Abstract
There is no consensus on the amount of 131I for treatment of patients with well-differentiated thyroid carcinoma; usual amounts vary widely. Body retention of 131I has been shown to be a valuable index of radiation toxicity. If a broad range of body retentions occurs among patients, then high and low retentions will be a basis for modifying the usual prescriptions for 131I to ensure safety and increase efficacy. Methods: After withdrawal of thyroid hormone in 87 patients, the fractional retention of diagnostic 131I in each body was measured at 2 d by a scintillation probe. In 43 patients, the retention was measured 2 d after therapeutic 131I. Results: Diagnostic retention varied from 0.01 to 0.51, with a median of 0.15. These retentions did not correlate with any index of health, thyroid hormone, or carcinoma status. Seventeen patients, previously treated with 131I, exhibited a significantly lower mean retention. In 43 patients, retention of diagnostic 131I was highly correlated with retention of therapeutic 131I: diagnostic predicted therapeutic retention with a mean error of 0.04. In 10 patients receiving thyroxine, the mean retention of diagnostic 131I after recombinant human TSH (rhTSH) was strikingly lower, 0.06, with a range of 0.016–0.16. Conclusion: Body retentions of 131I are easily measured and vary considerably among patients. Because increased therapeutic 131I will impart greater irradiation of tumor, and body retention has been accepted as an index of toxicity from 131I, the use of body retention could enable prescriptions of therapeutic 131I that enable increased efficacy while ensuring safety. If tumor retention is not proportionally decreased with the body retention of 131I after rhTSH, then rhTSH may enable increased therapeutic efficacy.
How many gigabecquerels (mCi) of 131I should be given to a patient with well-differentiated thyroid carcinoma (WDTC)? Excluding the 1.11 GBq (30 mCi) given to ablate residual normal thyroid tissue, most prescriptions for radioiodine have varied from 3.7 to 7.4 GBq (100–200 mCi), giving a broad range for usual treatments (1), and larger amounts have been prescribed after dosimetric measurements on radioactivity in blood and body to ensure safety (2–5). (“Dose” is not used to avoid confusion with absorbed dose of radiation given in cGy or rad.) Maxon et al. found that treatment to render cervical node metastases scintigraphically invisible was 14,000 cGy (6), but such measurements are difficult and often impossible in patients with WDTC. The relative efficacy of any program of therapy is unknown, and, in specified circumstances, there has been no consensus on how many gigabecquerels (mCi) a given patient should receive (7).
Although tumor dosimetry is not feasible, the retention of radioiodine in the body of patients, which is a component of dosimetry applied to prevent untoward events, can be readily measured in nuclear medicine laboratories. Assays of blood activity can be estimated from values of body retention (8) but are uncommonly needed for calculating a treatment with 131I if the circulating free thyroxine (T4) level is low (9). This article describes the method of assay of body retention, defines the broad range of retentions found in patients, and suggests how, in currently prescribed or usual 131I treatments, safety can be ensured and, in addition, efficacy can be increased.
MATERIALS AND METHODS
Experimental Subjects
Between July 1, 1999, and December 31, 2000, 97 patients were investigated for possible residual WDTC and for treatment thereof in the Nuclear Medicine Division at the University of Michigan Health System for this retrospective study. Excluded were 40 patients because of incomplete data collection and 2 others because of known large volumes of functioning tumor (9) that would make them atypical of the usual WDTC patients. For diagnosis, the remaining 55 patients were given either the adopted standard 37 MBq (1 mCi) or, as part of an investigation, 18.5 MBq (0.5 mCi) 131I. Data were also available on 32 patients who were treated with 131I between 1993 and 1996 and who received 74 MBq (2 mCi) diagnostic 131I. Thus, the total study population included 87 patients (29 male, 58 female; age range, 8–85 y; mean ± SD, 44 ± 15 y).
Patients were instructed to follow a low-iodine diet (10) for 1 wk before diagnostic radioiodine was given and until 1 d after therapeutic 131I if treatment was prescribed. 131I was administered orally in liquid form. Twenty-four of the patients who received 37 or 18.5 MBq (1.0 or 0.5 mCi) and all of those who received 74 MBq (2.0 mCi) 131I were subsequently treated with 1.07–12.95 GBq (29–350 mCi) 131I. Treatments were usually administered 2 d after the diagnostic administration and after the diagnostic studies on that day; occasionally treatment was delayed for 7 d. Retention of the therapeutic radioiodine 2 d after administration was available in 43 of the 56 treated patients.
