RAI  131-I  Ablation and Follow-up
For several decades the central aspect of follow-up for patients previously operated for thyroid cancer consisted of repeated Whole body scans done after thyroid hormone withdrawal. Development of sensitive and reliable TG RIA,  recognition that US is often effective in defining the presence of tumor in the neck, and introduction of rhTSH for stimulation of residual thyroid tissue, has led to a major reevaluation of the "standard" approach to follow-up of these patients. We present both the standard methods, and the revisions, along with the data supporting, or questioning, these changes. The basic differences are shown in the following table

Whole body scans have usually been done using 131-I. Its 8 day half-life allows scanning at 48-72 hours after administration of the tracer dose, at which time circulating free iodide has been largely excreted, and  abnormal tracer uptake is  easily defined. 131-I also has an energetic and easily detected gamma-ray signal. A potential problem with 131-I scanning is "stunning" of visualized thyroid tissue, as described below. To avoid stunning, 123-I has been employed, since its short half-life (6 hours) leads to a great reduction in radiation to thyroid tissue (and the patients). Scans are typically done at 24 hours, when background counts are still elevated, but  it is nevertheless reported to provide information satisfactory for treatment decisions(433a). 

.Most patients who have had a "total" thyroidectomy, and all patients who have had a subtotal resection, will have some functioning thyroid tissue remaining in the normal position after surgery, and will thus be candidates for 131I ablation. This is done to remove any possible residual tumor in the thyroid bed, to make subsequent scans and TG assays more interpretable, and (hopefully) to kill tumor cells elsewhere. There is no unanimity regarding the use of postoperative 131I ablation in Stage I tumors, since absolutely convincing evidence of its value is lacking (434, 435). But for all patients with papillary and follicular cancers as a group, 131I ablation correlates with improved survival (436, 437). Our data demonstrate that postoperative 131I ablation correlated with decreased recurrences for all patients with papillary cancers over 1 cm in size. Samaan et al (438), in a review of 1599 patients, observed that 131I treatment was the most powerful indicator for disease-free survival.

Ablation can be accomplished in most instances by one dose of 30 mCi 131I, giving the patients about 10 whole body rads (439). In our practice 80% of patients are ablated successfully with one dose of 30mCi, and the remainder require repeat therapy at the time of their second scan. Other clinicians find this dose insufficient, and give 50-150 mCi as an inpatient treatment. In part this difference may depend upon the surgeon, since small remnants of residual thyroid are more easily ablated than large amounts of residual tissue. Low dose (30 milliCurie) ablation of thyroid tissue after near-total thyroidectomy was recently reviewed by Roos et al. Surveying many studies, they concluded that 30 milliCuries was as effective as larger doses in inducing ablation, and since it could be administered without hospitalizing the patient, was an appropriate treatment.(440) Doses of 100 mCi may provide more certain ablation with one dose (although at the expense of greater patient radiation) but there is little difference between ablation rates with does of 30-75 mCi. There is no data proving that one method or the other provides superior results in terms of survival. A recent review of all available published series concluded that it was not possible to prove that a 100mCi 131-I ablative dose was more effective than a 30mCi dose. (Hackshaw A, Harmer C, Mallick U, Haq M, Franklyn JA. 131I Activity for Remnant Ablation Ablation in Patients with Differentiated Thyroid Cancer: A Systematic Review.J Clin Endocrinol Metab. 2007 Jan;92(1):28-38. Epub 2006 Oct 10.) Pacini and coworkers reported a prospective randomized trial comparing 50 and 100 mCi doses for ablation in patients eith differentiated thyroid carcinoma prepared with rhTSH, and found that therapeutic (131)I activities of 1850 MBq are equally effective as 3700 MBq for thyroid ablation in DTC patients prepared with rhTSH, even in the presence of node metastases (Pilli T, Brianzoni E, Capoccetti F, Castagna MG, Fattori S, Poggiu A, Rossi G, Ferretti F, Guarino E, Burroni L, Vattimo A, Cipri C, Pacini F. A Comparison of 1850 (50 mCi) and 3700 MBq (100 mCi) 131-Iodine Administered Doses for Recombinant Thyrotropin-Stimulated Postoperative Thyroid Remnant Ablation in Differentiated Thyroid Cancer. J Clin Endocrinol Metab. 2007 Sep;92(9):3542-6).

