Complications of Radioiodine Treatment

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Radioiodine therapy is well tolerated and usually lacks serious complications. Patients may experience nausea and vomiting, especially during the first 24 hours after administration; prophylactic use of metoclopramide 10mg 30 minutes prior to 131I is therefore recommended [90]. Radiation thyroiditis may occur within the first week and last for several days after ablation of a large remnant; this is characterized by local discomfort, pain on swallowing, neck swelling, and even transient thyrotoxicosis [91]. Nonsteroidal anti-inflammatory drugs such as aspirin are usually effective but corticosteroid treatment with prednisolone 30 mg daily may be required. Very rarely edema of the neck may threaten upper airway obstruction.

The salivary glands accumulate radioiodine and are thereby prone to damage. Salivary dysfunction (xerostomia and sialadenitis) following radioiodine may occur in up to a third of patients and is related to the cumulative activity of 131I administered [92]. Acute sialadenitis affecting the parotid or submandibular salivary glands occurs within 48 hours of administration and may last for a few days but may be protracted. This is more commonly seen with higher administered activities. Chronic symptoms include recurrent salivary tenderness, swelling, dry mouth, and altered (metallic or chemical) taste sensation [93].Lack of saliva can result in dental caries and teeth may require extraction (Figure 15.6). Several studies have quantified salivary damage by technetium scintigraphy and shown a direct relationship between administered cumulative radioiodine dose and severity of salivary gland dysfunction [92].

A liberal fluid intake, frequent use of sodium citrate containing lozenges and massage over the parotid areas will reduce salivary radiation. Intravenous administration of amifostine, an organic thiophosphate, has been reported to reduce salivary uptake of 131I. A double-blind placebo-controlled trial comparing 25 patients

Figure 15.6 Dental caries: multiple radioiodine treatments resulted in severe xerostomia and dental caries. Further radioiodine was refused due to these unwanted side effects.

treated with amifostine to 25 controls identified preservation of salivary gland function in the treated group but knowledge is limited regarding the effects of amifostine on tumor uptake [94]. Further study is therefore required to assess potential benefit before widespread use can be recommended. Sialadenitis of the parotid may progress to a chronic phase with recurrent episodes over several years and a persistent painful salivary mass may require evaluation for surgical removal.

Radiation pneumonitis (acute) and pulmonary fibrosis (chronic) have been reported in patients with diffuse pulmonary metastases following therapeutic radioiodine [95].Benua et al. reported 5 of 59 patients developing radiation pneumonitis which resulted in two deaths [81]. Single administrations exceeding 9GBq (243 mCi) may cause both pneumonitis and fibrosis. By limiting individual doses and increasing the interval between administrations to 9-12 months pulmonary complications can be minimized. In all patients with diffuse pulmonary metastases serial lung function testing should be performed and if deterioration occurs, the size of further 131I doses can be reduced. Wide-field external beam therapy should be avoided.

Brain and spinal cord metastases are rare in DTC. In our retrospective series of 649 patients with DTC treated between 1936 and 1991, only six patients with brain metastases were identified (0.92%) [96]. The Mayo Clinic series reported an incidence of 0.75% [97]. All of our patients were papillary tumors with active or previously treated metastases at other sites. Prognosis was poor with median survival of 4 months from the time of diagnosis of brain involvement. Multimodality treatment involving external beam radiotherapy, radioiodine, and surgery should be considered. Cerebral edema may follow radioiodine administration with potential life-threatening consequences and prophylactic dexamethasone is therefore recommended. Similarly, prophylaxis is required prior to radioiodine treatment of spinal metastases to avoid cord compression.

Differentiated thyroid cancer frequently occurs in the young and the possibility that iodine treatment may affect fertility has created significant concern [98]. We have previously reported a study of 496 women under the age of 40 who received radioiodine [99]. Of these, 322 had a single 3 GBq (81 mCi) ablation dose while the remainder received subsequent treatment for residual, recurrent, or metastatic disease (8.5-59 GBq, 230-1591 mCi, cumulative dose). Transient amenorrhea or menstrual irregularities lasting up to 10 months were experienced in 83 patients (17%). No case of permanent ovarian failure was recorded. In patients with amenorrhea, there was a temporary increase in both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels indicating transient ovarian dysfunction. Patients experiencing menstrual disturbance had received greater cumulative activities compared to those with normal menses (median cumulative dose 14GBq versus 3GBq).

