until the residual activity was ≤30 mCi, were outlined in the draft of The Licensing Requirements for the Medical Use of Byproduct Material, developed with the advice of the Advisory Committee on Medical Uses of Isotopes (ACMUI). We have been unable to locate this document. It should be noted that the Subcommittee on Human Applications was absorbed into the ACMUI in 1959. In addition, Price stated that these hospitalization “requirements for patients receiving the relatively large doses of iodine-131 used in cancer therapy are considered necessary to protect family members and others with whom the patient may come in contact from unnecessary exposure to radiation and to avoid contamination problems in the home and elsewhere.” However, no data existed to justify this activity-based hospitalization requirement.

Thus, by 1963, the AEC had imposed the requirement of hospitalizing patients until they contained no more than 30 mCi of byproduct material, the so-called 30 mCi rule, as a license condition (15), and few nuclear medicine professionals objected. The AEC, and its successor, the Nuclear Regulatory Commission (NRC), imposed this requirement without any relevant data demonstrating harm to any individual potentially exposed to a released patient. This license requirement dramatically altered the treating physician's use of ¹³¹I, as the therapist could no longer administer in an outpatient setting a single large ablative or therapeutic dose. The physician had to administer either multiple 30 mCi fractions or hope that a single 30 mCi dose might be efficacious. Inpatient therapy was costly and time-consuming for physicians and patients, and regularly provided challenges for nursing care, but this practice was not uncommon. This license requirement was codified into NRC regulations as 10 CFR 35.75 in 1987.

Unfortunately, most, if not all, treating physicians accepted the 30 mCi rule without significant resistance. However, Saenger et al. (12), writing in 1964, noted that their thyroid cancer patients had been ablated with activities of ¹³¹I up to 100 mCi as outpatients up to that point without difficulty. The reported data of Saenger et al. provided the first evidence as to how incorrect the AEC 30 mCi rule was. In a subsequent article in 1980, Saenger and Kereiakes confirmed that they treated their thyroid cancer patients on an outpatient basis without incident, and further stated that “Concern is expressed at this time because restrictive conditions that are not justified by scientific data of sufficient precision or quality are being imposed on the licenses of individual institutions and qualified physicians. Such restrictions may unnecessarily interfere with optimal patient care” (17).

Given the multiple groups providing information, many of which incorrectly described the regulatory requirements of the AEC in the early years of treatment with ¹³¹I, it should come as no surprise that there was confusion among treating physicians, leading to misunderstanding and unexpected consequences. Numerous authors (18 –21) have inaccurately stated that the 30 mCi ¹³¹I restriction imposed by 1963 was promulgated by the National Council on Radiation Protection and Measurements following the publication of NCRP Report No. 37 (22). However, this NCRP Report was not published until 1970. Furthermore, there is no statement in NCRP Report No. 37 that a patient must have <30 mCi in his body before he can be discharged. In fact, this report recommended that an activity value should not be used at all as the basis for patient release, stating that because “the exposure rates and half-lives of various radionuclides differ greatly, a more meaningful basis for release from the hospital is the possible exposure to other individuals with whom the patients are likely to associate.” Perhaps these authors confused NCRP Report No. 37 with the earlier incarnation of this group, the National Committee on Radiation Protection and Measurements, which published a series of handbooks of the National Bureau of Standards (NBS) (23).