We do not routinely use ablation in patients under age 21 with tumors under 1 cm. Patients with tumors above this size, older patients, or those with multicentricity or a history of neck irradiation are advised to take 131I. This practice is followed in most clinics.

An alternative to ablation for patients with Stage 1 tumors is follow up by means of TG levels and US. A recent study supports that approach.Totlontano et al (433a) investigated the role of neck ultrasonography (US), whole-body scintigraphy (WBS), and serum thyroglobulin levels (Tg) after recombinant human (rh) TSH in the follow-up of very low-risk PTMC patients in a 5-yr observational study after near total thyroidectomy. Eighty consecutive patients who had not undergone postoperative radioiodine treatment because of unifocal tumor without lymph node metastases and who did not have anti-Tg antibodies, were included. rhTSH-Tg was 1 ng/ml or less in 45 (Tg-) and more than 1 in 35 (Tg+) patients. WBS showed no pathological uptake in any patient. US identified node metastases in two Tg (+) and one Tg (-) patients. rhTSH-Tg levels positively correlated with thyroid bed iodine uptake (r = 0.40, P < 0.0001). During follow-up all node-negative patients had undetectable Tg levels on LT(4) treatment and negative US. For the initial follow-up of PTMC patients without risk factors and anti-Tg antibodies and who did not undergo radioiodine treatment, WBS was thought to be  useless, US was highly sensitive in detecting node metastases, and  detectable rhTSH-Tg levels mainly depended on small normal tissue remnants. In this subgroup of PTMC patients, the authors felt neck US might be regarded as the primary tool for the initial follow-up.

Whether or not to ablate residual thyroid tissue in patients with "low risk"  carcinoma, has remained a contentious and much debated issue. The opposing schools of thought were recently presented by Mazzaferri and Hay.
"It is unlikely that many patients will forgo treatment after understanding their risk, especially when total thyroidectomy and radioiodine (131I) therapy can reduce the PTMC recurrence or persistence disease rate to zero. Preoperatively diagnosed PTMC should be treated with total or near-total thyroidectomy, regardless of tumor size. For very low-risk patients with unifocal PTMC smaller than 1 cm that is removed by chance during surgery to treat benign thyroid disease, lobectomy alone without 131I therapy may be sufficient therapy if there are no concerning histologic features and no tumor extension beyond the thyroid, metastases, history of head and neck irradiation, or positive family history--any of which requires total or near-total thyroidectomy and remnant ablation with 30 mCi." (Mazzaferri EL. Management of low-risk differentiated thyroid cancer. Endocr Pract. 2007 Sep-Oct;13(5):498-512.)
"The outlook for patients with low-risk PTC is very optimistic, with rates at 30 postoperative years of only 1% for cause-specific mortality and less than 15% for tumor recurrence at any site. The long-term results obtained by potentially curative bilateral resection, appropriate regional lymph nodal excision, and selective use of RRA are excellent. Realistically improving these acceptably low rates for cause-specific mortality and tumor recurrence may be difficult."( Hay ID. Management of patients with low-risk papillary thyroid carcinoma. Endocr Pract. 2007 Sep-Oct;13(5):521-33)
As pointed out by Cooper (Thyroid 17, p596, 2007) , some of the differences have  to do with use of differing tumor classification systems. Papillary cancers in patients under age 45 over 4 cm, or with macroscopic extraglandular invasion, or over age 45 with multifocal diseae or microscopic extraglandular invasion, and follicular cancers if over 45 yrs and <1cm- are all placed in  AJC version 6 Stage I, but are placed in Stage II using the NTCCSG classification. Follicular cancers 1-2 cm in patients over age 45 are in AJC Stage I, but are in NTCCSG Stage III. Obviously the two groups believe the specific tumors have differing degrees of significance, thus leading to different therapeutic recommendations.

