Radioiodine Radiation Physics and Biologic Effects
Problems of Radiation Protection
The success of radioiodine therapy in the treatment of hyperthyroidism and thyroid carcinoma has been amply confirmed in the medical literature. However, over the last decade, the hazards related to the pollution of our environment have also become a problem of major concern. In this respect, the potential risks related to radiation hazards arising for the public, include the radiations delivered by 131I-treated patients themselves. Opinions and official policies are much different on both sides of the Atlantic and even within the European Union countries. Reasonable compromises have obviously to be found in order to allow the patient to continue to benefit from radioiodine therapy and at the same time, to minimize the radiation hazards to the public, even if these radiation hazards finally represent a relatively limited risk as compared to those related to the general problem of pollution of our world.
131I-radioiodine is used for therapy by virtue of its large beta particulate emissions of moderate energy delivering 90% of the energy of decay within a 1-mm zone, associated with a moderate 8-day half-life. Among various effects, the radionuclide deposited in the tissues results in ionization of the thyroid cell which in turn, leads to the damage of DNA and essential proteins like enzymes. It also indirectly allows the production of many reactive free radicals or short-lived toxic compounds able to damage essential biological molecules. All these events result in a delay or inhibition of the division of the thyroid cell. Depending on the dose administered, this will allow to reach the goal of the treatment, i.e. lowering thyroid hormone production and/or achieving thyroid tissue destruction.
The beta particles of 131I are essentially non-penetrating and thus act locally. An even less penetrating radionuclide as 125I has not proven itself to be more valuable than 131I, particularly with respect to the prevention of late hypothyroidism and increases the potential environmental contamination because of its long physical half-life (60 days). In the case of 131I, the whole-body radiation dose is derived from the gamma rays emitted from the accumulation of the radionuclide in the thyroid gland, the blood and the bladder. The SI unit for absorbed dose is the gray (Gy); 1 Gray = 100 rads. Dose equivalent is used to account for the variable biological consequences of radiation of different tissues. For this, the SI unit is the sievert (Sv); 1Sv = 100 rem. The amount of radioactivity is expressed in megabecquerels (MBq); 1 millicurie (mCi) equals 37 MBq.
As compared to external radiotherapy, the internally administered radionuclides are less radiotoxic per gray (rad) because their irradiation is delivered slowly over time. The risk of tumour is definitely lower with 131I as compared to X-rays (4).
Many people are frightened by radioactivity. It is indeed psychologically more impressive to swallow a glass of water containing radioiodine than to pass an X-ray examination. However, plain film X-ray and computed tomography often deliver a higher effective dose equivalent than many routinely used radiopharmaceuticals (5). In that respect, the long-term results of 131I treatment of hyperthyroidism are most reassuring on the basis of many hundreds of thousands patient-years' experience (6-10). Thyroid cancer and leukemia and to a lesser extent, other cancer and genetic or fetal defects do not appear to represent a significant risk consecutive to the use of radioiodine. Leukemia incidence in 131I-treated thyrotoxic patient is not greater than in those treated with antithyroid drugs and/or surgery. Exceptional cases of leukemia have been reported in patients repeatedly treated with high doses of 131I for thyroid cancer. There is no evidence of any genetic defects in the progeny of the patients treated with 131I-radioiodine either for thyroid cancer or hyperthyroidism at the time they were in a children's age (11).
There is only one significant risk for radioiodine therapy of hyperthyroidism, and this is thyroid insufficiency. Except if high doses of 131I have been administered, it is almost impossible to predict when hypothyroidism will occur for a given patient. It is a general observation that except for the first year of treatment, the development of thyroid insufficiency is slowly progressive. As an average, it will concern 3-8%/year of the group of patients treated depending more particularly on the dose administered and/or on the presence of high titers of antithyroid antibodies. Thyroid insufficiency can be easily screened by a yearly blood determination of TSH. An enhanced serum TSH will indicate the beginning of thyroid failure at a time when the patient is still clinically euthyroid. This observation will be immediately followed by an appropriate thyroid substitution therapy. The delay in the appearance of hypothyroidism is statistically dose-related but individually affected by significant differences in thyroid radiosensitivity. Thus, whatever the way of calculating the therapeutic dose to be administered to a given thyrotoxic patient, most of the efforts to avoid late hypothyroidism have been practically disappointing. The therapeutic trials using the bulk of the ß-like energy of 125I absorbed within a few microns has even given worse results than with 131I (12).
