British Journal of Radiology 74 (2001),429-433 © 2001 The British Institute of Radiology
Value of protein-bound radioactive iodine measurements in the management of differentiated thyroid cancer treated with 131I
P A G Hammersley, PhD
1
A Al-Saadi, MD, PhD
1
S Chittenden, BSc
2
G D Flux, PhD
2
V R McCready, DSc, FRCP, FRCR
2 and
C L Harmer, FRCP, FRCR
3
1 Departments of Nuclear Medicine
2 Physics
3 Clinical Oncology Thyroid Unit, Royal Marsden Hospital NHS Trust, Downs Road, Sutton, Surrey SM2 5PT, UK
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Abstract
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Measurement of the protein-bound radioactive iodine level (PBI131) in the plasma of patients following 131I-iodide administration for thyroid cancer has been re-examined in a retrospective study of 171 patient episodes. It is shown that whereas the previously used threshold value for the measurement at 6 days does not correlate well with the 3-day whole body scan, there is good agreement between the scan and the temporal changes in PBI131 from 1–6 days: an increasing PBI131 correlates with a positive scan, and a decreasing PBI131 with a negative scan. The area under the curve (AUC) for the PBI131–time curve is related to the absorbed dose for the tumour. For a small group of 11 patients, dosimetry estimates were made from serial scans, quantified with phantoms; these absorbed doses correlated with the AUC and the 6-day PBI131. Therefore, it is suggested that these parameters may be useful in predicting absorbed radiation dose in these patients.
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Introduction
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Radioiodine (131I) therapy for differentiated thyroid cancer (DTC) has been in use for over 50 years [1–3]. The administered 131I-iodide becomes concentrated in the functioning thyroid cells, where it is ultimately metabolized into thyroxine (T4), which is released into the circulation, as required, under the influence of thyroid stimulating hormone (TSH). This circulating 131I has been described as "organic" as opposed to the inorganic free iodide, and as "protein-bound iodine" (PBI), since the T4 is predominantly bound to thyroxine-binding globulin (TBG).
Measurement of PBI131 was considered to reflect the presence and activity of thyroid cells. Thus, after surgery and 131I ablation for DTC, the quantity of PBI131 was considered diagnostic for the continuing presence of tumour cells. Pochin [4] suggested values of PBI131, measured 6 days after therapy, which were indicative of the likely presence of tumour.
PBI131, however, is not a specific assay for thyroid hormones, and may include various quantities of other iodinated organic compounds, such as amino acids and proteins. The most common method of separating organic PBI from free iodide is by use of an anion exchange resin. Earlier methods included various precipitation [5, 6] and solvent extraction techniques [7]. The advantages of the anion exchange method are its simplicity and ease of use in a routine laboratory. With the advent of radio-immunoassay methods for the measurement of thyroglobulin (Tg), the PBI131 assay has dropped out of general use. However, it is considered of value and forms part of the treatment protocol at our hospital [8]. In several recent reviews of the management of patients with DTC there is no mention of the use of PBI131 [9–11].
This paper reports our results on the value of serial PBI131 measurements in 127 patients with DTC who have been treated with 131I-iodide. PBI131 has been measured from 1–6 days after therapy and related to the results of the whole-body scan performed on day 3. For a small group of 11 patients, the PBI131 values have been compared with the absorbed radiation dose, estimated from the scans.
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Methods
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Data from 171 episodes in 127 patients presenting for 131I ablation or therapy have been examined. Initial surgical treatment comprised near-total thyroidectomy plus removal of any metastatic nodes. 32 patients had repeat therapies, with 1 patient having six therapies over a period of 32 months. Blood samples were taken into heparinized tubes on days 1, 2, 3 and 6 following 131I administration.
