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Treatment of Hyper-Thyroidism and Breast Irradiation

Part 1.   Surgery versus Radiation in the Treatment of Hyper-Thyroidism

          Hyper-thyroidism was the subject of repeated battles between the surgeons and the radiologists. In the decades 1920-1930 and 1930-1940, an almost endless literature appeared with two separate conclusions, each staunchly defended, (a) hyper-thyroidism is a disorder to be treated surgically or (b) hyper-thyroidism can be better treated in a high percentage of the cases by ionizing radiation, either with radium or x-rays. An occasional author would suggest there might be an intermediate ground, but that was definitely not the rule.

          The case made by the radiologists was that there was a definite surgical operation mortality, and that such mortality was highly related to the amount of experience and skill of the surgeon. The radiologists suggested that there was virtually no mortality associated with the radiation therapy (at least not in periods of a decade or so). The surgeons countered with the slowness in response of patients if treated by ionizing radiation, whereas surgery produced almost instantaneous results (not always sustained). Some of the surgeons pointed out that dangerous cardiac deterioration would occur during the weeks and months it took for a full radiation effect to be produced in this disease, which hazard could be avoided by surgery.

          The meaning of this conflict in the field is that we have real trouble ascertaining the frequency of radiation therapy in a given year for a given locale. It is enough of a problem to ascertain the total number of cases treated per year in a given locale because we do not know that all the treating radiologists are reporting their treatment. When we add to the problem --- not knowing the relative number of patients surgically treated versus those radiation-treated --- it becomes difficult to eliminate errors of a factor of two or more. But we do believe we can still get the general order of magnitude of radiation contributions from hyper-thyroidism treatment, by using the work of several authors. We shall explain. Also, in general the error will result in an underestimate of radiation dose, which is consistent with our conservative position.

Part 2.   The Principles Involved in Therapy of Hyper-Thyroidism

          Hyper-thyroidism is a disorder of great complexity, and it still is not really understood. Many writers use fine distinctions to decide whether a particular patient's disorder deserves the label, Basedow's Disease, hyper-thyroidism, Graves' Disease, or toxic adenoma. It was early pretty well agreed that even if many symptoms were similar, the cases with a defined nodular thyroid plus symptoms should be separated out and should be treated surgically. Over a long period there seemed to exist agreement on this one point. For the remaining cases, some wished to single out those cases with exophthalmic features (protrusion of the eyeballs, so that the patients exhibited the "hyperthyroid" stare). Others did not agree with this feature as a clinical sorter among cases. Most authors cautiously (very cautiously) tended to consider the disorder the result of overproduction and release of thyroid hormone. So, to most workers, sensible treatment meant stopping the function of part of the thyroid gland, either by high-dose radiation, or by surgical removal of large parts of the gland --- with each of these maneuvers intended to lower the subsequent output of thyroid hormone.

          This was not wholly agreed to, and in this early period there are papers which doubt the logic of removal of thyroid structure or function. Some advocated pituitary irradiation, others, adrenal irradiation in addition to thyroid irradiation. We quote Read (1949):

          "It should be stressed here that roentgen therapy, as well as surgical treatment, is directed at the thyroid. The thymus, of course, is also irradiated and sometimes the pituitary (the adrenals only rarely) thus recognizing the disturbed function of the whole endocrine system in this strange disease."

Some Blamed the Thymus for Hyper-Thyroidism

          Our readers may raise an eyebrow concerning the "thymus, of course, is also irradiated." That statement is perfectly correct for the time. Having reviewed many years of early literature on this subject, we know that over and over the physicians considered the thymus in some way responsible for hyper-thyroidism about as much as the thyroid itself. Many, many papers simply described their routine: "irradiate the left lobe, irradiate the right lobe [of thyroid], and then irradiate the mediastinum in order to suppress the thymus gland." Read is by no means alone.