1. There are firstly important clinical considerations. If the state of hyperthyroidism is responsible for many patient's complaints or clinically severe, the antithyroid drugs come as a priority in the therapeutic strategy. Euthyroidism has to be reached as soon as possible. If there is only moderate hyperthyroidism, 131I represent an excellent choice, particularly if the thyroid is diffusely enlarged. Since radioiodine takes 6 to 8 weeks to produce its effects, ß adrenergic blocking agents will in the meantime efficiently control the patient's symptomatology. Normally, euthyroidism is to be expected to be reached 3-6 months after 131I administration. If not, the administration of a second dosis of 131I has to be considered.
For obvious reasons, pregnancy and breast-feeding represent absolute contraindications to radioiodine administration. Age per se is not a difficulty in the decision - making procedure favouring radioiodine administration since there is neither any evidence of 131I-induced secondary cancers (including leukemia), nor any enhanced prevalence of genetic defects in the progeny of radioiodine-treated thyrotoxic patients (6-11). Important to be remembered: because of a longer life expectancy, the chances of late hypothyroidism are higher in a young patient treated with 131I. Depending on the radioactive iodine dose, up to 50% of the treated population may be hypothyroid after 15 years (13). Radioiodine treatment or surgery are advised if there are problems of patient's compliance with the antithyroid drugs. The choice will depend on the patient's preference, the excellency of the surgical team and the medical pressure to quickly solve the problem medically. From the literature, it is very difficult to assess whether or not, subtotal thyroidectomy is less often complicated by thyroid insufficiency than radioiodine. For obvious reasons, the practitioner and the surgeon will favour to protect the patient from any post-surgical thyrotoxic relapse and therefore, will be reluctant to leave too much thyroid tissue in the neck: thyroid insufficiency is then almost unavoidable. Nowadays again, thyroid substitution therapy is cost-effective and thyroid insufficiency is easily corrected. Although all doctors, especially the endocrinologist, dream of "the” ideal treatment leading to a full recovery of the euthyroid status such a goal is not met in the case of toxic goiter... We are left with a relatively empirical strategy when the antithyroid drugs have failed to solve the patient's problem.
2. Methodological criteria have to be met before administering radioiodine. A tracer uptake study will assess the avidity of the gland for iodine, and more particularly will exclude any significant iodine overload of the thyroid gland which would in turn, reduce the efficiency of the radioiodine treatment. Thyroid radioactive iodine uptake studies are recommended to be calculated in gray (rad), the radiation given to the gland. Because of the heterogeneous distribution of the radioisotope, a higher dose of 131I is given in multinodular goiter as compared to diffuse hyperplasia. Relatively higher dose of 131I are also needed in toxic adenoma, probably because of the biological properties of the autonomous thyroid tissue.