Beginning in 1990, petitions for rulemaking by Carol Marcus, MD (who introduced the concept of occupancy factor), and the American College of Nuclear Medicine were submitted to the NRC to rescind the 30 mCi rule. A 1992 Journal of Nuclear Medicine Newsline article related that the Society of Nuclear Medicine (SNM) and the American College of Nuclear Physicians (ACNP) believed that the NRC should maintain its 30 mCi rule, at least as far as treatment with ¹³¹I was concerned, although no rationale was given. The article continued: “There is a virtual consensus that the optimal way to use ¹³¹I to treat a thyroid carcinoma is to administer a single cell-killing dose of the radionuclide well above 30 mCi” (authors' italics). Several prominent nuclear medicine physicians are quoted as being unaware of any practitioners treating patients with fractionated doses to avoid hospitalizations, which they considered to be suboptimal therapy (24). But according to the AEC, its Advisory Subcommittee, and others (14,21,22), as we have documented and discussed, this was exactly what was happening in many cases from the 1950s to that time. In a 1993 commentary regarding this Newsline piece, Marshall Brucer, MD, asserted that physicist Edith Quimby, a member of the AEC Advisory Subcommittee, had tried to limit the use of ¹³¹I and had championed the AEC's 30 mCi rule. He stated that physicians at that time objected to this limit because it was considered to be a “medical dose” and that the AEC had no business intruding into the practice of medicine. Brucer urged every practicing physician to acknowledge that a 30 mCi dose of ¹³¹I does not represent an unsafe source of radiation in order to persuade the NRC to do away with its 30 mCi rule (25). Thus, up to this point, with the exception of Drs. Saenger, Kereiakes, and Brucer, many in the nuclear medicine professional community and their professional societies believed that the 30 mCi rule was not a baseless requirement and should be retained, at least as far as treatment with ¹³¹I was concerned.

Finally, after much consideration of the two petitions for rulemaking and more than 30 years after its unjustified imposition, the 30 mCi rule was rescinded by the NRC in 1997 in a revised 10 CFR 35.75. This revision allows the release from control of a licensee “any individual who has been administered unsealed byproduct material, or implants containing byproduct material, if the total effective dose equivalent to any other individual from exposure to the released individual is not likely to exceed 500 mrem (5 mSv).”

The incorrect, but widespread, belief in the 1960s, or earlier, that a 30 mCi dose of ¹³¹I represented a threshold for potentially dangerous consequences and/or threats to public health led to unfortunate effects because many thousands of patients were forced to be hospitalized over a period of many years. This led to unnecessary and ever rising hospital bills, loss of work time (and, for many, loss of salary), plus an unmeasurable fear factor during the process. The adoption and selection of this dose as a valid and appropriate ablative prescription, without much debate by the treating physicians, was remarkably fortunate, as it has coincidentally proved to be the lowest effective ablative dose in the early 1980s (Tables 2 and 3). Thus, use of a dubious, regulatory-derived 30 mCi ablative dose morphed rather early into a medically accepted standard of care and subsequent studies, summarized in Tables 2 and 3, showed that the 30 mCi ablative dose generally provided results equivalent to those from higher activities.

Table 2.

Nonrandomized Studies of Ablative Efficacy of 30 mCi of ¹³¹I

Year	Administered activity in MBq (mCi)	Patients with complete ablation (%)	Reference	Comments^*
1980	925–1106 (25–29.9)	8 (n=13)	Kuni et al. (19)	Partial thyroidectomies; rescan at 3 mo.
1981	1073–1110 (29.0–30.0)	10 (n=10)	Siddiqui et al. (26)	Bovine TSH given; rescan 9–15 mo.
1982	1084±56 (29.3±1.5)	61 (n=69)	Snyder et al. (27)	Recurrence in 6/69 in 2–5 years; rescan at 3 mo.
1992	1117–1569; median 1132 (30.2–42.4; median 30.6)	Successful ablation in all patients with pre-rx uptake 10% or less (n=34)	Leung et al. (28)	20% failure rate if pre-rx uptake >10% (n=33); rescan 10 wks.
1993	1110 (30)	27 (n=44)	Comtois (29)	Total ablation more likely in smaller patients with smaller residual tissue and no goiter
2002	1110 (30)	THW patients (with vs. without rhTSH), 79% vs. 84%; rhTSH patients 54%	Pacini et al. (30)	Lower remnant uptake with rhTSH but ¹³¹I given 2nd day after last rhTSH; all groups had 14–16% pos. Tg when visually ablated; rescan 10 mo.
2003	1110 (30)	THW 75% vs. rhTSH 81% at 1 yr. (n.s.)	Barbaro et al. (31)	Tg levels neg. in 88% rhTSH patients and 79% THW patients; rescan 1 yr.