          Quigley, for example, (1932) treated his series of patients with radium externally. He writes:   "Some cases of exophthalmic goiter are accompanied by persistent thymus. In these it is necessary to irradiate the thymus as well as the thyroid. Care must be taken not to mistake a persistent thymus for a substernal goiter (enlarged thyroid). Here a therapeutic test may make clear the diagnosis, as a thymus always shrinks very quickly after radiation, while the substernal goiter requires operation. Patients with persistent thymus invariably present an unnaturally youthful appearance, seeming to be from 10 to 15 years younger than their real age."

          Dr. Quigley's series of 137 cases treated with radium externally, from 1915 to 1927, not only had some breast irradiation from the gamma rays directed downward against the thymus region, but may have had additional exposure from gamma rays coming sideways out of the radium capsule. There are not enough data to enable calculation of breast-dose as a result of the external pathway from the radium applied to the neck.

          Williams (1932), in reviewing his experience with radiation treatment of hyper-thyroidism in 200 patients over a period of 15 years, says the following:

          "Some good authorities state that there are no contraindications to surgery; others say this idea is very much open to question. In the one opinion, radiation therapy is temporizing, and curative in the other. The cause of the goiter illness begins in the thyroid or elsewhere, subsequently upsetting the thyroid. Goiter histopathology is, or is not, consistent with the symptom complex. The thymus has, or has not, anything to do with the disease..."

          Williams does not really tell us whether he explicitly attempted to irradiate the thymus in his roentgen therapy of "goiter illness." His technic section simply relates treatment of an area 10 x 12 centimeters. It is not possible to state how much chest irradiation is received since we do not know the placement of those 10 to 12 centimeters. This is not too surprising, since many reports indicate that thymus treatment is casually expected in treating hyper-thyroidism.

          Menville (1932) queried radiologists all over the USA for their experience, and accumulated data on 10,541 cases of hyper-thyroidism treated with roentgen therapy. With respect to the radiation received by the thymus in such therapy, Menville states:

          "The excellent results obtained in the treatment of toxic goiter by irradiation are not alone due to the changes produced in the gland when it is in a state of hyperfunction, but they are also thought to be due in a measure to the irradiation of the thymus gland. It is presently believed that the thymus gland undergoes certain changes in cases of thyrotoxicosis, and also that the benefit received in post-operative hyper-thyroidism by radiation therapy is probably due, to a certain extent, to the irradiation which the thymus gland receives. Schwarz (1928) recommends that the thymic region should be included in the field of treatment while irradiating the thyroid gland, and that the larynx and trachea should be protected."

Part 3.   Breast-Dose in Hyper-Thyroidism Therapy: A Division of Time Periods

          As we go on to consider the possible assessment of breast-dose from radiation therapy for hyper-thyroidism, we shall divide our considerations into those of the pre-1940 era and those of the post-1940 era. We do this because after 1940, and particularly after 1945, iodine-131 therapy became the leading choice among the radio-therapists for treating hyper-thyroidism. Of course, some surgical therapy continued over all periods.

Approximations to the Breast-Dose in the Pre-1940 Era of Roentgen Therapy

          We have already stated that it is difficult in the literature to find a single source of roentgen therapy of hyper-thyroidism where we have confidence that essentially all the cases in a geographic region have been so treated. If any series we use does not include all cases which were treated, we will be seriously underestimating the breast-dose from such therapy. We will still be getting a minimum value for breast irradiation and breast-cancers.

          Menville's data provide one reasonable source of treated cases, with some data borrowed from other studies. From the study of 200 cases by Williams, we have the datum that 77.5% of cases are female, 22.5 % of cases are males. This is quite consistent with Read's data.

          Williams' studies also include the datum that 31.5 % of cases are under 30 years of age and 68.5 % of cases are over 30 years of age. If we assign 45 years as average age of those over 30 years of age, and 25 years of age of those under 30 years of age, the average age of all the cases is 38.7 years of age.

          Menville received back one report from Illinois of 1,020 treated cases. All other Illinois entries were lower than half this number, so we presume this one entry must be that of a large hospital practice in Cook County. Menville does not give us the number of years over which these cases were accumulated, but since his paper was delivered in 1931, it would be reasonable to say that the cases accumulated over no more than 10 years. This would reduce the number of cases to 102 cases per year. And then accounting for 77.5% females, we would have (0.775 x 102), or 79 female cases treated per year.