3. For more than 30 years, there has been a literature-consuming debate regarding the best definitive way to calculate the dosis of 131I to be administered for the treatment of hyperthyroidism. A dose calculated from thyroid size and 131I thyroid uptake parameters theoretically remains the ideal approach. Unfortunately, this remains an unsolved problem: important functional characteristics of the thyroid gland often remain unknown or poorly defined on an individual basis, particularly the exact thyroid volume of the gland and the thyroid cell radiosensitivity. In the literature, there are indications of a lower prevalence of hypothyroidism in patients treated with a calculated 131I dose as compared to those receiving an empirically chosen radioiodine dose, at least after the first 5 to 10 years of treatment. On a longtime run, there is actually no evidence that the calculated approach gives better results than the so-called standard for 131I administration. Different elements of uncertainty associated with the fact that hyperthyroidism is usually evaluated on an ambulatory basis, have thus practically led many thyroidologists to administer standard fixed doses between 5 to 15 mCi (185-555 MBq) of 131I depending on the goiter size and the severity of the disease. The results of a recent prospective, randomized and well conducted as a multicentered study on standard vs calculated 131I therapy by Peters et al. are worth mentioning (14). A total of 230 patients with Graves' disease were enrolled in this prospective study. One group of patients received a standard dose of 555 MBq (15 mCi) of 131I while the other received a calculated dose which was expected to integrate the thyroid volume and the radioactive iodine thyroid uptake parameters in order to deliver 100 Gy (10,000 rads) to the gland. The results clearly indicate that the therapeutic outcome remains dose-related and inversely correlated with the thyroid gland size. It is unfortunately too early to assess the incidence of hypothyroidism since such a study is based on a group of patients enrolled between 1987 and 1990. It is however already concluded that to obtain a 100% therapeutic success, the calculated target dose should average 200 Gy (20,000 rad). If this is true, one may expect that a high therapeutic success will be highly correlated with a high incidence of hypothyroidism. It is interesting to note that 25 years ago, the goal for the calculation of the 131I therapeutic dose was mainly to avoid late hypothyroidism, and now is to quickly and effectively control thyrotoxicosis. This last approach makes sense: a longstanding medical antithyroid treatment often keeps the patient in "an atmosphere of disease” and can be a source of personal and professional problems while the risk of an early thyroid insufficiency is easily controlled by thyroid substitution therapy.
4. Graves' ophtalmopathy has been reported to be worsened by radioiodine therapy, but this can be efficiently prevented by short-term glucocorticoid administration. Taking into account the fluctuations observed in the course of Graves' ophtalmopathy, there is no statistical convincing evidence that radioiodine per se aggravates the ophtalmopathy. There are even some authors who advocate ablative dose of 131I to cure Graves' ophtalmopathy (15). Prospective studies are badly needed even if they are difficult to perform.
5. 131I treatment does not enhance the risk of carcinogenesis or of any deleterious genetic defects (6). The dose to the gonads is roughly of 2 cGy (200 mrad/mCi) of administered radioiodine which is lower than many commonly performed radiologic procedures like a plain film X-ray for the lumbar spine, an intravenous urogram or a barium enema (5). The risks of 131I treatment on a longrun evaluation is truly negligible.
So what, to correctly and efficiently treat my patient? An algorithm tries to approach this problem (Fig. 1) and can be commented as follows:
1. If one admits that 50% of the patients treated by antithyroid drugs relapse after stopping the medication, the other 50% benefits from a well conducted treatment with methimazole (thiamazole) or propylthiouracil and will not relapse. It is thus generally reasonable to start with the antithyroid drug treatment, except if there are problems like compliance, oversensitivity, allergy or mechanical problems. Generally, euthyroidism will be reached within 2-3 months. It is easy to maintain euthyroidism, even if in some cases, a small dose of thyroxine has to be combined with the antithyroid drugs. The therapy is maintained for 15-18months. In cases of Graves' disease, a disappearance of the circulating TSH-receptor antibodies is to be expected and is expected to be associated with a good prognosis.
2. In case of relapse after such a medical treatment, 131I is to be considered. However, if the patient has a large multinodular goiter, with severe compressive signs of the trachea or the esophagus, surgery is primarily to be advised, provided the patient can be referred to an experienced surgical team.
3. If the patient is in the category of those at risk of relapse (large diffuse goiter, multinodular goiter, persistence of high levels of TSH-receptor stimulating antibodies,...) or if there are problems of compliance, it is advised (a) to attempt to reach euthyroidism through a 4-6 months antithyroid drug treatment, followed (b) by the administration of a relatively large dose of 131I, after stopping the antithyroid medication. Surgery may be prefered, if there is severe tracheal compression. The patient is at risk of hypothyroidism and an appropriate follow-up of the patient is advised. In case of thyroid insufficiency (high TSH levels), thyroid substitution therapy is started.
HYPERTHYROIDISM |
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TOXIC ADENOMA | |
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QUESTIONS: |  |
| Severity of thyrotoxicosis? | ||
| Relapse? Compliance? | ||
| Antithyroid drug intolerance? | ||
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RENDER THE PATIENT EUTHYROID | |
| Antithyroid drugs - Propanolol | ||
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| Antithyroid drugs
15-18 month |
RADIOIODINE (131I) | SURGERY |
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Progressive control | Immediate control |
| 50% of patients cured,
especially if low TSI and small diffuse goiter |
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| No surgical risk
Progessive action Risk of hypothyroidism? |
Surgeon's expertise?
