Abstract
The recognized side effects include an increased risk of hematologic malignancy and damage to nontarget tissues (Table 1). Tissues most affected include those with active radioiodine transport and accumulation, those that receive high radiation doses when they serve as conduits or reservoirs of radioiodine excretion, and those with increased radiation sensitivity. These mechanisms of action offer strategies to limit the potential for damage (Table 2). Still, randomized clinical trials demonstrating benefit are lacking for nearly all of these strategies and, assuming benefit, the optimal application of each of these interventions is unknown. Examples of these unknown details include when hydration, secretagogues, and laxatives should be started, how much should be consumed, how frequently should they be administered, how should the dose or frequency be titrated, and when should they be stopped.
FDG-PET, 2-deoxy-2[18F]fluoro-
Decreasing the prescribed radiation activity is an important method to limit toxicity that must be balanced against the risk of delivering an ineffective therapy. Additionally, 131I may be avoided in subgroups of patients unlikely to benefit from therapy either because their already excellent prognosis is unlikely to be improved (4) or because their tumors are unlikely to respond (Table 2). The American Thyroid Association Guidelines suggest utilizing the lowest activity possible for remnant ablation, especially in low-risk patients (4). Recent randomized clinical trials of remnant ablation have shown that 30 mCi of 131I was as effective as 100 mCi in low-risk patients in the hypothyroid state (5); Thyrogen-assisted (Genzyme Corporation, Cambridge, MA) ablation with 50 mCi of 131I was as effective as a Thyrogen-assisted 100 mCi ablation (6); and, despite delivering less radiation dose to the blood, Thyrogen-assisted ablation with 100 mCi of 131I was as effective as 100 mCi after thyroid hormone withdrawal in two randomized clinical trials (7,8), and recurrence rates appear to be similar after short-term follow-up (9). It is also important to recognize clinical situations in which the toxicity of 131I is more likely to occur, such as in pediatric patients and the elderly and in patients with small body size, impaired renal function, and diffuse functioning metastases in the bone marrow or lungs (4). Still, whether the current use of fixed empiric radioiodine activities or individually determined target or blood dose activities (to avoid over and under treating) is optimal for patient outcome remains unknown (10).
Amifostine has been used for the protection of normal tissues against harmful effects of radiation or chemotherapy. Bohuslavizki et al. (11) reported salivary gland protection against 131I using amifostine 500 mg/m2 intravenously in a placebo-controlled trial. Similarly, Mendoza and colleagues (12) demonstrated favorable radioprotection using amifostine 500 mg subcutaneously. However, Kim et al. (13) recently studied amifostine 300 mg/m2 in a randomized trial of thyroid cancer patients and found that amifostine pretreatment did not prevent parenchymal damage to major salivary gland function. Thus, the role of amifostine in current thyroid cancer management remains unknown.
