131-I Treatment using empirically determined doses of 100-250mCi

Patients who have significant uptake of 131I in metastases (usually above 0.5% of the tracer) are given 150-250 mCi 131I. This dose can be tolerated without acute radiation sickness, and is below the level that would promote pulmonary fibrosis if diffuse pulmonary metastases are present, unless uptake in the lungs exceeds 50% (see below). Although use of these empirically derived doses is the most common practice, some centers do careful dosimetry with a tracer dose of 131-I prior to therapy, in order to judge the appropriate, or maximal safe, dose. This requires 2-5 days of observation. The methodology and results have been recently discussed (465.2).  Individual doses of 131-I of 200mCi or more can occasionally give whole body radiation exposure of 200cGy (Rad) or more in elderly individuals, and should be carefully considered(465.3). Kinetic studies are advisable in this situation. Whether administration of maximally large individual doses is more effective than use of somewhat smaller doses of 131-I has not been established. In perhaps four-fifths of patients accumulating 131I, it is possible to administer a dose of RAI that should be useful in destroying tumor. For normal thyroid tissue 10,000-15,000 rads is destructive, and a dose of 20,000 rads or more is probably needed for therapy of cancer. Assuming, for example, a standard 150 mCi 131I dose, and delivery to tumor of about 100 rads per microCurie retained per gram, a 1% tumor uptake distributed through 10 g of metastatic tissue could provide an effective treatment. The treatment dose can be estimated by the following formula:

Rads delivered = 74 x energy of beta ray (.2 mev) x µCi given  x fractional RAIU in site of interest x half-life in days (usually 6 or less) / ml distribution volume of site in question

Obviously the distribution volume in tumor is difficult to ascertain, and great variation in tissue distribution and sensitivity may occur. Some groups have attempted to measure tumor volume by use of quantitative PET scanning (465.3). The effective half-life can be determined from serial counts of the tracer over the metastasis. If 10 g of tumor in the neck accumulated 1% of a 150-mCi dose, and isotope turnover in the tumor was extremely slow, the radiation dose might be as follows:

Rads = 74 X 0.19 X 150,000 X 0.01 X 6  / 10 = 12,654

The question of whether a subcancericidal dose should be delivered in patients with low levels of tumor isotope accumulation needs further investigation, since radiobiologic studies suggest that radiation could preferentially spare the more radioresistant cells, ultimately leaving a more lethal tumor. It may be possible to give conventional x-ray therapy after 131I in those instances in which 131I uptake is present but the total dose delivered to the metastasis is less than adequate. This procedure may provide another therapeutic approach to the thyroid cancer patient, but it has not yet been given adequate trial. Maxon et al (465.4) report that radiation doses of at least 30,000 rads for thyroid ablation, and 8,000 for therapy to metastasis, improve the rate of response.

Lithium was found to be a potent adjuvant in ¹³¹I therapy of metastatic well differentiated thyroid cancer. Koong et al administered 600 mg of lithium carbonate orally followed by 300 mg three times daily and adjusted the dose to maintain a lithium concentration of 0.6 – 1.2 mEq/L, which is effective in blocking ¹³¹I release from the thyroid. The estimated ¹³¹I radiation dose to metastatic tumor tissue was increased on average 2.29-fold. It is possible that lithium would be of value in managing a large fraction of patients treated with radioactive iodide. It must be noted that lithium has a narrow therapeutic index and that serum concentrations must be monitored. Care must be taken in patients with reduced renal function. It would be imperative in patients who are to receive "maximal ¹³¹I therapy" that the measurement of ¹³¹I retention in blood and body be performed while the patient is receiving lithium prior to therapy. The use of lithium might also reduce the required ¹³¹I dosage for ablation of thyroid remnants (465.5).

It is useful to do a scintiscan on patients who have received therapeutic doses of 131I at 5 - 7 days following the treatment, thus using the treatment dose as a more powerful scanning dose. While often offering no new information, this may reveal unsuspected metastasis, especially in younger patients who have previously had 131I treatment. Fatourechi et al found that 13% of follow-up scans demonstrated abnormal foci of uptake not seen on diagnostic scans, and changed management in 9% of their patients (465.6, 465.7).