Mechanical problems? Risk of hypothyroidism, hypoparathyroidism and vocal cord paralysis? |
The ablative efficiency of 131I is well recognized for more than 40 years. It remains essential to point out that several conditions have to be met for a successful result in the treatment of thyroid cancer:
(a) It is necessary to wait 4-6 weeks after surgery before the administration of a radioiodine therapeutic dose. The reason for this is to benefit from the development of thyroid insufficiency which in turn, is associated with an enhanced TSH level in the serum which last but not least, will stimulate the 131I uptake by the thyroid remnant.
(b) A dose of 3,700 MBq (100 mCi) 131I is given during a short hospitalization of the patient (in agreement with the legal requirements for radioprotection). In some countries like Germany, the radioprotection requirements are much more difficult to be met and require a long hospitalization. This may raise social and professional problems for the patient. The opportunity of the administration of a therapeutic 131I dose is used to perform a whole-body scan, 5 days later.
(c) A new thyroid scan is to be repeated 6 months later, after stopping for 4 weeks the TSH suppressive thyroid hormone therapy. This will ensure at the time of the scintigraphic control, an optimal stimulation of the remaining thyroid tissue or metastases. It is important to stress that the TSH enhancement after discontinuation of thyroid hormone therapy has not only to reach a certain level (at least 30 mU/L) as reflected by the serum TSH but this for several days (8-10 days) in order to reinforce the thyroid uptake and thus, the sensitivity of the 131I scintigraphy. The tracer dose has to be in order of 185 MBq 131I in order to maximize the chance of detection of the remaining tissue. However depending on the iodine environment, this "tracer” dose may vary between 74 to 3700 MBq (2 to 10 mCi). Strictly speaking, there is advantage not to give more than 185 MBq (5 mCi) 131I in order to reduce the radiation thyroiditis which, secondarily, may diminish the accumulation of the therapeutic 131I dose in the thyroid tissues, that will be subsequently administered. Thus, the enhancement of thyroid tissue detection by a high dose of the therapeutic 131I dose has to be balanced against a reduced efficiency of the treatment itself in case of post-diagnostic thyroiditis. Generally speaking, Europe is characterized by a low iodine environment and therefore, the detection sensitivity is higher than in other countries, especially in the USA. In the follow-up of thyroid cancer, a 185 MBq (5 mCi) 131I diagnostic doses should be advised.
(d) A thyroid scan after stopping of thyroid medication is performed every 6 months until the scintigraphic investigation and/or the thyroglobulin becomes undetectable in the serum (under conditions of withdrawal of thyroid hormones). A positive scan is followed by 131I treatment. Once a scan becomes negative, the controls will be progressively spaced at 12 months intervals, 2 and 4 years intervals as long as they remain negative.
(e) Advantage will be taken of the enhanced TSH level at the time of the thyroid scan, to measure the circulating serum thyroglobulin. Thyroglobulin measurement is an important tool in the cancer follow up, probably best in conditions of thyroid hormones withdrawal. In our hands, a value higher than 2 ng/ml indicates the persistence of active thyroid tissue, even if the thyroid scan is negative.
(g) Ideally and as already stressed, the 131I thyroid scan should be interpreted in conjunction with the results of the serum thyroglobulin determination in the context of a high TSH level, at the time of the diagnostic 131I thyroid scan. There should be an agreement between a negative thyroid scan and a serum thyroglobulin level below 2 ng/ml, or preferably undetectable. False negative scans resulting from an iodine overload should be excluded by measuring the iodine concentration of a urinary spot sample at the time of administration of the diagnostic 131I dose. A negative thyroid scan associated with a serum thyroglobulin level higher than 2-5 ng/ml (depending on the sensitivity of the methodology) indicates the persistence of thyroid tissue. In contrast, a positive thyroid scan associated with undetectable levels of thyroglobulin will a few months later usually be followed by a negative thyroid scan.