It is possible to administer ablative 131-I doses outside of the hospital setting by using fractionated doses given on successive days, immediately after  the diagnostic WBS. Czepczynski  et al (440b) did diagnostic  whole body scans  44-46 hours after a 111MBq oral dose, and patients were treated on the same day, and 24 hours later in a split dosage protocol. Patients (113) with DTC (29.3%) were treated with one (131)I dose of 2.2 GBq and 273 patients (70.7%) with fractionated doses (1.1 GBq + 1.1 GBq administered in 24 hour intervals. The early outcome of the initial therapy  was evaluated 6-8 months later by radioiodine uptake test, thyroglobulin concentration, whole-body diagnostic scan, and neck ultrasound. No difference in measured parameters was found in the groups at the follow-up evaluation. In uncomplicated cases of DTC, therapy using a regimen of a fractionated dosage, seems equally effective as  therapy with a single dose. No influence of stunning was observed in patients treated with a fractionated dosage, but the time interval between the doses was 24 hours.

The factors associated with ablation failure are not fully understood. In particular, it is not certain whether the use of doses higher than 3.70 GBq (100mCi) would result in any additional benefit, or whether there is a 'stunning' effect of the diagnostic dose of 131I on the subsequent ablation rate. A retrospective analysis was reported by Karman et al (440c) on all patients (n=389) with well-differentiated thyroid cancer treated  between 1992 and 2001. The therapeutic dose was the only variable found to be associated with success (odds ratio, 1.96 per 1.85 GBq increment; 95% confidence interval, 1.11-3.46). The results confirmed the presence of a significant percentage of ablation failures (24.4%) despite the use of high ablative doses (3.70-7.40 GBq). Higher therapeutic doses are associated with higher rates of successful ablation, even when administered to patients with more advanced stages.  Higher diagnostic doses were not associated with higher rates of ablation failure.

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. Schlumberger concludes that routine radioactive iodide ablation is not indicated in patients with differentiated thyroid carcinomas of less than 1.5 cm in diameter, and advocates restricting RAI ablation to patients with poor prognostic indicators for relapse or death (441). Wartofsky points out a secondary benefit of postoperative low dose ¹³¹I ablation in that, for many patients, it provides a high degree of certainty and peace of mind when subsequent scans are negative and TG is undetectable. Another argument for radioactive iodide ablation and early detection of any recurrence is the data presented by several groups, including Schlumberger and colleagues, that there is a reciprocal relationship between the success of cancer therapy and the size and duration of the lesions.

In patients with Stage II to IV disease, we proceed to destroy all residual thyroid and to treat demonstrable metastases if they can be induced to take up enough 131I. Use of 131I therapy is investigated in these patients, regardless of the histologic characteristics of the resected lesion, although significant uptake rarely is found in Hurthle tumors (442, 443) or in patients with anaplastic lesions. (Fig.18-16)

Preparation for 131-I ablation

The "classical" approach has been to induce hypothyroidism prior to the ablative dose in order to raise TSH and stimulate uptake of RAI in residual thyroid or tumor. This may be done by simply leaving the patient without T4 therapy for 3 weeks post op. Alternatively patients can be given thyroid hormone suppressive therapy for 6 weeks or so after operation, so that any malignant cells disseminated at the time of thyroidectomy will not be stimulated by TSH. The value of this measure is admittedly unknown. Patients then receive 25 µg L-T3 bid for 3 weeks, and therapy is then stopped for at 2-3 weeks to allow endogenous TSH (which may reach 20-60 µU/ml) to stimulate uptake of the 131I by the remaining fragments of thyroid tissue or metastatic lesions in the neck or elsewhere before proceeding with 131I therapy. The usual scanning dose is 2 mCi 131-I, and scans are read at 48 or 72 hours when body background has diminished. If TSH is sufficiently elevated the initial scan can reveal distant metastases as well as residual thyroid gland. If large thyroid tissue remnants are present, TSH may not become very elevated, but will do so after the first ablation dose. Patients with Class I and Class II disease under age 45 are given 30 mCi as an out-patient treatment. Older patients with Class II disease and patients with Class III or IV disease are given doses of 75-200 mCi as an inpatient treatment.  Whole body scans are obtained about 7 days after the ablative dose of 131I (or after therapeutic doses), since unsuspected metastasis may be visualized on scans at this time. Serum Tg is always measured at the time of 131-I therapy. At 24 hours after initial ablation, we replace hormone therapy and continue this therapy for 6-9 months
    Some physicians proceed without prior scanning directly to 131I ablation 2-4 weeks after surgery and perform a post-therapy scan 5-7 days later. If this is done it is considered important to measure urinary iodine in order to prevent ineffective treatment. Presumed benefits of this approach are patient convenience, less expense, and avoidance of possible thyroid "stunning" by the scan dose. In fact stunning has not been demonstrated with the 2 mCi 131-I dose, although it may occur. Arguments for doing a pre-ablation scan include finding out the actual percent uptake of the treatment dose in the neck and elsewhere, establishing if in fact there is uptake, and recognizing disease that may dictate a larger initial dose. The final word on these different approaches is not in. Variations on this approach were studied by Pinchera's group (444),who compared induced hypothyroidism with rhTSH stimulation. The Pisa group found that either thyroid hormone withdrawal, or hormone withdrawal plus 2 doses of rhTSH, produced higher percentage uptakes and more frequent ablation with 30 mCi doses (in about 80 % of cases), compared to rhTSH alone. Although not yet an approved use, THYROGEN administration has been reported to be an effective preparation for post operative ablation as well as for subsequent scans (445).