The 131-I treatment cycle is repeated at 24-52 weeks, as long as there is no evidence of systemic radiation damage, and as long as the metastases continue to accumulate iodide (Fig. 18-16, below). The total 131I dosage may vary from 150 to (rarely) 2,000 mCi. It may be possible to induce further uptake of iodide and thus deliver additional radiation therapy after administration of recombinant TSH, but this is under investigation. (Fig. 18-22, below) Both papillary and follicular cancers respond to 131-I therapy. Small metastses from papillary cancer, especially if functional in the lungs but not large enough to be visualized on X-ray, are typically cured. Follicular tumors often have relatively few metastases and high uptake, thus seem ideal targets for therapy. However portions of the metastases, especially in bone, appear to be resistant and finally continue growth despite 131-I treatment.
    Nevertheless 131-I therapy is beneficial even in advanced and aggressive tumors. Pelikan et al report their experience on the use of radioactive iodide in treating advanced differentiated thyroid carcinoma and report that up to 50% of patients who have distant metastases can be cured by ¹³¹I therapy (465.8). Aggressive high dose radioiodine therapy has been advocated for treatment of advanced differentiated thyroid cancer by Menzel and colleagues. These physicians gave repeated doses of 300 mCi (11.1 GBq ¹³¹I) with mean accumulated total activities of, on average, 55 GBq per patient. Repetitive high dose therapy appeared beneficial in the majority of patients with papillary carcinoma, but the majority of follicular thyroid cancer patients had progressive disease despite treatment (465.9).
    The National Thyroid Cancer Treatment Cooperative Study Registry Group recently evaluated the therapy of high risk papillary and non-Hurthle cell follicular thyroid carcinoma. The study confirmed the utility and benefit of radioactive iodide therapy to reduce recurrence and cancer-specific mortality among patients in the high risk group (465.10). Pittas et al recently reviewed an extensive series of 146 patients with documented bone metastasis from thyroid carcinoma seen at Memorial Sloan Kettering in New York City. Bone metastases were most common in vertebrae, pelvis, ribs, and femur, and multiple lesions were present in more than half the cases. Overall ten year survival rate was 35%, and from diagnosis of initial bone metastasis, was 13%. Favorable prognostic signs for survival included radioiodine uptake by the metastases and absence of nonosseous metastases. Hurthle cells had a favorable response to treatment, rather surprisingly, whereas undifferentiated thyroid tumors fared the worst.(465.11). Durante et al reported on efficacy of RAI in a large series of patients with metastatic cancer. They found therapy to be apparently curative in young patients even with small lesions visible by Xray, and suggest treatment until lesions disappear or 22GBy has been administered. Their treatment schedule employed 100mCi doses given at 3-9 months for 2 years and then annually. Disease progression signaled need for other therapies (465.12)
    Arterial embolization has been combined with radioactive iodide treatment for management of large bone metastasis from differentiated thyroid carcinoma with apparent improvement in effect over the use of radioactive iodide alone. In the study by Van Tol et al, embolization was not accompanied by any severe complications (467).

rhTSH is now available for routine use, and allows 131I therapy without induction of hypothyroidism (468). This will probably increase acceptance of scanning and therefor increase the frequency of the procedures. Another (although almost never employed) means of stimulating 131I uptake in these patients is by administration of antithyroid drugs. Iodide depletion by dietary control and diuresis, including furosemide or mannitol administration, can also double the fractional uptake of 131I in metastases (469, 470). Finally, when the diagnostic scan shows no 131I uptake, even with TSH, the potential benefits from this mode of therapy have been probably exhausted. However, before giving up to 131-I therapy, some authors suggest using high doses of 131-I and obtaining a post-therapy scan, which in some cases may show areas of uptake not seen in the diagnostic scan (see below).