No serum thyroglobulin (Tg) was employed as a criterion of complete ablation unless so indicated under Comments.

Table 3.

Comparative Studies of Low and Higher Ablative Activities of ¹³¹ I

Year	Administered activity in MBq (mCi)	Patients with complete ablation (%) +	Reference	Comments^*
1976–1999
1976	925–1099 (25–29.7) vs. 2960–5550 (80–150)	925: 58% (n=280); 2960: 64% (n=36) (n.s.), but more than one dose, more often required in the low-dose group	McCowen et al. (18)	No randomization, no TSH measurements; total activity required to eventually ablate was 5916 MBq (159.9 mCi) in the low-dose group and only 3148 MBq (85.1 mCi) in the high-dose group (p<0.004)
1982	1110 (30) vs. 2775 (75)	1110: 40% (n=20) 2775: 67% (n=9) (p<0.05)	Ramacciotti et al. (32)	Tg employed; nonrandomized; half of the low dosage group needed more treatment
1982	1110 (30) vs. 1850–2220 (50–60)	1110: 83%; 1850: 100% (p>0.05)	DeGroot et al. (33)	Nonrandomized; three patients in the low-dose group received an extra 30–50 mCi; scanned before 6 mo.
1985	1110 (30) vs. 3700 (100)	1110: 11% (n=19); 3700: 53% (n=19) (p<0.05)	Ramanna et al. (20)	2 of the 19 received 50 mCi, not 30 mCi, but are counted in low-dose group without separate outcome noted; unlikely that both total ablations came from this subgroup; nonrandomized
1991	1073 (29) vs. 3700 (100)	1073: 81% (n=36) 3700: 84% (n=27) (p>0.05) (after first dose of ¹³¹I for each group)	Johansen et al. (34)	Randomized; after “ablation” in 40% vs. 44%; groups equal in number of additional doses required to ablate; scanned before 6 mo.; Tg assay insensitive
1996	1110 (30) (n=27) 1887 (51) (n=54) 3293 (89) (n=38) 5737 (155) (n=30)	1110: 63% 1887: 78% 3293: 74% 5737: 77%	Bal et al. (35)	Randomized; concludes that 1887 MBq gives about 300 Gy—no larger dose needed; Tg assay insensitive
2000–2012
2000	1074 (29) (n=48) vs. 3700 (100) (n=22)	1074: 63% 3700: 82%	Doi et al. (36)	Only patients with total thyroidectomy included; meta-analysis also favors high over low dose; nonrandomized
2004	1110 (30) (n=65) vs. 3700 (100) (n=90)	1110: 72% 3700: 86%	Rosario et al. (37)	Randomized; success rate always better for larger activity patients regardless of postop uptake; Tg assay insensitive
2004	¹³¹I uptake: <5%: 2800 (76) (n=128); 5–10%: 1850 (50) (n=31); >10%: 1100 (30) (n=33)	2800: 66% 1850: 45% 1110: 39% serum Tg >1 μg/L=50% post-rx in all groups	Verkooijen et al. (38)	Tg used; not randomized; study indicates this dosing strategy a problem, but no real therapy dose comparison in patients with same size remnant
2004	555 (15) 740 (20) 927 (25) 1110 (30) 1295 (35) 1480 (40) 1665 (45) 1850 (50) (n=509)	555: 60% 740: 64% 927: 81% 1110: 84% 1295: 79% 1480: 78% 1665: 84% 1850: 82%	Bal et al. (39)	Randomized but >10% patients excluded; major statistical difference was ablation rate with <927 MBq vs. ≥927 MBq (p<0.05); rescan 6–10 mo; Tg used
2007	1850 (50) (n=36) vs. 3700 (100) (n=36)	1850: 89% 3700: 89% (based on scan, not Tg)	Pilli et al. (40)	Randomized; p=0.46; 34 patients had neg. Tg. pre-rx, so Tg assay insensitive; rescan 6–8 mo.
2010	1110 (30) vs. 2220 (60); 2220 (60) vs. 3700 (100) (n=309)	1110: 78% (n=86); 2220: 83% (n=128); 3700: 89% (n=95)	Kukulska et al. (41)	Randomized in two separate studies; Tg <10 ng/mL accepted as evidence of ablation (p>0.05); second rx needed in 22% patients with 30 mCi, 10% in other two groups; rescan 12 mo.
2012	1110 (30) vs. 3700 (100) (n=421)	1110: 85% 3700: 89%	Mallick et al. (42)	Tg used; randomized 10% low-dose and 4% high-dose patients need retreatment; rescan 6–9 mo.; THW vs. rhTSH also studied, with no differences; more adverse events in high-dose group: p>0.05 lower dose gave lower ablation rate in 2 comparisons
2012	1110 (30) vs. 3700 (100) (n=684)	1110: 93% (THW) 1110: 90% (rhTSH) 3700: 93% (THW) 3700: 93% (rhTSH)	Schlumberger et al. (43)	Randomized; 6–10 mo. follow-up with Tg; pos US studies more than with scan: p>0.05 lower dose gave lower ablation rate in rhTSH but not THW comparisons