PBI131 was determined by passing plasma through a column containing a strongly basic anion exchange resin [12]. A 3 ml plastic syringe was plugged by glass wool and fitted with a No. 23 needle; 2.5–3 ml of anion exchange resin (Amberlite IRA400, Amberjet 4200; Rohm & Haas Company, Philadelphia, PA) in the chloride form was packed in the syringe and washed with 2 ml of distilled water. Then, 2 ml of plasma was carefully added and the resin eluted with 4 ml of water. Organic 131I passes through the column, while iodide is retained. The activity in the total eluate (6 ml) was counted in an automatic gamma counter together with a standard 131I sample. PBI131 was expressed as % dose l-1. For each patient, the pattern of change of PBI131 over the 6 days of sampling was classified into one of two types: rising (increasing) or falling (decreasing). The area under the PBI131–time curve was calculated from day 1 to day 6.
At 3 days after the 131I dose, patients were scanned on a dual-headed gamma-camera (ADAC VERTEX). 131I localization was classified either as strong/intense or weak/negative.
For the patients on whom dosimetry estimates were made, anterior and posterior scans were carried out two to four times during the week following 131I therapy. Activity in the tumour was calculated by comparison with phantoms of known activity and volume. Tumour mass was assessed from a PET scan with Na124I in one case or alternatively from tomographic scans using Na123I. The mean absorbed dose in the tumour was calculated using the MIRD method as described by Fielding et al [13].
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Results
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The conventional way of relating PBI131 to the presence or absence of residual normal thyroid or tumour in the patient has been to consider the value of the PBI131 at 6 days [4]. Disease status is reflected in the scan at 3 days; the relationship between the 3-day scan and the 6-day PBI131 is shown in Figure 1
. There is a wide range of values for the 6-day PBI131, especially when the scan is positive, so that although there is a significant difference between the means for the two groups of positive or negative scans (Table 1), there is considerable overlap in the values. Table 2 shows that half of the patients whose scans are weak/negative have a 6-day PBI131 greater than 0.01% dose l-1. This is also true when the patients are separated into those receiving the first ablative dose (3 GBq) and those receiving a subsequent therapeutic dose (5.5 GBq or greater).
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Figure 1. 6-day protein-bound iodine-131 (PBI131) and scan at 3 days. The horizontal bars represent the mean value of the PBI131 for each group.
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Table 1. Mean ± SD values of 6-day protein-bound iodine-131 (PBI131) % dose 1-1 in relation to the scan at 3 days
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Table 2. Numbers of patients (n) with 6-day protein-bound iodine-131 (PBI131) greater than 0.01% dose 1-1 in relation to the scan at 3 days
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The changes in PBI131 with time from 1–6 days after treatment showed either increases, which ranged up to 15 times the initial value on day 1, or decreases, most of which were of the order of 1/2 to 1/3. The relationship between the change in serial measurements of PBI131 and the 3-day scan is shown in Table 3. For all patients, 85% of rising PBI131 values are associated with a positive scan, and 89% of falling PBI131 values are associated with a negative scan. Considering the first 3 GBq ablation dose only, 89% of rising PBI131 values are associated with positive scans; for patients receiving a subsequent therapy dose, the association of a falling PBI131 with a weak or negative scan is also strong (92%).
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Table 3. Relationship between the scan at 3 days and the temporal change in protein-bound iodine-131 (PBI131) from day 1 to day 6
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The magnitude of the PBI131 may be considered to reflect the amount of 131I that is incorporated into functioning normal or malignant thyroid tissue. Therefore, the time-integrated PBI131 from 1–6 days, i.e. the area under the PBI–time curve (AUC), may be an indication of the radiation dose received by the tumour. For a limited number of 11 patients, the tumour dose has been assessed independently from the intensity of uptake on the scans. It can be seen from Figure 2 that there is probably a correlation between the absorbed dose and the AUC for PBI131 corrected for the administered dose.
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Figure 2. Estimated absorbed radiation dose to the thyroid and the area under the curve (AUC) for protein-bound iodine-131 against time from 1–6 days corrected for administered dose.
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Over the wide range from 0.003–2% dose l-1, there is a good correlation between AUC and the 6-day value (Figure 3). Hence, a plot of absorbed dose against 6-day PBI131 for the 11 patients (Figure 4) shows a similar distribution as the AUC in Figure 2
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Figure 3. Area under the curve (AUC) of protein-bound iodine-131 (PBI131) % dose l-1 with time from 1–6 days against PBI131 % dose l-1 at 6 days.