131-I Therapy with "Negative" scans

In some patients tracer studies fail to show uptake, and serum TG is elevated. Some investigators recommend treating these individuals with large doses of 131I (100-150 mCi) and report that tumor uptake can be visualized after treatment, and that serum TG may fall (471). The clinical efficacy of this approach is not known. In a few cases reported by Schlumberger et al. (472) and Pineda et al. (473) TG became undetectable, which clearly is a striking and hopeful result. (Fig. 18-23) As of this date, there is no data proving that this treatment improves prognosis (474). The utility of radioactive iodide treatment of patients with papillary and follicular cancer was recently reviewed in a series of articles by Wartofsky, Sherman, and Schlumberger and their associates (475). Sherman and Gopal analyze the use of 100 mCi doses of ¹³¹I for treatment of scan negative TG-positive patients and conclude that this must, at this point, be considered an experimental procedure of uncertain benefit. They argue against its use in young patients with elevated although apparently stable TG values and without radiographic evidence of disease. Fatourechi et al analyzed results of this treatment in a series of patients treated at the Mayo Clinic and concluded that it rarely produced significant effect, although it possibly helped stabilize disease in patients with micro metastases in the lung. It is clearly ineffective in patients who have metastases large enough to be detected on chest X-ray of CAT (476). Alzahrani et al (476a) followed patients who were " TG+, Scan-"  and found that soft tissue invasion at original operation strongly predicted this development. They observed that many of these patients appear to progress very slowly, especially if TG is only modestly elevated. Wartofsky suggests that, rather than initial treatment with ¹³¹I of patients who are scan negative and TG-positive, thorough imaging studies are appropriate. These might include a CAT scan of the chest, an MRI of the neck, ^99mTc-MIBI, or 18-fluorine fluorodeoxyglucose PET scanning, or even ^99mTc-tetrafosmin, or ²⁰¹TI thallium. Localization of malignant tissue by any of these means may allow surgical excision or external radiotherapy. This series of articles provides many very useful thoughts on management of difficult patients with recurrent thyroid carcinoma.

Maximal dose protocols

The therapeutic protocol used at Memorial Hospital in New York, by Maxon (477), and as well at some other centers, has for years been designed to give maximal-tolerable radiation doses to cancer patients (478). The dose is calculated on the basis of prior isotope tracer kinetics. The aim is to give a blood dose of under 200 rads, or less than 120 mCi retained at 48 hours, or 80 mCi retained at 48 hours if diffuse lung metastases are present. This method has theoretical advantages since it potentially provides the most cancericidal dose, but the difficulties of calculating the dose and the occasional adverse reactions have so far prevented this method from being generally employed. The dosimetric approach has been carefully reviewed by Van Nostrand et al (479).

Radiation precautions

Before radiation therapy, female patients should be carefully screened for pregnancy and lactation. Confirmed or possible pregnancy constitutes a firm contraindication to therapy because of the risk of damage to the fetus.

A patient who has ingested many milliCuries of 131I can cause serious radiation contamination, and appropriate precautions must be followed. If less than 30 mCi 131I is given, it is permissible to have the patient dispose of urine and feces into general sewage. If amounts of 131I greater than 30 mCi (or the allowable dose in a particular country or state) are given, the patient should be kept in a private room in the hospital until less than 30 mCi is retained in the body. Urine can be directly disposed in sewage, or can be collected by the patient and stored in bottles behind protective lead shielding. After physical decay, usually after about 6 weeks, it may be discarded in the sewage. Contaminated bedding and utensils should be stored for 10 half-lives (80 days), thoroughly washed, and monitored for residual contamination before being used again. Alternatively, disposable bedding and utensils may be used.