No serum thyroglobulin (Tg) was employed as a criterion of complete ablation unless indicated.

+Ablation results: (%) from low activity group always listed first.

The first study to compare a 30 mCi ablative dose with higher activities began collecting data in 1960 (18), confirming that a single 30 mCi ablative dose was likely being employed before the AEC-imposed license condition. Thirty mCi doses were usually not intended as a single ablative dose, but rather as part of a fractionation scheme involving a total administered activity of at least 100 mCi (18,19,26,27). Thus, one finds multiple single dose studies (Table 2) (19,26 –31), and also research studies (Table 3) (18,20,32 –43) comparing 30 mCi with higher activities, most often 100 mCi of ¹³¹I, for ablation. These studies showed a progressive improvement of ablation rates from the 30 mCi dose as the year of publication progressed, until the ablation rates in individual studies were generally reported as equivalent.

The data in Tables 1 –3 demand further analysis. While there is full agreement that a scan following the ablative dose of ¹³¹I must be negative to qualify as a fully successful ablation, current oncologic criteria for successful ablation also include a negative or very low stimulated thyroglobulin (Tg) level <1–2 ng/mL (42 –44). Tg assays were not available until the 1980s, and even then were not easy to obtain, so the completeness of ablation must remain uncertain in any study wherein the serum Tg was not included as a criterion. The time required for ¹³¹I ablation to eliminate functioning thyroid tissue fully appears to require at least six months, but three months was the imaging time for several of the studies found in Tables 1 and 2 (10,27,28), so reporting ablation failure from scan data obtained at such early imaging times following the ablative dose was in error.

Table 3 contains a list of studies comparing 30 mCi of ¹³¹I ablative therapy with higher doses, found through a PubMed search of “thyroid cancer” plus “¹³¹I” with a review of the resultant bibliographies by the authors. One comprehensive review of the 30 mCi versus higher single dose ablation controversy found no relevant articles on the subject published before 1980 (45), while the current authors discovered just one more (18), making a total of 14 studies. These data were analyzed in terms of a set of quality attributes or criteria that the authors felt must be fulfilled to be considered as credible research: (a) comparison of at least two doses of ¹³¹I for the ablation of differentiated thyroid cancer post-total thyroidectomy; (b) patient randomization performed prior to the choice of ¹³¹I dose; (c) use of the stimulated serum Tg levels of ≤2 ng/mL as confirmation of thyroid ablation in addition to the negative ¹³¹I scan; and (d) thyroid scintigraphy of potentially ablated patients not performed until at least six months after ¹³¹I administration.