Options in Follow-up scans and treatment- including recently described variations

The conventional preparation for follow-up scans has been to induce hypothyroidism in order to stimulate uptake of 131-I by residual thyroid tissue or tumor cells and production of TG. Several methods have used. Firstly, hormone therapy may simply be withdrawn 4 weeks. More commonly, triiodothyronine is given (25 ug bid) for three weeks (this induces mild hypothyroidism, and T3 disappears rapidly after withdrawal) and then T3 is omitted for 2-3 weeks. Children appear to develop adequate TSH elevation for treatment after two weeks without T4 therapy (445a). Recently a "HALF DOSE" protocol has been used, since it minimizes symptoms. Elevation of TSH in patients on T4 therapy by using injectable recombinant human TSH has been added to our options. (See below). Other options include omitting scans after initial ablation in patients deemed to be at low risk, and relying entirely on measurement of serum TG. Another option in patients known to have residual disease because of elevated baseline TG, is to give therapeutic 131-I without preliminary scanning. General plans for performing scans and reducing stable iodide intake during scanning are given below.

Half-Dose Protocol and Thyroid Hormone Withdrawal

Six-9 months after initial treatment, patients are often again prepared for scanning. After initial ablation, little thyroid tissue is present, and patients can be conveniently prepared using the "half-dose" protocol (446). Half the usual dose of thyroxine is given for six weeks. TSH is tested in the fifth week, and if over 20 uU/ml, scanning is done in the sixth week, or preparation is prolonged if needed. On this protocol patients usually feel quasi-normal and conduct normal activities, in contrast to their function during withdrawal scans. On the half-dose protocol, FTI falls to bottom normal, and TSH on average reaches about 60uU/ml in the sixth week. Patients who start with TSH below 0.1uU/ml may take longer to reach a satisfactory level for scanning, which is generally considered to be with TSH at least 30uU/ml. Alternatively, patients are switched to 50 µg L-T3/day for 3 weeks. This medication is then stopped, and after 2-3 weeks imaging is again performed. Patients who are completely without hormone for >2 weeks become severely hypothyroid, and should be advised against driving an automobile or participating in any activity in which their slowed responses could cause danger.

Thyrogen

The aim of the follow-up of patients with papillary and follicular thyroid carcinoma is the early discovery of persistent or recurrent disease. This is possible through the use of serum thyroglobulin (Tg) determination or total body scanning with 131I (131I-TBS), or a combination of both tests. Both procedures, to be effective, require elevated serum TSH levels above some arbitrary figure such as 25 or 30 mU/L (447), obtained by withdrawing l-thyroxine (L-T4) suppressive therapy for 4 to 6 weeks, or by substituting the more rapidly metabolized triiodothyronine (L-T3) for thyroxine for 3 weeks, and then withdrawing it for 2-3 weeks, or the half-dose method noted above. Even if L-T3 substitution is used, patients may experience a wide range of hypothyroid signs and symptoms which may be severe and may result in a substantial impairment of the patients' lives and ability to work (448), and occasional tumor growth. Recombinant human TSH (Thyrogen) has been developed to meet the need for safe, adequate exogenous TSH stimulation in patients with papillary and follicular thyroid carcinoma.