Personnel caring for a patient who has received 131I therapy are often concerned about exposure to excessive radiation. This is almost never a real problem. Isotope can, at a practical level, only be passed from the patient to another person via saliva or urine. Monitoring by means of a portable counter is important in making certain that no person receives more than an allowable radiation dose from the isotope in the patient's body. Table 18-9 gives a rough estimate of the amount of radiation received while performing ordinary hospital tasks at various distances from a patient who has received 131I. In general, all ordinary patient care can be performed without hazard. It is best to avoid close contact between hospital personnel and patient during the first 48 hours after therapy because of undue apprehension that may be induced. However, even after doses of up to 100mCi, normal personal actvities such as eating at the same table, or driving in the same car, carry no risk to others.

The US Nuclear Regulatory Commission has published new guidelines which allow release of patients treated with isotopes from the hospital if the total effective radiation exposure from the treated person to any other individual is not likely to exceed 5 mSv (0.5 rads). Grigsby et al (480) found that when using precautions such as those described above in a group of patients given on average about 100mCi 131-I, the exposure to other individuals in their household and to pets did not exceed this level.

Definition of the amount of tracer 131I collected by a tumor is often inaccurate, and it is difficult to estimate whether the dose localized in the tumor can produce a worthwhile effect. For these reasons, opinions vary on the practical value of 131I therapy. An operational rule is that if (1) a focal area of isotope concentration on scan is visible or (2) an area of tumor can be shown to collect over 0.1% of the 131I tracer on scintiscan, then 131I therapy is worth trying. Maxon (481) finds that a dose of 30,000 rads is needed to achieve thyroid ablation, at least 8,000 rads are needed to treat metastatic foci, and ideally 14,000 rads to treat nodes.

Table 18-9. Radiation Exposure to Personnel During Care of a Patient Who Has Received 100 mCi 131I *

Radiation damage from 131-I Therapy

The use of RAI in large doses is not without hazard. The radiation dose delivered to the whole body, the gonads, or bone marrow is usually assumed to be the same as that of the blood. The blood dose depends on the amount of isotope administered; its distribution space and turnover; the degree of heterogeneity of distribution in the tumor; the uptake, synthesis, and secretion of labeled compound by the tumor; and perhaps other variables. The radiation is usually largely due to inorganic iodide, since little protein bound 131I ordinarily appears in the blood. Sometimes tumor destruction is such that much PB131I appears in the blood and can yield a major fraction of the total whole body radiation dose. As a rough estimate, the blood, gonadal, or bone marrow radiation may be assumed to be 0.3 - 1.5 rads/mCi 131I administered (482), or 45-150 rads per treatment with 100mCi. The genetic risks are discussed in Chapter 11 and are not reviewed here. Ordinarily, when 131I therapy is needed for carcinoma, the necessity of treating the patient outweighs the risks of genetic damage.

Various unwanted effects of radiation may occur in patients receiving large doses of 131I. Mild radiation sickness is seen. Metastatic deposits or surrounding tissues may become painful over 2-4 weeks from radiation-induced inflammation. Damage to the salivary glands can cause sialadenitis, and xerostomia, and can lead to loss of teeth. Increasing salivary flow following treatment is partially protective (beginning 24 hours after treatment, 482a). Therapy with amifostine has been advocated to reduce salivary damage fro RAI treatment. Kim et al performed serial quantitative salivary scintigraphies  in 80 newly diagnosed DTC patients. Forty-two patients received 300 mg/m(2) amifostine intravenously before (131)I administration. In both amifostine-treated and nontreated groups statistically significant declines of functional parameters after (131)I treatment were revealed by quantitative salivary scintigraphy. Amifostine pretreatment did not prevent the parenchymal damage to major salivary gland function after (131)I treatment. The dose of (131)I had significant adverse effects on salivary gland function.( Kim SJ, Choi HY, Kim IJ, Kim YK, Jun S, Nam HY, Kim JS.Limited cytoprotective effects of amifostine in high-dose radioactive iodine 131-treated well-differentiated thyroid cancer patients: analysis of quantitative salivary scan.Thyroid. 2008 Mar;18(3):325-31)