(h) Thyroid hormone therapy is maintained within the intervals between the thyroid scans. Appropriate doses of T4 maintain the serum TSH level undetectable or in the very low range. TSH has a mitotic action which has to be avoided in thyroid cancer. In fact the patient is not treated with a substitution dose but with a suppression dose of T4. This is the least dose of T4 that suppresses TSH below normal levels.
A strong policy is recommended in order to maximize the chances to definitely cure a patient suffering from thyroid cancer. We do have all the tools in our hands ... In this respect, 131I undoubtly plays a key role. The requirement of stopping thyroid suppression therapy for an appropriate time represents a decision that often makes the patient's life uncomfortable but a high sensitivity of the thyroid scan and of the thyroglobulin measurement is the reward. The use of recombinant h-TSH may circumvent these discomforts provided its cost-effectiveness is clearly demonstrated.
An ablative dose of 131I ranging between 3.7 and 5.55 MBq (100-150 µCi) of 131I/g of thyroid tissue retained at 24 hr is used. It is notorious that whatever the method used (palpation, neck circumference, thyroid scintigraphy), the estimation of the volume of the thyroid gland remains imprecise. Echography is not applicable for the evaluation of the volume of large goiters, especially in the case of intrathoracic goiters. Nuclear magnetic resonance imaging can be used but may raise problems of accessibility or costs. All these considerations practically lead to the administration of 131I doses of 1,000 to 370,000 MBq (about 30 to 100 mCi). Doses of 131I of that magnitude imply hospitalization of the patient for reasons of radioprotection and for the risk of radiation thyroiditis which can result in a thyrotoxic crisis and/or a thyroid swelling aggravating any compressive symptoms of the trachea. The clinician has to carefully watch these potential complications which can usually be handled by corticosteroid therapy. Since these patients are expected to become hypothyroid sooner or later, they have to be started on substitution thyroid therapy shortly after 131I administration.
According to the literature, the results of 131I treatment even of large goiters are encouraging and rarely accompanied by significant side effects. The administration of radioiodine in these patients undoubtly remains a reasonable therapeutic approach.
For the patient, somatic and genetic consequences of radiation therapy represent the potential risks to be evaluated. As previously discussed, late hypothyroidism is the true risk of radioiodine therapy but its consequences can be easely prevented by a yearly screening test based on serum TSH determination. The question of carcinogenesis has been examined in great details, particularly in the United States and in Sweden(6-9). These studies include several hundreds thousands patient-years: no significant excess of malignant diseases, particularly leukemia and thyroid carcinoma, have been demonstrated in the 131I-treated patients as compared to the control groups.
Therapeutic radioiodine should not be given to premenopausal women whose last period finished more than 10 days previously. Pregnancy is to be avoided for 4 months after radioiodine therapy. An absolute contraindication for the administration of radioiodine is pregnancy or the possibility of pregnancy and breast-feeding. For these reasons, it is important to obtain the patient's informed consent.
Theoretically, the risk of inducing a genetic abnormality by radioiodine treatment has been estimated at 0.003%(16). Such a risk has not been identified in treated thyrotoxic patients, even in large studies. Any theoretical increase should be evaluated in the light of the spontaneous incidence of (partly) genetic disorders. A somewhat similar conclusion arises from the follow-up of a fixed cohort of approximately 13,000 children born to parents exposed to the Hiroshima and Nagasaki bombs(17). Several reports indicate that deliveries in women treated with 131I below the age of 20 years have not demonstrated any particular genetic abnormalities. The same is true for the observation of the progeny of thyroid cancer women treated with much higher dose of 131I (17,18). The gonadal dose after radioiodine treatment for thyrotoxicosis is usually less than 30 mSv, thus much less than what is delivered by many routine radiological procedures.