In vitro studies have shown that rhTSH can effectively stimulate cAMP production and the growth of human fetal thyroid cells. The in vivo biological efficacy of rhTSH was demonstrated in normal subjcts, in whom it is able to increase serum T4 and T3 concentrations and stimulate thyroidal radioiodine uptake. A single dose of 0.1mg rhTSH is a potent stimulator of thyroid function in normal subjects (449).

A first clinical trial of recombinant humand TSH (rhTSH- THYROGEN) (phase I/II) was completed in 1994 in 19 patients after a recent thyroidectomy for differentiated thyroid cancer (450). The encouraging results of this limited study were confirmed in a larger multicenter phase III study conducted between 1992 and 1995 in the USA in 127 patients (451) and in a second phase III  trial, which included US and European centers (452). The results of this trial can be summarized as follows: scans were similar after rhTSH and thyroid hormone withdrawal in 92% of the patients, with no difference between the two dose regimens investigated. When the results of 131I WBS and post-rhTSH Tg levels were combined, the detection rate increased to 94%. Among the patients with persistent or recurrent disease, 80% had concordant scans, 4% had superior rhTSH scans and 16% had superior withdrawal scans. Interestingly, serum TG levels were detectable in 80% during thyroid hormone therapy and were detectable in all following either rhTSH stimulation or withdrawal of thyroid hormone treatment. However, the TG level reached after rhTSH stimulation was in general lower than that obtained after thyroid hormone withdrawal. Tissue RAI uptakes obtained in the patients undergoing hormone withdrawal were twice the values found after rhTSH, indicating that withdrawal provided a much greater stimulus to thyroid or tumor tissue. However, as noted, the diagnostic results were nearly equal. Quality of life was much better during rhTSH than during hypothyroidism induced by thyroid hormone withdrawal, and side effects were minimal, mainly consisting in mild and transient nausea or headache in less than 10% of patients. No patient has developed detectable anti-rhTSH antibodies, even after receiving repeated courses of rhTSH in successive clinical trials .All together these clinical trials have clearly shown that rhTSH is an effective and safe alternative to thyroid hormone withdrawal during the post-surgical follow-up of papillary and follicular thyroid cancer, although not as sensitive as scanning after hormone withdrawal in some patients. A few patients have been reported with metastases demonstrated on withdrawal scans that were not evident on rhTSH scans (452.1).

In an important study, Frigo et al ablated thyroid remnants with 3.7 GBq 131-I in 10 patients with T4 withdrawal for 30 days, and 10 with rhTSH pre-treatment. Bone marrow radiation exposure was 0.1+/- 0.03 mGy/MBq (2 rads) in withdrawal patients and 0.06+/- 0.01 (1.2 rads) in rhTSH treated patients. Six to twelve months after 131-I administration, the withdrawal  patients had a higher chromosome translocation rate. This study clearly suggests that by inducing a lower extrathyroid exposure, rhTSH reduces the potential risk of chromosomal aberrations associated with blood irradiation. Three important caveats must be kept in mind in reviewing the study. . Firstly, the significance of the translocations, and the small radiation dosage (a fraction of the dose given with one CAT scan) is uncertain, although no one can “favor” extra radiation. Secondly,  if a “partial T4 dose “ pre-treatment had been used, the patients would not have been rendered hypothyroid, and probably would have similar responses to the rhTSH group.. Thirdly,  the dose of 131-I given, 3.7GBq, is three times higher than the dose needed to ablate most patients. (Frigo A, Dardano A, Danese E, Davì MV, Moghetti P, Colato C, Francia G, Bernardi F, Traino C, Monzani F, Ferdeghini M Chromosome translocation frequency after radioiodine thyroid remnant ablation: a comparison between recombinant human thyrotropin stimulation and prolonged levothyroxine withdrawal. J Clin Endocrinol Metab. 2009 Sep;94(9):3472-6.)