Ovarian function is often temporarily suppressed (483), and if there are pelvic metastases that collect 131I, the gonads may receive a sterilizing dose. Sperm count may be reduced for months (484, 485).Rosario et al observed elevated FSH  and diminished sperm counts after high dose 131-I therapy, and suggest sperm banking for men who will be exposed to 14Gbq or more, especially with pelvic metastases. Patients with lower doses (mean 4.25 Gbq) also had transient increases in FSH. Testosterone levels were not altered(485a). Leukemia occurs with increased frequency in patients who have received large doses of 131I (usually > 600 mCi) for cancer (486). Transient hypoparathyroidism has been reported (487). Transient or permanent alterations in liver function and lymphoma of the parotid gland have been reported as possible sequelae (488). Pulmonary fibrosis has occurred in patients with functioning lung metastases who have received unusually large doses or who have very active metastases (489, 490). Leukopenia, thrombocytopenia, and anemia are encountered with accumulating doses. A mild effect on the bone marrow is seen with each therapeutic dose, and after several hundred milliCuries, aplastic anemia may develop (491). The hemoglobin level, white cell count, differential count, and platelets should be monitored periodically in order to judge recovery of the marrow between treatments and to prevent excess total radiation damage to the marrow. Large radiation doses may cause transient swelling of metastasis in the brain or spinal canal.

Lin et al (492) recently reviewed pregnancies following ¹³¹I treatment of well differentiated thyroid carcinoma among a group of 58 pregnant women and found no evidence of demonstrable adverse effects, but suggest that it would be wise to avoid pregnancy during the first six months after the last administration of ¹³¹I. Bal et al (492a) reported on 1282 women treated with high dose 131-I. In this group 43 mothers delivered infants without evidence of genetic damage after receiving doses of ca 3.5-60 rads to the ovaries. With the exception of possibly increased rate of miscarriages, no other adverse effect of radioiodine has been found on the outcome of 2113 pregnancies after radioiodine treatment and on their offspring (493).

Two special complications need be noted. Occasionally withdrawal of hormone suppression, in preparation for isotope therapy, leads to rapid growth of the tumor, and reinstitution may not seem to return the patient to the prior condition. Special care should be taken if metastases are present in areas such as brain or spinal column, where growth could cause serious sequelae. Glucocorticoids are occasionally given prophylactically in an effort to prevent tumor swelling in this situation

RAI was introduced into the treatment of thyroid carcinoma with the hope that it would be a panacea for this disease. Unfortunately, the results have not been universally beneficial. Most tumors in children appear to be treatable, and among adults 80-90% of metastatic carcinomas accumulate sufficient 131I to warrant a serious therapeutic trial. Patients who harbor this form of the disease are fortunate, since 131I may totally eradicate the metastases. Even multiple pulmonary metastases occasionally disappear after 131I therapy (Fig. 18-22, above). The final value of 131I therapy has been difficult to define, largely because of a lack of controlled series and because of other treatment (especially thyroid hormone) given at the same time (494-497). Mazzaferri found that 131I ablation and therapy significantly improved the prognosis in papillary cancer by decreasing recurrences (498). Varma et al. (499) found that RAI treatment had no effect on the survival of persons under age 40 but did lower the death rate of patients over age 40. Leeper (500) concluded that 131I treatment appears clearly to benefit patients under 40 years of age with papillary cancer, but the course of this cancer in older patients is rarely affected; follicular cancers in older patients are treatable, and survival is prolonged even if the disease is not eradicated. Soft tissue lesions, especially of the lung and mediastinum, respond best to 131I. Osseous lesions are often highly functional but are infrequently totally destroyed by 131I (Fig. 18-18) (501). Lesions detected on whole body scans, with negative bone X-rays, are most likely to be cured. In another report, 59 of 400 patients were considered candidates for 131I therapy after using antithyroid drugs or TSH to stimulate uptake. Of these, 61% with metastatic disease were benefited (502). The follicular, papillary, and mixed cancers responded equally well. Numerous reports indicate that ablation of metastasis with 131I is associated with a better prognosis than failure to ablate, but obviously this outcome may relate to the histologic nature and function of the lesion rather than to the therapy per se.