Male patients also develop transient elevation of FSH levels following 131I treatment. In our study of 93 patients, 106 children were fathered by 59 patients; the remainder had no wish to have children [100]. Of these 59,12 had received a single 3 GBq ablation dose, 19 had been treated with up to 14 GBq, and 28 had received up to 44 GBq. No major malformations were reported. In 14 patients followed prospectively with determination of dose to the testes using thermoluminescent dosimetry, the median dose to each testis was 6.4cGy following 3 GBq, 14.1 cGy following 5.5 GBq, and 21.2cGy following 9.2GBq. There was transient elevation in serum FSH after radioiodine which normalized within 9 months from the last administration. LH levels rose transiently in only two patients. Serum testosterone did not change significantly. The germinal epithelium of the testes is more sensitive to radiation damage than the ovary and male patients likely to require repeated doses of radioiodine should be offered sperm banking because of the potential risk of permanent sterility [101]. A reduction in sperm count proportional to the administered activity may occur but permanent testicular damage with azoospermia appears to be rare.

There is no significant difference in observed fertility rates, birth rates, or premature delivery among women treated with radioiodine compared with those who have not received 131I. In our series of 496 patients, temporary amenor-rhea and minor menstrual irregularities were seen in 20%; 427 normal children were born to 276 women and only one patient was unable to conceive [99]. On the basis of these data there is no reason for patients who are treated with radioiodine to avoid subsequent pregnancy.

However, it is recommended to avoid conception (for both males and females) for at least 4 months after 131I administration, by which time all radiation-induced chromosomal alterations should have been eliminated or repaired. During pregnancy thyroid hormonal levels should be monitored every 2 months and thy-roxine replacement increased only if required [39]. Thyroxine requirement may increase during the antenatal period but complete TSH suppression is unnecessary and levels can be permitted to rise into the normal range.

Patients may develop a transient slight reduction in platelet and white cell counts (mainly lymphopenia) after 131I therapy [90], which is of no practical importance. These effects reach a nadir at 5-9 weeks after therapy with recovery in the majority within 6 months. Bloods counts should be monitored before each therapy dose, which is withheld if significant depression is present. Patients with multiple bone metastases, the elderly, and patients previously exposed to external beam irradiation are more prone to bone marrow suppression and demonstrate a more protracted recovery. Myelodysplasia leading to aplastic anemia is rare and likely to occur only in those who have received a very high cumulative blood dose in excess of 2 Gy per treatment [81]. Use of autologous stem cell transplantation may have a potential role in the future prior to planned high activity treatment.

The carcinogenic hazard of 131I in the treatment of thyroid cancer has been the subject of several reports [102]. An increased risk of acute myeloid leukemia was seen in the past, especially in patients receiving a cumulative activity in excess of 40 GBq (1081 mCi), although patient numbers were small [103]. In more recent series the incidence of leukemia is much lower, probably owing to efforts to limit the total blood dose to 2 Gy per treatment and the longer interval of 6-12 months between doses. A recently published multicenter study involving 6841 thyroid cancer patients from Sweden, Italy, and France has quantified the risk of subsequent second primary malignancy [104]. Compared to the general population an increased risk of 27% was seen. It was estimated that 3.7 GBq (100mCi) of 131I would induce an excess of 53 solid malignant tumors and 3 leukemias in 10000 patients during 10 years of follow-up. In addition, a strong correlation existed between the cumulative activity of radioiodine and the risk of bone, soft-tissue, colorectal, and salivary gland cancers. These results highlight the need to restrict radioiodine treatment to those likely to benefit.

The radiation dose delivered by 131I to each organ is difficult to estimate from established mathematical models; uptake by metastases may modify the dose delivered to a given organ and the hypothyroid status at the time of iodine administration decreases renal clearance of 131I, thereby increasing the body retention of iodine by a factor of 2-4. Liberal fluid intake, frequent micturition, and use of laxatives will promote iodine excretion and reduce radiation exposure.

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