Only a few of the studies in Table 3 qualified. Lack of randomization of patients eliminated a number of these (18,20,32,33,36), while rescanning some of the treated patients before six months had passed excluded two more (33,34). In two studies (35,37), a stimulated serum Tg could be <10 ng/mL and <5 ng/mL respectively as a criterion for complete ablation—both levels too high by current standards. In another study (38), the higher the ¹³¹I uptake was found to be, the lower the ablative dose of ¹³¹I given, contrary to the format of all the other studies, so this research could not be used in our inquiry. Serious concern about the sensitivity and accuracy of the thyroglobulin test was raised in a further study (40), where 72 patients with visible remnants were treated, but 34 (47%) of these had a negative thyroglobulin level even before ¹³¹I ablation. In yet another study (41), the investigators allowed the acceptable value of the stimulated Tg to be <30 ng/mL in one part of the study (where patients with T4 and N3 tumors were excluded), but a Tg level <10 ng/mL in a later, follow-up part of this study, where the patients could have N1 and T4 tumors. These inconsistencies were considered too problematic for the study results to be included.

This analysis leaves three studies (39,42,43) for consideration. Experimental design is excellent in these, and our criteria are fulfilled to the extent that one can recommend a dose of 25–50 mCi (39), or 30–100 mCi (42,43) of ¹³¹I as adequate for ablation of post-thyroidectomy remnants. However, the patient follow-up in one of these studies (43) was largely by post-ablative ultrasound rather than ¹³¹I scanning, and it is not clear that this ultrasonographic criterion is more sensitive, or more easily standardized, than the follow-up ¹³¹I scan (42). The authors of an editorial commenting on two of the studies (42,43) raise the important question of whether radioiodine ablation is even required in the very low-risk patient groups studied (46), as defined in recently published Guidelines (4,47). Others have raised these concerns about such data as well (48 –53). Thus, the equivalence of 30 and 100 mCi doses for successful ablation may be irrelevant in low-risk patients who may not require any ¹³¹I ablation.

We also looked for patterns in the studies appearing in Table 3. It is perhaps not surprising that the higher dose ablation rate always exceeded that of the lower dose, except for three studies where the ablation rates were essentially equal (39,40,43). The lower dose never led to a better ablation rate than the higher ablative activity. This difference in ablation rate favoring the higher dose was found in all 10 evaluable studies (one study (38) has an experimental design that does not address this question, and the sign test requires elimination from analysis of all studies with equal outcomes (39,40,43)) of the 14 in Table 3, and was statistically significant (p<0.01, two tailed sign test). However, since the study quality in this formal analysis varied considerably, and referral bias cannot be excluded, the import of this observation is not unequivocal in favoring the higher dose. The data were too heterogeneous for a meta-analysis to be performed. In five of the six studies where the requirement for a second ablative doses was examined (18,32,33,41,42), the patients receiving the lower dose required a subsequent second ablative dose more often, while one of these six studies reported equal percentages of patients requiring a second dose (34). Furthermore, the sum of the first and second doses (when required) in these analyses always exceeded 100 mCi.

One could therefore hypothesize that the higher ablative dose might have a greater cytocidal effect on thyroid cells, normal and malignant, and could, in theory, lead to a lower incidence of recurrence and mortality. However, comparative data are not available for these post-ablation variables, or for the incidence of second primary malignancies, because of the prolonged survival rate for thyroid cancer and the resultant long follow-up time required to obtaining such data, at a potentially high cost.

The use of the lower dose of 30 mCi after the early 1960s is the result of the license condition imposed by the AEC. Prior to this time period, we are unsure if the origin of the “magical” single 30 mCi dose was due to the AEC or to treating physicians, as the historical record is not clear in this matter. During the time from the end of World War II until the early 1960s, some patients were hospitalized after receiving high doses of ¹³¹I for research studies (8), and some were treated without incident as outpatients with 100 mCi (12).

The use of fractioned doses of 25–50 mCi of ¹³¹I is documented in the 1940s (5,13,14) when some physicians were uncertain of the total dose to achieve ablation and kept treating until this occurred. Thus, physicians were cautiously administering 30 mCi ablative doses of ¹³¹I before any regulatory guidance was even contemplated. Beginning in 1959, one group administered fractionated doses of 20–30 mCi to achieve a total administered dose of 50–90 mCi (21) but never achieved complete ablation with that first dose of 20–30 mCi. These authors concluded that with this fractionated regimen, they achieved a success rate comparable to that of conventional single, higher dose regimens.