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Figure 4. Estimated absorbed radiation dose to the thyroid against 6-day protein-bound iodine-131 (PBI131) % dose l-1.
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Discussion
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The management of patients with DTC has been greatly aided in recent years by the introduction of the radio-immunoassay for Tg, which is especially useful in those patients who have had a total or near-total thyroidectomy and 131I ablation. In these cases, the presence of Tg in the serum may be considered a marker for residual or recurrent disease [14]. The 131I scan is also an indicator of functioning thyroid tissue, and the protocol at the Royal Marsden Hospital relies on a scan at 3 days following 131I ablation together with a follow-up scan at 4 months plus PBI131 and serum Tg [8]. However, there are often difficulties, such as the situation of a negative scan with abnormal Tg [9].
To assist in making the decision whether to administer a further 131I-iodide treatment in patients with borderline values, it is desirable to use as many indicators as possible. Here we consider the contribution of PBI131. This parameter, obtained from plasma samples following 131I therapy, was used in the early days of this therapy. It was reasoned that the quantity of administered 131I that appeared in the form of thyroid hormone would indicate the amount of functioning normal thyroid or malignant tissue. A threshold value of 0.01% dose l-1 at 6 days was suggested as a marker of the presence of tumour after total ablation [4]. An alternative, but indirect, method to determine the presence of carcinoma was to measure the whole-body retention of administered 131I. If an iodine-concentrating tumour was present, the 6-day whole-body retention would be increased. However, although this relationship was shown to hold for many patients, the 6-day retention increased markedly in patients with impaired renal function [15].
The data in Table 2 show that while positive scans are associated with PBI131 values greater than 0.01% dose l-1, about half of the patients with weak/negative scans also have PBI131 values greater than 0.01% dose l-1. This is true not only for those receiving the first ablation dose, where surgery may leave some residual normal thyroid tissue, but also for those patients receiving subsequent higher therapy doses. If the threshold value were raised to 0.015% dose l-1, there would still be 28% of patients with a higher PBI131 but a negative scan; at 0.02% dose l-1 the proportion is 17%. However, at this value 39% of therapy patients with positive scans would have PBI131 values below the cut-off value. It should be noted that for the value of 0.01% dose l-1, Pochin [4] stated that the presence of tumour was a "certainty" while for the lower value of 0.006% dose l-1 tumour was "likely" to be present.
These discrepancies arise because the scans and the PBI131 measure different factors. The uptake scan shows the accumulation of 131I in the thyroid. This may be in the form of iodide as first transported into the organ, and in any intermediate stage through to the final form as T4. So, although a positive scan is usually due to functioning, thyroxine-forming tissue, it may also arise from an accumulation of iodide if further synthesis is blocked. It has been reported that radiation can cause an inhibition of the organification pathway before the 131I accumulating faculty is damaged [16, 17].
The PBI131, however, measures primarily the secretion of hormonal 131I, that is T4, in the circulation. Although the rate of synthesis of T4 in the thyroid is probably the most important factor, the quantity of administered 131I that is incorporated into the T4 is dependent on the size of the iodide pool. This is diminished after surgery or 131I therapy, and also sometimes when normal thyroid is replaced by a non-functioning carcinoma. In this situation the synthesized T4 has a higher specific activity of 131I, leading to a larger value for the PBI131.
Since the convergence of the results for the scan and a single PBI131 value at 6 days is so low (Table 2), we have investigated the changes in PBI131 over the 1–6 days following therapy. We have found that we can classify the serial measurements of PBI131 according to whether they are rising or falling with time. Then, as shown in Table 3, some strong correlations emerge. Thus, in the therapy patients, 92% of those with a falling PBI131 have negative scans, and 78% with a rising PBI131 show positive scans. For patients receiving the first ablation dose, 89% with a rising PBI131 have positive scans, and 78% with a falling PBI131 have negative scans.