Recently a  theoretical analysis was done to determine the cost-utility of rhTSH prior to ablation in the United States. Use of rhTSH yielded an incremental cost-utility of $52,554/QALY (95% confidence interval $52,058-53,050/QALY) (incremental societal cost of $1,365/patient; incremental benefit of 0.026 QALY/patient). Differences in cost are due to cost of rhTSH and differences in productivity loss (days off work). (Wang TS, Cheung K, Mehta P, Roman SA, Walker HD, Sosa JA. To stimulate or withdraw? A cost-utility analysis of recombinant human thyrotropin versus thyroxine withdrawal for radioiodine ablation in patients with low-risk differentiated thyroid cancer in the United States. J Clin Endocrinol Metab. 2010 Apr;95(4):1672-80)

    It has been found that Thyrogen administration induces a reduction of serum vascular endothelial growth factor, even in the absence of thyroid tissue (452a). The clinical significance of this observation, if any, is unknown, but it does imply possible action of rhTSH on receptors other than in thyroid tissue. Another unlikely by-product possibly associated with rhTSH was reported by Berg et al, who observed development of severe ophthalmopathy in a patient with disseminated thyroid cancer treated with rhTSH and RAI while on retinoic acid (Berg G, Andersson T, Sjodell L, Jansson S, Nystrom E. Development of severe thyroid-associated ophthalmopathy in a patient with disseminated thyroid cancer treated with recombinant human thyrotropin/radioiodine and retinoic acid.Thyroid. 2005 Dec;15(12):1389-94).
    Use of rhTSH in managing thyroid cancer has recently been extensively reviewed (452b)

Follow - up treatment based on TG assays--

As assays for thyroglobulin (TG) have become more sensitive and reliable, measurement of TG assumes more and more importance in determining the management of patients followed after thyroidectomy and radioactive iodide ablation treatment for thyroid cancer. Serum TG levels, in the absence of antibodies interfering in the assay, correlate well with tumor burden, although detectable tumor may well be present even in the presence of negative TG assays in individuals who are on replacement thyroid hormone (453). Pacini et al report that, in a retrospective study of 315 patients who had undetectable serum TG in the hypothyroid state at the time of the first control body scan after thyroid ablation, no useful information was provided by the body scan. Thus they propose that diagnostic ¹³¹I whole body scans can be avoided in patients with undetectable levels of TG on T4 after initial ablation, and that the patients can be monitored with clinical examination, ultrasound, and serial TG measurements on thyroxin treatment. However, some concerns may be noted. The TG assay used in their study recognized a value of < 3 ng/ml as "undetectable". Also, of the 90 patients in the study with thyroid bed RAIU, 54 received a second course of treatment, and seven received two additional courses. This seems to question the recommended approach (454). In a second study they found that an undetectable TG, when hypothyroid at the time of the first control scan after ablation, predicted complete and permanent remission. They propose that subsequent 131-I scanning is unneeded, and follow-up clinically and by TG assays while on thyroxin, would be sufficient (455). However a negative TG (with negative antibodies)  after initial ablation is not fool proof. Phan et al observed that 8 out of 94 (8.5%) patients with initially negative Tg and TgAb showed persistent/recurrent disease.  Tg and TgAb negativity at the time of ablation is not a predictive determinant for future recurrent status(455a).
    Castagna et al evaluated the utility of a second rhTSH-Tg in DTC patients 2-3 yr after their first evaluation. The second rhTSH-Tg was informative in patients who had detectable stimulated Tg in the first exam but not in those who had undetectable Tg at the first test. They suggest rhTSH-Tg should be repeated only in patients who have had a positive first rhTSH-Tg and negative imaging(455b).