For reference, the 2-d body retentions of 131I were measured in 10 patients who received intramuscular injections (0.9 mg) of recombinant human thyroid-stimulating hormone ([rhTSH] Thyrogen; Genzyme Corp.) on each of the 2 d preceding the administration of diagnostic 131I. These patients were clinically euthyroid, although their basal TSH levels were suppressed below the normal range by thyroxine therapy.
Papillary carcinomas were staged by 2 systems: MACIS (metastasis, age, completeness of resection, invasion, and size), which provided numeric scores (11); and TNM, which determined stages 1–4 (12). Five patients did not have typical papillary carcinoma (1 tall-cell papillary, 1 follicular, 1 poorly differentiated, and 2 Hürthle cell carcinomas) and were not staged by the MACIS system. Data for staging were insufficient in 2 patients who underwent surgery at other institutions; in 1 patient, the presence or absence of cervical node metastases was unclear so that TNM could not assessed; in the other patient, too little information was available for staging by either system.
Techniques
A Captus 2000 uptake probe (Capintec) containing a 2 × 2 cm crystal was used to measure body retention. Using mock sources of 131I in a flat field at 2.5 m from the probe, the isoresponse (coefficient of variation in the counts, 1.2%) region was a 63.5-cm square; there was a decrease in response of 5%–8% of counts in the centimeters above and below the isoresponse square. Patients sat on a stool with the probe aimed at their xiphoid so that a span of 65.5 cm would encompass all but the top of the head and the legs below the knees in virtually all patients. Counts were obtained in the anterior and the posterior positions, each for 2 min; background activity was subtracted, and a geometric mean was determined. The efficiency of the probe was evaluated each day. In each patient, 100% of the activity was determined 2 h after ingestion of 131I (and before voiding of urine), and the fraction of residual activity was determined from counts made on day 2 (45–54 h) and after voiding. Day 2 was selected because retention at this time point is part of the assessment for safety by dosimetry (2).
Body retentions of therapeutic 131I were also assayed from the counts made at 2 d using the probe. The cpm/MBq (cpm/mCi) calculated from the diagnostic data enabled the therapeutic counts to be converted to GBq (mCi); the fractional retention of the therapy was then determined from the administered GBq (mCi). No dead time (loss in efficiency) was found for the probe in counting 131I sources up to 1.81 GBq (49 mCi). The largest retention of therapeutic 131I at 2 d was 1.78 GBq (48 mCi).
On day 1, uptake of diagnostic 131I in the necks of patients was measured by the same probe at 50 cm from the neck; counting with a lead shield in place provided the background radioactivity. A sample of 131I of known radioactivity provided the reference standard.
Whole-body images were made for 10, 20, and 40 min after diagnostic 131I of 74, 37, and 18.5 MBq (2.0, 1.0, and 0.5 mCi), respectively, using a Siemens Bodyscan camera (Siemens Medical). The images made at 2 d after administration of 131I were inspected separately by 2 of the investigators for retention of radioactivity in the neck and chest and in the abdomen. Retentions in each area were scored 0–4 and a mean score was calculated.
Measurements of serum for TSH, free T4, total T4, and creatinine and of blood for urea nitrogen (BUN) were performed in the clinical laboratory by standard methods. For purposes of comparison, total T4 values were multiplied by 0.15 to approximate the free T4 level in the patient when there was no reason to believe that the total T4 concentration was altered by unusual protein binding. Serum thyroglobulin and thyroglobulin antibodies were assayed by kits (Immulite) obtained from Diagnostic Products Corp.; when thyroglobulin antibodies were present, the thyroglobulin level was not used in the correlation. The lower limit of detection of TSH was 0.01 μU/mL and of thyroglobulin was 0.5 ng/mL; in analyses of data, concentrations below these detection limits were assigned values of 0.
This investigation was approved by the Institutional Review Board for Medical Research at the University of Michigan.
Statistical Analysis
Analysis was by t test, ANOVA, and least-squares regression.
RESULTS
The mean retention (±SD) of 131I at 2 d in the 87 patients was 0.165 ± 0.087 with a range of 0.010–0.505 (Table 1). Slight and insignificant differences were observed in the retentions of patients receiving diagnostic 131I of 74, 37, and 18.5 MBq (2.0, 1.0, and 0.5 mCi). The mean retention in females, 0.166, was almost identical to that in males, 0.164. A range of 0.090–0.248 included 68% of patients with 34% above and below the median of 0.152. The retention in the 56 patients who were subsequently treated with 131I, and therefore were deemed to have persistent carcinoma, was 0.180 ± 0.088 and significantly higher (P < 0.05) than the retention for the 31 patients who were not treated and had no evidence of persisting disease (Table 1). In 17 patients, 131I treatment had been given ≥1 y previously, and the mean retention (0.121) in these patients was significantly less (P < 0.01) than the mean retention (0.176) in the 70 patients previously untreated (Table 1).