          Rosenstein's thymus-irradiated children (Hildreth et al 1985), mostly irradiated before 6 months of age, were finally estimated by us to have received 32.5 medical rads to breast-tissue, adjusted for supra-linearity. But we do not believe that the effort to irradiate the thymus in adults would lead to as great a fraction of breast irradiation as in the child. So we shall avoid overestimation, and suggest that the breast-dose in adults treated for hyper-thyroidism was 5 medical rads, as a result of deliberate irradiation of the thymic area. Our choice of less than 1/6 of the breast-dose in the young infants may well underestimate breast-dose in these adult hyper-thyroid cases.

          For those under 30 years of age, we estimate 0.315 of cases, or (0.315 x 79) female cases, or 25 cases. This leaves 54 female cases for the over-30 year age group.

          If we distribute the under-30 year cases to age bracket 20 to 29 years, we have 25 / 10, or 2.5 cases per age-year. And if we distribute the 54 cases at 30 years of age or older to those 30 to 59 years of age, there will be 54 / 30, or 1.8 female cases per age-year.

The Person-Rads calculation

          For the under 30 year age group: (2.5 persons) x (5 medical rads) = 12.5 person-rads to breasts per age-year.

          For the over 30 year age group: (1.8 persons) x (5 medical rads) = 9 person-rads to breasts per age-year.

Arriving at the Population-Dose in Each Age-Year

Comments on the Hyper-Thyroidism Therapy's Contribution to Breast-Dose:

          (1)   We have reduced the radiation dose to the breasts from 32.5 rads to 5 rads, since we are not sure the thymus was as avidly treated in the hyper-thyroid therapy as in direct thymus therapy. We may have been too conservative.

          (2)   We do not know that one Cook County hospital is the only one doing such therapy and we do not know whether private radiologists may have been doing such therapy. For all we know, we may have underestimated the population being treated by 5 or 10 fold. But we prefer to underestimate than to overestimate.

          This completes the assessment for the 1920 - 1940 part of the whole period. We must now assess the 1940-1960 part, with introduction of radioiodine-131 in the therapy of hyper-thyroidism.

          Dewing (1965) describes the transition-era very well:   "It is extremely interesting to follow the literature of the latter 1920's and early 1930's when surgical and radio-therapeutic claims to control of hyperthyroidism were closely competitive. The issue of Radiology for March 1932 (Vol. 18) contains a good symposium on the current status of surgical, medical, and radiation management of the disease. An article by Williams contains an excellent general discussion from the radiologist's standpoint and a bibliography of 156 references. Another, by Menville, analyses some 10,541 cases treated by some seventy-five radiologists throughout the United States." And:

          "Then, during the 1930's the surgeons pulled ahead for a while. However, as recently as 1949 Read reported a twenty-five year follow up of patients treated with x-ray and concluded that the results were quite equal to those of surgery." And:

          "Reichel, in Europe, also reported in 1949 a twenty year followup, and similarly showed that surgery and radiation both gave good results in about 80 per cent of cases." And:

          "After World War II the wheel had come around, and artificially produced Iodine-131 at reasonable cost brought radiation to the fore again. Most surgeons, who know all too well the hazards and complications of thyroid operations, are now among the happiest to refer hyper-thyroid cases to another department...."

          But this did not mean that x-ray and radium therapy immediately went by the board for hyper-thyroidism --- papers on technics of using x-ray and radium continued to appear in the literature of the 1940's and 1950's.

Part 4.   Breast-Doses Incident to the Use of Radio-Iodine-131

          For our purposes, we wish to gain an estimate of how the iodine-131 use in the latter third of the 1920-1960 period may have altered our estimate of radiation to the breast in the therapy of hyper-thyroidism.

Dose to the Breast as a Result of Total-Body Irradiation by Iodine-131

          Gofman (1981) at pp. 643-644, using data from MIRD Report 5, reported that a value of about 0.71 rads of whole-body radiation is reasonable per milli-Curie of iodine-131 ingested. If we take into account the high energy of the beta particles from iodine-131, we would reduce this estimate to 0.35 medical rads per milli-Curie.