In 1990, another group compared a single ablative dose of ¹³¹I, in the range of 50–150 mCi, to two or three doses of 30 mCi given at weekly intervals to deliver the same total activity. The successful ablation rate in this prospective study in patients with well-differentiated thyroid carcinoma who had undergone total thyroidectomy was the same for both groups, and the authors concluded that dose fractionation to avoid hospitalization was a reasonable approach (54). These authors followed their patients' wishes in assigning them to inpatient or outpatient therapy; the patients' work, family pressure, and dislike of hospitalization all favored outpatient ablation. This study is unique in that the authors documented reasons for preferring 30 mCi outpatient to inpatient ablation, and it is one of the few studies suggesting therapeutic equivalence between fractionated outpatient versus inpatient therapy. To the reasons noted above for preferring not to stay in the hospital, we would add the following: cost of hospitalization, loss of patient work time and salary, inconvenience of the hospital stay for the patient and family, additional time required on the part of the physician in caring for the inpatient, and clinical experience suggesting a lower probability of adverse reactions when employing the 30 mCi doses compared to the higher ones (42).

In exploring the results of lifting the NRC 30 mCi rule, it is clear that there were distinct ¹³¹I treatment ablation paradigms in clinical use prior to 1997:

1. Patients were given multiple 30 mCi doses as outpatients to achieve a higher total administered activity in order to avoid hospitalizations.

2. Patients were administered single larger doses (e.g., 100–150 mCi), and all patients were hospitalized.

3. Patients were administered a single dose of 30 mCi as outpatients.

It is highly probable that most patients who fell into group 2 are now treated as outpatients and patients from group 1 are now being ablated with single doses of 30–100 mCi, usually as outpatients. There are no formal survey data to verify our impression. Anecdotally, all 15 medical centers represented by the authors of the Society of Nuclear Medicine and Molecular Imaging (SNMMI) Practice Guideline for Therapy of Thyroid Disease with ¹³¹I 3.0 (4) have moved to outpatient ¹³¹I ablation, and the Guideline strongly reflects this. Before approval of the Guideline by the SNMMI Board of Trustees, it was reviewed and endorsed by well over 100 nuclear medicine physicians who perform this procedure. It is the distinct impression of the authors that there are relatively few hospitalizations now solely for a range of ablative therapy doses of 30–100 mCi with ¹³¹I, but formal survey data on this point are not available.

Summary

The authors sought the origin of the regulatory version of the 30 mCi rule, which became a license condition by 1963, was codified into NRC regulation in 1987, and was finally removed from NRC regulations in 1997. Prior to the early 1960s in the United States, ablative activities of ¹³¹I, sometimes in fractionated doses, of 30–200 mCi or more were administered both in outpatient and inpatient settings (6,12). Tables 1 –3 trace the chronology of the use of higher and lower doses for ablation of thyroid remnants post-thyroidectomy. The AEC indicated in 1954 that a significant number of applicants were proposing use of single or multiple doses of 25–30 mCi and therefore asked their Advisory Subcommittee to consider whether this represented a true therapeutic dose or an attempt to avoid hospitalization of the patient to be treated. We must assume there were also concerns about radiation safety, patient dose, and exposure to others, but the AEC advisors and consultants, who were quite capable of employing existing calculational techniques to estimate the likely exposure of the public, never did so, or never left such a record of such activity anywhere. In this same year, a member of the AEC's Subcommittee on Human Applications stated that “A single dose of around 30 millicuries repeated at intervals to provide a total dose of 100 to 200 millicuries may be satisfactory.” This low 30 mCi ablative dose morphed rather early (1960s or before) into a medically approved minimal prescription for ablation of thyroid cancer remnants without supporting data. Surprisingly, and coincidentally, this 30 mCi ¹³¹I dose has proven to be the least activity of ¹³¹I capable of providing a reasonable rate of ablation (Tables 2 and 3), with documentation showing progressively better ablation rates with 30 mCi as one peruses the published record from 1980 to 2012. However, the hospitalization requirement due to the undocumented fear that 30 mCi would cause adverse health effects in others who may be exposed to these patients was certainly unjustified.