Diagnostic Body Retention at 2 Days
After 131I therapy, the retentions at 2 d in the 43 patients for whom data were available gave differences (respective diagnostic value -therapeutic value for each patient) with a range of −0.078 to +0.127 with a mean difference of 0.041 (Table 2). The correlation between retentions of diagnostic and therapeutic 131I was high (r = 0.797) and P < 0.001 (Fig. 1). However, there was no statistically significant correlation between the administered therapeutic 131I and the retention of therapeutic 131I in 43 patients (r = 0.281).
Scatter plot of diagnostic and therapeutic retentions of 131I at 2 d in bodies of 43 patients.
Relationship of Retentions: Diagnostic and Therapeutic
No significant correlation was found between the retentions of diagnostic 131I and the respective indices of age, body weight, BUN, TSH, free T4, neck uptake at 1 d, apparent radioactivity in neck and chest and in abdomen on images at 2 d, serum thyroglobulin, and the staging level determined by MACIS and TNM (Table 3). The neck uptakes at 1 d were significantly higher (P < 0.001) in the 43 patients who received subsequent treatment than in those who were subsequently not treated. The higher uptakes reflected persisting disease, but in these 43 patients there was still no significant correlation with the respective retention values (Table 3). Retention of diagnostic radioiodine and serum creatinine approached statistical significance (r = 0.37; P = 0.06 in a 2-tailed analysis).
Correlations of Body Retention of Diagnostic 131I with Other Indices
The mean body retention of 131I at 2 d in patients who had received injections of rhTSH before diagnostic 131I was 0.056 and highly significantly (P < 0.0005) less than those obtained in the hypothyroid patients (Table 4). Although the range of retentions seemed large, 0.016–0.160, only 2 of the 10 patients had values above 0.060.
Body Retention of 131I in Patients Receiving rhTSH
DISCUSSION
Assessment of body retention is no more difficult or time consuming than assays of thyroid uptake. Such evaluations can readily be made in any clinical nuclear medicine laboratory. Our data also delineate kinetics of radioiodine not previously reported.
In our study, retentions of diagnostic 131I varied widely, from 0.01 to 0.504. The variations were not related to different diagnostic amounts of 131I. However, there was reasonable agreement between the respective retentions of diagnostic and therapeutic 131I. In 43 patients, the largest errors were underestimating the therapeutic retention by 7.4% and overestimating it by 12.7%. Differences were not related to the amount of 131I given in treatment. Retentions were significantly higher in patients with residual carcinoma that required treatment than in patients apparently free of disease and receiving no therapy; this pattern was also seen in the neck uptakes at 1 d. Such observations are not unexpected. However, the neck uptakes in the patients with residual disease still did not correlate with the respective retentions and, therefore, neck uptakes cannot substitute as an index for toxicity.
Because hematologic toxicity is the most common untoward consequence of 131I therapy, dosimetry of red marrow would be an ideal assessment. However, measurements of 131I in the important bones have been at best very difficult. Moreover, guidelines to prevent toxicity from therapies with 131I have been derived empirically from correlations of body retention and clinically observed events (2). The guidelines provide the best index of body dosimetry currently available (3–6). In a recent review of dosimetry in thyroid carcinoma, Van Nostrand et al. concluded that “dosimetrically determined doses of radioiodine are logically an improvement over empiric fixed doses” (13). In keeping with this logic, increased retention should dictate a smaller amount of therapeutic 131I, and decreased retention should permit more gigabecquerels (mCi). However, this concept has not been adopted into the everyday practice of most physicians who treat patients with thyroid carcinoma. Although there is no consensus on how much radioiodine to administer to patients, our data show how the usual gigabecquerels (mCi) selected for a given patient could be modified by measuring retention of diagnostic 131I in the body at 2 d to ensure safety and possibly increase efficacy. Arbitrarily, 1 SD around the median (68% of the values) was 0.09–0.248, and values within this range could be considered average so that the originally selected amount of 131I would not be modified. The prescribed gigabecquerels (mCi) of 131I could be increased if the value was <0.09 and decreased if the value was >0.248. The degree of change in the amount of treatment administered would be left to the therapist, but for retentions of ≤0.05 consideration could be given to increases of 50%–100%. Similarly, substantial reductions in treatment gigabecquerels (mCi) should be considered when retentions are ≥0.40.
With the exception of prior treatment with 131I, no index in the clinical and laboratory profiles of the patients correlated with the body retention. Thus, there is currently no way of determining body retention of 131I except by measuring it in a given patient.