| Whole body exposure to 0.1 mSv of ionising radiation |
| Smoking 1.5 cigarette |
| Travelling 50 miles (80 km) by car |
| Rock climbing for 1.5 minutes |
| Being a man aged 30 for 9 hours |
| Being a man aged 53 for 53 minutes |
| Being a man aged 63 for 17 minutes |
| Adapted from E.E. Pochin - Community Health, 1974, 6 : 2. |
| Days of life | |
| Health risk | expectancy lost |
| (average) | |
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| Unmarried (male) | 3500 |
| Cigarette smoking (male) | 2250 |
| Overweight (by 30%) | 300 |
| Car accident | 200 |
| job with radiation exposure | |
| (10 mSv - 1 rem/year/40 years) | 40 |
| Adapted from Brill - Low level radiation effects: | |
| a fact. SNM Press, New York, 1985 | |
The International Commission on Radiological Protection (ICRP) has recently recommended to lower the annual effective dose for members of the public to 1 mSv. Actually, the regulations regarding the administration of radioiodine (131I) on an ambulatory basis vary from country to country. The maximum limits for 131I activity permitted for out-patient treatment is 75 MBq (2 mCi) in Germany and 1110 MBq (30 mCi) in the United States; the average limit in the European countries is 555-800 MBq (15-20 mCi).
A reasonable consensus has obviously to be met to protect the patient and the general public aswell. In this respect, the Committee on Radioiodine (131I) Therapy in Thyrotoxicosis of the European Thyroid Association has issued recommendations for the 131I-treated thyrotoxic patients (Table 3). These recommendations have to be used as guidelines, taking into account each patient with her/his own environment. The effectiveness of these recommendations is based on the cooperation and the willingness of the thyrotoxic patient her/himself. If these recommendations cannot be followed, the only alternative is hospitalization for an appropriate period of time, a decision which requires the allocation of high expenses. At all levels, an effort has to be maintained to reduce the radiation hazards but it is essential to keep in mind that there are many other sources of background radiation - not necessarily deleterious - like living in Cornwall (0,1 mSv/week) or in a radon-build house for years or generations (1.2 mSv/year). Such radiation hazards are only a small part of the general risks of living, taking into account those related to chemical pollution of our environment. In 1994, the United Nations Scientific Committee on the Effects of Atomic Radiations (UNSCEAR) published its report on radiation hormesis, entitled "Adaptative responses to radiation in cells and organisms” (21). In living cells, several adaptive processes to low-level radiation have been observed, including the key role of the DNA repair enzymes. Such mechanisms may apply not only to ionizing radiation but also to chemicals including pesticides and carcinogenic agents. A reexamination of the "no-treshold hypothesis” based upon the hypothetical linear extrapolation of high-doses effects to effects of very low doses approaching zero are urgently needed. Pollycove concludes in an editorial: "...Instead of wasting many billions of dollars annually for protection against hypothetical risks of low-level radiation exposure, the resources could be used productively for effective health measures...” (22). Adaptive processes to low-level radiation allows to observe beneficial effects at dose levels between 1 and 50 cGy (1-50 rads) (23). It should be remembered here that the concept of hormesis is very broad. As an example comparing with the radiation risks, one may mention vitamins which are beneficial at low concentrations but which may become toxic at higher doses. The concept of radiation hormesis has undoubtly to face the difficult goal of the analysis of the long-term effects of low-dose radiation (23). The continuity of the living process is in harmony with the concept of "good sense” of life. This is so for cosmic and terrestrial radiations that stimulated the evolution of life in our world. Mother Nature has teached us that too much of anything may be dangerous but a touch of something can be most beneficial. It is our responsibility to define the reasonable limits to protect a safe environment but at the same time, to avoid disturbing the members of the public without appropriate justification.
| Period of restriction (Days:A/B/C)* after 131I | |||
| Advice | therapy for administered activities of | ||
| 200MBq | 400 MBq | 800 MBq | |
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| A B C | A B C | A B C | |
| Avoid non essential | 2 7 8 | 9 14 15 | |
| 15 20 21 | |||
| contact with children | |||
| Avoid close contact | 0 0 0 | 0 0 1 | 2 5 6 |
| with partners/spouses | |||
| Avoid close contact | 0 0 0 | 0 2 5 | 2 8 11 |
| with other people | |||
| Stay of work** | 0 0 0 | 0 2 5 | 2 8 11 |
| Avoid public places | 0 0 0 | 0 2 5 | 2 8 11 |
| Avoid travel on | 0 0 0 | 0 0 0 | 1 1 1 |
| public transport*** | |||
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