          Suppose we consider a dose of 10 milli-Curies of I-131 --- a common dose. Then, the whole-body dose (and breast-pair dose) is 3.5 medical rads. This is in the same range as the 5 medical rads we took from the thymus part of hyper-thyroidism therapy. But we can be quite certain that iodine-131 enjoyed a large surge of use in the 1940-1960 era, and it would be quite conservative to expect that at least 5 times as many persons per 1,000 received radio-iodine for hyper-thyroidism than had ever been the case broadly for x-ray or radium therapy.

          We have a dose-reduction factor of 3.5 / 5, or 0.7 for I-131, and an increased use factor of 5, so the radio-iodine net dose to breasts would be 3.5 times what we estimated above from x-ray therapy. But this is not the end of the calculation. We must now take into account the direct external air pathway transfer of gamma radiation from the thyroid glands being treated to the breast tissue, without any other tissue intervening [except of course some thyroid tissue and some skin tissue]. We are referring to the energetic gamma rays being emitted from the iodine-131 residing in the thyroid gland. Elsewhere (Gofman 1994, Chapter 2), we have calculated a mean effective half-life for I-131 to be 7.16 days. This means that the mean residence time will be Effective Half-life / 0.693, which makes mean residence time (7.16 days / 0.693), or 10.33 days in the thyroid gland. These calculations are for euthyroid persons, and hence will be somewhat different for each hyper-thyroid patient. But for our "range" estimates, 10.33 days as mean residence time is a value we can use.

          We are going to calculate dose to breasts from the iodine-131 resident for 10.33 days in the thyroid gland. We shall be estimating rads per hour received by the breast, and multiplying it by the number of hours the radiation continues from the thyroid gland. That number of hours will be (10.33 days) x (24 hours / day) = 248 hours, rounded off.

          The I-131 is distributed in a diffusely enlarged thyroid gland, in the two lobes (and some in the isthmus), all of which we can treat as a point source considering its distance of about 20 centimeters from the midplane of the breast tissue being reached by I-131 gamma rays.

          Various sources differ in the abundance and exact energies of the various gamma rays emitted by I-131. We shall use the following distribution and the weighted average as calculated from the distribution.

Energy of Gamma Photons     Percent abundance
	0.72 MEV                  3%
        0.64 MEV                  9%
	0.36 MEV                 81%
        0.28 MEV                  6%
	0.08 MEV                  6%
Average Gamma Energy per Disintegration = 0.377 MEV.

          We agree with Shapiro (1990) on the dose rate for a given flux of gamma rays.

          That dose rate due to 100 photons / cm^2-sec of Energy E per photon will be (0.172) x (E) milli-rads per hour. Our value of E for I-131 gammas is 0.377 MEV.

          If now, we consider a point source of I-131 and a sphere of 1 cm radius, the surface area is 4 x pi x 1^2, or 12.566 cm^2.

          NOTE: Here and elsewhere in the book, the common symbolic representation of an exponent in modern computer spreadsheets, such as x raised to the y power, is x^y.

          For one milli-Curie of I-131, we have 3.7 x 10^7 disintegrations / sec.

          Flux over the spherical surface of 1 cm radius will be

          (3.7 x 10^7 dis/sec) / (12.566 cm^2) = 0.294 x 10^7 dis/sec/cm^2

          And dose-rate will be ((0.294 x 10^7) /100) x 0.172 x 0.377 milli-rads per hour.

          This is 1906 milli-rads per hour, or 1.91 rads per hour at a distance of 1 cm from the point source. Shapiro gets 1.86 rads per hour, but he uses only two of the gamma rays. The literature often gives 2.2 rad / hr but Shapiro points out that this is the result of using a more complete set of gamma rays. We can regard our 1.91 rads/ hour for a one milli-Curie source of I-131 at 1 cm as satisfactory.