The retentions in patients who had received prior 131I treatment were significantly lower than those in patients who had not been treated. The reason for this difference is unknown. A lesser amount of functioning thyroid tissue was present in patients previously treated (mean neck uptake at 1 d, 1.1% of dose), but the mean neck uptake of 131I at 1 d in patients treated for the first time was only slightly higher (2.7%), so it is not clear that thyroid tissue accounted for the difference in body retention. Because iodide is reabsorbed by the kidney tubules (14,15), it is possible that irradiation of the tubules by 131I in some way impaired the reabsorption mechanism. Compared with mean retention (0.176) in patients not previously treated, the mean retention (0.121) in those who had previous treatment with 131I was reduced by 5.5%. Whether this reduced retention affected the uptake of 131I by the carcinomas is not known, but attention to body retentions will give information that will enable increases in the gigabecquerels (mCi) to be prescribed with safety in repeated therapies.
Although not part of the goal of this study, the difference in body retention of 131I in the clinically euthyroid patients who received injections of rhTSH was striking. Rapid washout of the radioiodine has been recognized on images but retentions have not been quantitatively related to those in patients who are hypothyroid (16). Impairment of glomerular filtration rate, the main mode of iodide excretion, by hypothyroidism has been clearly established (17,18), but the reduction in iodine excretion is disproportionately greater than the decline in glomerular filtration (14), thereby at least partially explaining the lack of correlation between BUN and body retention. During euthyroidism, the more rapid excretion of 131I may reduce that available for the carcinomas. When evaluating images for detection of thyroid carcinoma, the scans made after rhTSH appear to have sensitivity similar to that in images attained during hypothyroidism in some studies (16,19), but the latter appeared to be a more sensitive approach in another report (20). If the quantitative uptake and retention of 131I by carcinomas after rhTSH is not reduced proportionally to the reduction in body retention, then, by using the rhTSH protocol, efficacy of treatments could be increased and safety maintained through administration of larger than the usual gigabecquerels (mCi) to patients who remain euthyroid.
Concern has been raised about a stunning effect by diagnostic 131I on thyroid tissue including carcinoma—that is, reduction in the fractional uptake of subsequent therapeutic 131I. Evidence for this effect has been changes in appearance of the thyroid tissues on diagnostic and therapeutic scintigraphic images (21,22), decreases in measured fractional uptakes of radioiodine in the tissues after diagnostic 131I (22–24), and decreased responses to therapies when diagnostic 131I has been used (25,26). However, the observed phenomenon may be due to, or largely due to, the effects of therapeutic 131I; much of the consequence may arise from the early (first 2 d) effects from irradiation by the therapeutic 131I. To avert possible stunning, 123I has been proposed for diagnostic imaging (26). However, 123I does not appear to be suitable for dosimetry. Compared with 131I, 123I imparts less energy per gigabecquerel (mCi) to tissues and, therefore, should have a lesser radiation effect, but this agent is not easily quantified at 2 d. Moreover, in one study there appeared to be little or no stunning effect when diagnostic 131I was reduced to 74 MBq (2 mCi) (27). The value of the information obtained from body retention would seem to outweigh any effect of 74 MBq (2 mCi), and especially 37 MBq (1 mCi), of 131I on the carcinoma to be treated.
CONCLUSION
The concept for this project was previously described (28). In summary, body retention of 131I can be readily measured in a nuclear medicine laboratory. The diagnostic retention provides a reasonable estimate of retention of therapeutic 131I. No clinical or laboratory index will predict the body retention. Because most patients with thyroid carcinoma receive modest treatment amounts of 131I and appear to do well, it may be that the usual amounts are sufficient and do no major harm. Yet, for treatment of patients with more advanced disease, and for other patients in whom the therapist wishes to consider body burdens of radioiodine, body retention should be an important factor. Thus, measurement of diagnostic retention can serve to modify the usual prescription for therapy to ensure safety and increase efficacy in as many as 32% of the patients treated with 131I for WDTC.
Acknowledgments
The authors are indebted to Dr. Barry England (Ligand Laboratory, University of Michigan) for information on thyroglobulin assays. Denise Regan provided invaluable help in determining the probe responses to flat-field radioactivity.
Footnotes
Received Sep. 3, 2002; revision accepted Feb. 13, 2003.
For correspondence or reprints contact: James C. Sisson, MD, Hospital B1 G505A, 1500 Medical Center Dr., University of Michigan Health System, Ann Arbor, MI 48109-0028.
E-mail: jsisson{at}umich.edu
REFERENCES
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