It is interesting to note that the largest decrease in PBI131 from day 1 to day 6 is of the order of 1/2 to 1/3, which agrees with the clearance half-time for T4 from the circulation of 4–5 days. So, in these patients there is a small transient uptake of 131I-iodide, which is converted into a small quantity of T4 that is then released into the circulation over a short period of time. Thus, a falling PBI131 indicates a small volume of functioning thyroid or malignant tissue and there is a high correlation with a weak/negative scan, regardless of the specific activity and the magnitude of the PBI131.
Conversely, a rising PBI131 indicates a high uptake of 131I-iodide and conversion to T4, which is stored and released as required over a long period of time so that more is released to the circulation than is lost by the normal metabolic rate with a half-life of 4 days. This implies a large quantity of thyroid tissue or tumour, leading to a positive scan.
Some patients may show a positive scan because the thyroid tissue concentrates iodide, but radiation damage inhibits the enzymes responsible for conversion to T4, so yielding a low PBI131. Three of the six patients with positive scans after therapy but falling PBI131 do have low PBI131 (<0.01% dose l-1 at 6 days). Conversely, three of the six therapy patients with negative scans but rising PBI131 have 6-day values less than 0.01% dose l-1, so that these low values indicate very low and slow conversion to thyroid hormones, consistent with the negative scan.
The good correlation obtained between the slope of the serial PBI131 curve and the localization of radioactivity as shown on the scan suggests that the PBI131 activity integrated over time could be used to estimate the radiation dose absorbed by thyroid tissue. Figures 2 and 4 show that there is a relationship between the absorbed dose and the PBI131, expressed both as the AUC and as the 6-day value. This has been done for only a few patients and is to be extended to a larger number. The errors involved in dosimetry are notoriously difficult to estimate; many potential sources exist although no serious attempt has yet been made to isolate and quantify these errors. The problem is attracting greater attention [18]. The measurements reported here were carried out with planar scanning; they are being extended using SPECT and 3D dosimetry to enable estimates of the absorbed dose distribution to be determined and will be subject to detailed error analysis (GD Flux, Personal communication). If there is indeed a close correlation, then the PBI131 measurement from an assessment dose (185 MBq) of 131I could be used to calculate the activity of 131I required to give an adequate radiation dose to the tumour. Low PBI131 values would suggest that further 131I therapy would be likely to deliver a suboptimal or ineffectual dose and wasteful treatment could be avoided.
Currently, under the protocol at the Royal Marsden Hospital, further 131I therapy is recommended on the basis of the 6-day PBI131 value when other parameters, for example elevated serum Tg, suggest that tumour may be present. Following this study, the serial PBI131 appears to be more reliable.
Much effort has been expended over many years to obtain a reliable estimate of the radiation dose to thyroid tumours. Scanning methods are very time consuming, suffer from large errors in quantification, and there is always the problem of obtaining an accurate estimate of the tumour mass. PET has been used to improve the accuracy [19] but with limited success. In contrast, the PBI131 method is a simple technique, taking less than 30 min for each blood sample.
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Conclusions
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Effective and efficient management of patients with DTC is improved by the integration of all possible diagnostic modalities: serum Tg, 131I scan and PBI131. All these tests form part of the diagnostic protocol at the Royal Marsden Hospital [8]; further therapy, if necessary, depends on these post-treatment assays. The Tg assay is usually a reliable marker [14] but recurrence of disease has been reported in patients with no detectable Tg and no Tg antibodies [20]. Our results show that the simple measurement of 6-day PBI131, although rather a blunt instrument, can be a useful diagnostic aid, and that serial measurements correlate better with the scans than does the single 6-day assay. This retrospective study of the place of the PBI131 assay confirms its value and further studies are in progress to relate the PBI131 and the uptake scan to the serum Tg and the clinical outcome (A Al-Saadi et al, Personal communication). The first results shown here suggest that the PBI131 assay may be a useful method of quantifying the absorbed dose from131I therapy. This could prove to be of considerable value in tailoring 131I therapy to therequirements of each individual patient. Avoidance of therapeutically ineffective repeat 131I treatment would be of considerable benefit.
Received for publication August 11, 2000.
Revision received December 4, 2000.
Accepted for publication January 24, 2001.
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Abstract
Introduction