Disseminated pulmonary metastasis can sometimes be eradicated by 131I, but radiation pneumonitis or fibrosis may be produced and may be fatal (503, 504). On first observation of pulmonary metastases, this therapy should be considered, but no more than 75 mCi should ever be deposited in the lungs in one treatment. Progress of the lesion and pulmonary function should be carefully evaluated before and between treatments (505-510). Occasionally patients present with locally advanced papillary thyroid cancer which is not surgically resectable. In some instances preoperative treatment with radioactive iodide sufficiently reduces the extent of the lesion to allow subsequent definitive surgery (511)..

L.F., 43-Year-Old Woman: Follicular Carcinoma and 131I Therapy

A thyroid mass developed and a right lobectomy was done for follicular carcinoma. A recurrence was found 3 years later, and a left lobectomy and cervical lymph node dissection were carried out. The patient subsequently developed hypoparathyroidism. Cobalt therapy was given. Eight years after diagnosis, lytic lesions developed in the right humerus and right ileum, and she was given a course of x-ray therapy to the humerus. She was first seen in our clinic at this time. Her health was apparently good despite the known thyroid carcinoma, and she had no complaints. She was receiving replacement therapy of 120 mg desiccated thyroid daily. BP was 140/70 and pulse was 90. She was sweaty and tremulous. There were multiple small supraclavicular lymph nodes, a lobulated mass in the right hilar area (Fig. 18-22, above), and osteolytic lesions in the right humerus, both femurs, and the right ileum. Ten days after thyroid therapy had been discontinued, the TT4 level was 9.1 µg/dl and the FTI was 12.7, indicating that the metastases were sufficiently active to produce mild hyperthyroidism. Forty-seven percent of an RAI tracer was accumulated in the chest metastases after the patient was given 5 units of TSH daily for 3 days . She was given 60 mCi 131I at this time, and again 3 months later. Two months later, the patient received 100 mCi 131I after a 17% RAIU was demonstrated in the pulmonary metastases. Four months later, there was clear evidence of reduction the size of the pulmonary and mediastinal metastases, and the RAIU was only 2% 3 weeks after withdrawal of thyroid medication. Metastases were visible in the lower lung fields, and in the pelvis, the right humerus, both femurs, and in addition in the left first rib. Because of pain in the left shoulder area and the osteolytic metastasis, she was treated with 4,000 rads x-ray to the apex and given 100 mCi 131I after 4 days of 5 units of TSH daily.

In 4 months the mediastinal and pulmonary lesions were largely gone, but there was obvious extension of metastatic deposits in the vertebrae D-2 and D-3. The patient developed spinal cord compression that required installation of a Wilson plate to stabilize the vertebrae. The next month, a scan, done 3 weeks after discontinuation of replacement therapy when the FTI was less than 1 and the TSH level was elevated to 60 uU/ml, indicated small amounts of uptake of isotope in the metastases in the vertebrae D-2 and D-3, the right humerus, the mediastinum, both lung fields, the right iliac crest, and both femors. Total uptake was approximately 2%. She received 100 mCi 131I.

Three months later, total isotope accumulation after a tracer was less than 0.5% of the dose in all the areas of the body containing visible metastases, and further 131I uptake could not be stimulated by TSH . Maximal tolerable radiation had been given to the metastatic lesions in the humerus and vertebrae. The leukocyte count hovered between 2,000 and 3,000. The patient received a course of bleomycin over 14 days without producing objective benefit. Later the same year she was immunized with homogenates of her own tumor and pertussis vaccine, and again there was no evidence of objective benefit. Progressive paraplegia and weakness occurred, and she died of the illness in August of the next year.

In this all too frequent story, initial lobectomy was followed by recurrence and dissemination. Functional pulmonary metastasis produced mild hyperthyroidism. These deposits were readily ablated with RAI therapy, but osseous metastasis progressed at the same time. The course, from first diagnosis to death, was 11 years.