In contrast, a consensus statement made by the SNMMI and the ACNP in 1992 indicated that the best way to ablate was with a single radioiodine dose “well above 30 mCi” (24). Thus, single high dose and multiple fractionated smaller doses to achieve higher total ablative radiation doses were being given during these years, as well as the single 30 mCi dose. The latter dose was compared successfully to a dose of 100 mCi for ablation rates as early as 1960 (18) and as recently as 2012 (Table 3). Ironically, the ablative effects of 30 and 100 mCi are quite similar in the largest and best-designed comparative studies (42,43); this range has been approved in Guidelines of the SNMMI (4) and the American Thyroid Association (49). An average difference of almost 12% favoring the higher dose in earlier studies could be due to referral and ablative therapy bias and to questionable scientific design. There is a statistically significant higher ablation rate for patients receiving the higher dose in the studies analyzed in Table 3 when compared to 30 mCi of ¹³¹I (p<0.01, two-tailed sign test), but the long-term implications of this finding, in terms of rates of recurrence, survival, and second primary malignancies, have not yet been studied. Furthermore, the use of ¹³¹I ablation in patients with very low-risk tumors with an excellent prognosis would color any results reporting long-term outcomes.

For more than 30 years, the 30 mCi rule was forced upon physicians, health physicists, and hospitals caring for patients with thyroid cancer. However, there is no health risk or scientific justification for hospitalizing these patients. No harm to family members living with the ¹³¹I-ablated patient has ever been documented. The 30 mCi rule, by requiring unnecessary hospitalizations, resulted in undue financial hardship for patients (including sometimes loss of salary) and unnecessary time away from family and work.

Conclusions

1. An extensive review of available AEC documents and early literature reveal no rationale to justify the 30 mCi requirement to hospitalize thyroid cancer patients for ablation or therapy of thyroid cancer with ¹³¹I. With the exception of Drs. Saenger and Brucer, many nuclear medicine professionals and the SNM supported the 30 mCi rule for ¹³¹I as recently as 1992.

2. It is a striking coincidence that the 30 mCi activity level of ¹³¹I, which the AEC unjustifiably believed would cause a radiation safety hazard and thus mandated patient hospitalization for this and higher doses, proved to be the lowest effective dose for ablation of remnants post-thyroidectomy. It is likely that the 30 mCi dose employed as a comparator in subsequent research studies was chosen because of this choice by the AEC. A dose of 30 mCi probably provides an essentially equal level of ablation to higher activities of ¹³¹I (39,42,43), although the ablation rate was lower in a number of single dose studies of 30 mCi published earlier (Table 2), perhaps due to patient selection bias. However, we do not possess long-term follow-up data to document that 30 mCi of ¹³¹I yields equivalent recurrence and mortality rates as 100 mCi or a lower incidence of second primary malignancies.

3. The first goal in the care of the patient with thyroid cancer must be to determine who should, and should not, be treated with ¹³¹I, based on valid scientific studies with sufficient follow-up to provide the data on tumor recurrence and overall survival. It is unknown from all previous studies how many low-risk patients have really needed any ¹³¹I at all, and how they were distributed in the groups compared in Table 3.

4. Appropriate imaging and dosimetric techniques should be employed to define the radiation dose from ¹³¹I optimally required for the ablation of post-thyroidectomy remnants and the destruction of metastatic disease. Only then will scientific debate become properly centered on the required target dosimetry, but the controversy surrounding the decision to administer high or low ablative doses may not fade into obsolescence until careful follow-up studies demonstrate no difference in long-term outcomes of recurrence, survival, and second primary malignancies.

5. Finally, the historical record developed over seven decades around this issue, involving unjustified federal regulations, blind faith, and absence of scientific rigor by clinical practitioners, must never be forgotten by the medical community.

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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