          But our midplane of breast tissue is about 20 cm from the I-131 source in the thyroid gland, so the dose would be that for photons passing through a spherical surface of 20^2, or 400 times larger than that for which we had calculated. Therefore, the dose at breast midplane would be 1.91 rads per hour / 400, or 0.00478 rads / hour to the breasts for a one milli-Curie point source in the thyroid gland.

          But above, we have calculated the mean residence time to be 248 hours, so the radiation dose would be (248 hours) x (0.00478 rads/hr), or 1.185 rads total dose --- if there is one milli-Curie in the thyroid gland.

          We estimate that a frequent dose was 10 milli-Curies administered. And since the hyper-thyroid gland has a higher uptake than euthyroid glands, we can say about 40% of the dose administered will be taken up in the gland. So we will estimate dose to breast as (1.185 rads / milli-Curie) x (4 milli-Curies), or about 4.74 rads to the breast tissue. But since this is quite energetic gamma radiation, we should reduce this to about 2.37 medical rads to the breasts. And, because some small part of the gamma radiation will be absorbed at the thyroid and in skin, we could round this dose off to about 2 medical rads to breast from the 4 milli-Curies of I-131 deposited in the thyroid gland of hyper-thyroid patients given a total dose of 10 milli-Curies.

Total Dose of Medical Rads from I-131 Therapy of Hyper-thyroidism

          Above we estimated, for the I-131 in the whole-body irradiation that the breasts would receive 3.5 medical rads for a 10 milli-Curie I-131 ingestion. And for the direct gamma transmission in air from thyroid to breasts, we estimate another 2 medical rads, bringing the total dose to 5.5 medical rads. This is very close to the 5 medical rads we estimated from the thymic irradiation part of x-ray treatment of hyperthyroidism. On the other hand, it is quite reasonable to expect that five times as many people per 1,000 got radioiodine as therapy as did those getting x-ray therapy.

          So, for under 30 years, instead of 2.5 persons treated per age-year, it would be 12.5 persons. Person-rads = (12.5 persons) x (5.5 medical rads)

          And for a population of 25,744 in each age-year, we would have an average dose experienced by the under-30 year group of (12.5 x 5.5) / 25,744, or 0.00267 medical rads.

          And, for over 30 years of age, instead of 1.8 persons treated per age-year, it would be 9.0 persons. Person-rads = (9.0 persons) x (5.5 medical rads).

          And for a population group of 25,744 in each age-year, we would have an average dose experienced by the over-30 year group of (9.0 x 5.5) / 25,744, or 0.00192 medical rads.

Part 5.   Combined Estimates, Pre-1940 and Post-1940, for the Master Table

          Now to combine the pre-1940 and post-1940 results, we are using the estimate that the early period is 25 years (1920-1944), and the later period is 15 years (1945-1959). Early period is 5/8 of total; later period is 3/8 of total. From Part 3, we have:

Annual population breast-dose, 1920-1944, below age-30 = 0.00049 rads.
Annual population breast-dose, 1945-1959, age-30+ = 0.00035 rads.

          For under 30 year age-group, (5/8 x 0.00049) + (3/8 x 0.00267) =
                    Mean Value, overall, = 0.00131 rads. Ages 20 through 29 years of age.

          For over 30 year age-group, (5/8 x 0.00035) + (3/8 x 0.00192) =
                    Mean Value, overall, = 0.00094 rads. Ages 30 through 59 years of age.

          These entries are transferred to Column L in the Master Table. (A more refined calculation could be done using the exact population at each age-year, instead of the average of 25,744. But the change in estimate would be small indeed.)

          We note that after 1960, the higher results characteristic for use of I-131 treatment of hyper-thyroidism would be applicable.

# # # # #

1920:   "I can truthfully say that a physician makes a grave and deplorable mistake if he allows his patient to be operated on before getting massive doses of x-ray over the thyroid and thymus glands." He is arguing for the superiority of x-ray over surgery for hyperthyroidism.

o - C. Augustus Simpson "A Word to the Roentgen Therapeutist," American Journal of Roentgenology Vol. 7, No.7: 357-358. July 1920.

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