Increasing the elimination or excretion of 131I from nontarget tissues, or preventing its uptake into these tissues, seems logical for limiting toxicity (Table 2). Hydration is believed to be important to promote excretion of radioiodine from the renal collecting system and bladder, the gastrointestinal tract, and salivary glands. Laxatives promote elimination of 131I from the lower gastrointestinal system, which is at additional risk when hypothyroidism-induced constipation is present. Atropine and reserpine are reported to decrease radioiodine uptake into salivary glands (14). Similarly, salivary stimulation with secretagogues or sialogogues (including pharmacologic agents such as pilocarpine or cevimeline; sour candies; gum; and lemon drops, juices, and candies) have long been recommended as a logical intervention to promote the excretion of 131I from the salivary glands despite never having been studied in a randomized clinical trial. This practice was challenged by Nakada et al. (15) who studied 116 consecutive patients who were instructed to suck one to two lemon candies every 2–3 hours in the daytime for 5 days starting within 1 hour of 131I therapy (group A). Subsequently, 139 consecutive patients were given the same instructions except they were to wait until 24 hours after therapy to begin candy (group B). The incidence of salivary gland side effects was determined prospectively over >24 months using patient interviews, questionnaire, visual analog scale, and salivary scintigraphy. The authors reported increased radiotoxicity (acute sialoadenitis, taste dysfunction, dry mouth, and xerostomia) in patients who sucked lemon candies within 1 hour of 131I therapy compared to those who waited 24 hours before starting the same therapy. The authors proposed that sucking candies early, when the level of radioiodine in the blood was high, delivered more radioiodine to this vulnerable tissue and unfavorably altered the risk/benefit ratio of iodine uptake via blood flow versus salivary emptying as opposed to 24 hours later when the blood activity was low. The study was important because it provided real data to a practically unstudied problem and its findings continue to influence the treatment of patients around the world to this day. Still, the study was limited because it was a nonrandomized and unblinded study of two patient cohorts treated and followed over different periods in time and lacked a control group that was not treated with lemon candies. The authors report that upon encountering unexpectedly higher side effects in group A, their first cohort, that patients in group B tended to be treated more aggressively for side effects including the additional use of steroids or nonsteroidal anti-inflammatory drugs for sialoadenitis, and a drug containing zinc acetate or vitamin B12 for taste dysfunction; 52% of group A and 81% of group B received such treatment (16). Whether this more aggressive treatment altered the outcome of group B is unknown.
Upon this background enters the case-study of Van Nostrand and colleagues published in this issue of Thyroid (17). Their findings in one patient suggest a benefit to early and repeated salivary stimulation after 131I therapy as opposed to delaying salivary stimulation. The authors imaged and quantified the parotid glands in this patient to study the effects of lemon juice (LJ) in the parotid glands using the whole body thyroid cancer 131I diagnostic dose and calculated time–activity curves starting 2 hours after 131I administration. In the first ∼60 minutes they studied the effect of a single LJ administration. LJ promptly reduced the radiation activity in the salivary glands with subsequent gradual reaccumulation that approximated the starting activity after ∼30 minutes. They calculated that this single administration of LJ reduced the area under the radiation–time activity curve in the first 1 hour by 30–38%. Over the next ∼1 hour they studied the effects of repeated LJ administrations at 15–20 minute intervals. After each LJ administration there was a significant and rapid decrease in parotid radioactivity with a subsequent gradual reaccumulation of activity with peak and trough patterns that did not support a recruitment of additional 131I activity, or rebound phenomenon. They calculated that this repeated administration of LJ in the second hour reduced the area under the radiation–time activity curve 61–67%. These findings did not support a harmful effect of salivary stimulation and appear to contradict the findings of Nakada and colleagues.
This study by Van Nostrand and colleagues is important because it raises serious doubt about the harm of salivary stimulation and re-opens the possibility of benefit from this simple intervention. A criticism of this study is that this method of salivary quantification has not been shown to correlate with changes in the actual occurrence of salivary injury. What this bird's eye view of the global salivary gland radioactivity burden means in relation to the radiosensitive serous cells (18), the mucous acini, or to the symporter-bearing ductal cells (19) is uncertain, especially when most of the energy from 131I beta particles is deposited within 1–2 mm of the radiation decay event (20). Still, the reduced radiation–time activity curves using LJ are provocative and beg for a randomized clinical trial to further address this question.
Should all clinicians now prescribe prompt salivary stimulation to all patients undergoing radioiodine therapy? In my opinion, the definitive answer to this question remains unknown. In fact, Alexander et al. (21) administered oral pilocarpine (when tolerated) to their patients and found no salivary protective effect. Further, it remains unclear if it is more important to suppress salivary radioiodine uptake, stimulate salivation, or a combination of both (16). Thus, clinicians must once again use their judgment when advising patients about strategies to protect their salivary glands from 131I damage. Most importantly, researchers should now embrace that the “correct” answer is once again unknown and that any ethical limitations to perform a much needed randomized clinical trial are dispersed.