    Mazzaferri and Kloos studied retrospectively 107 patients who were “clinically free of disease” and had undetectable or very low serum TG levels during thyroid hormone therapy. The TG levels on treatment were all 1 ng/ml or less, and 95% were under 0.5 ng/ml in their assay, which was a commercial (Nichols Institute) chemoluminescent antibody assay. In response to the administration of two doses of recombinant TSH and assay of TG on samples taken on the fifth day, 20% were found to have a value above 2, with values ranging from above 2 up to 18 ng/ml. Twenty percent of the patients who had low or undetectable TGs had elevation above 2 ng/ml after rhTSH stimulation, and many of these patients ended up with therapy. However, the authors found that radioactive iodide whole body scans often failed to localize the source of the elevated TG, which was found after post-therapy scans or by other imaging methods. This study suggests that even with a TG level below 1 while on replacement therapy, persistent disease may sometimes be present and be detected by stimulation using recombinant TSH or thyroid hormone withdrawal (456). Wartofsky comments on these studies and supports the idea that TG testing, both on suppression and after TSH stimulation, can help in determining therapy. He suggests that, in patients with a serum TG < 0.5 ng/ml on suppression, and in a low risk category, that stimulation by recombinant TSH and measurement of TG, rather than scanning, is satisfactory. If the TG remains < 1, the patients can be evaluated annually with such a stimulation test. In patients with slightly higher TGs, up to 2, he suggests measuring a recombinant TSH stimulated TG, and scanning. In patients with higher TGs, he suggests that thyroid hormone withdrawal and radioactive iodide treatment, without initial scanning, may be appropriate (457-459).
     In a study done by the rTSH-Stimulated Thyroglobulin Study group and published in 2002 (NR22), a cutoff level of 1ng/ml for stimulated TG was taken as the safe level for patients with low risk. This group would presumably be monitored by repeat rTSH stimlated TG assays rather than scans. It is of interest that in this study 14 of the patients with stimulated TG <2ng/ml underwent isotope scanning and 9 were positive. These "could be interpreted as false negative" tests. Five had uptake outside the thyroid bed. This group suggests that patients with stimulated TG above 2 would have subsequent thyroid hormone withdrawal and possible 131-I therapy without scanning.    
    A recent “consensus” statement by a group of thyroidologists also supports the categorization of patients into high and low risk groups, and use of TG as described above for following low risk patients (459a). David et al )459b) also support the primacy of rhTSH-stimulated TG, and US, in follow up, and indicate that any rise of TG after stimulation should raise suspicion of persistent or recurrent disease. Although 131-I scans showed uptake in lung, bone or mediastinum in 11 of 27 patients who had TG > 5ng/ml after stimulation, they found that TSH-whole body scans "provides little adjunctive information".
    As the sensitivity of TG assays  increases, the need for rTSH stimulated-TG assays will diminish. Smallridge et al report that patients with a post–op and post-ablation suppressed TG of 0.1ng/ml or less, rarely elevate >2ng/ml with rTSH stimulation. The authors suggest monitoring with measurement of suppressed TG and US, and reserving more extensive review for patients who elevate  TG to a detectable level during suppression therapy, or develop abnormal nodes(459d).

This figure shows their results from rTSH stimulated TG assays in patients whose basal suppressed TG was < 0.1ng/ml in a sensitive assay. Only one of 46 patients elevated TG significantly. Obviously this approach depends on the availability of a highly sensitive and reliable TG assay. 
    Interestingly, Bachelot et al (459c) point out that neither serum TG (with sensitive assay) nor 131-I body scan can be considered entirely reliable for indicating the absence of disease in patients previously treated by ablative RAI. However when both are negative, the risk of persistent disease is minimal.
    While these studies clearly describe current trends in approach to therapy, utilizing sensitive TG assays and recombinant TSH, it probably will take some time and more studies before most thyroidologists are willing to forego radioactive iodide scans, at the time of the initial ablation and later on in follow-up. There is no evidence that 2 mCi scans cause tumor stunning, and scanning clearly does provide useful information in many patients on disease localization, presence of residual thyroid in the neck, or even depressed uptake from iodide contamination at the time of the scan. Many thyroidologists will be reluctant to administer large doses of radioactive iodide (100 mCi or more) in therapy, without having a clear idea of where the isotope may go (460, 461). However it is certain that clinicians are placing more reliance on TG assays and US during followup, especially in low risk patients. Whether this will be come standard after the first ablation, or as is more common now, after 1 or 2 negative scans, is less clear. Clinicians may also be reluctant to accept the approach of administering large therapeutic does of 131-I based solely on elevated TG values, above 2 or 5ng/ml, in the absence of prior scanning, considering potential dangers, cost, uncertainty of distribution of the isotope, or whether there is any RAIU at all. We note that although not yet approved for this use, Thyrogen has been shown to be effective for 131-I therapy of residual or metastatic disease (462)
Criteria for identification of neck nodes that might harbor tumor have been presented by Schlumberger and coworkers. Cystic appearance, hyperechoic punctuations, loss of hilum, and peripheral vascularization can be considered as major ultrasound criteria of LN malignancy. LNs with cystic appearance or hyperechoic punctuations are highly suspicious of malignancy. LNs with a hyperechoic hilum should be considered benign. Peripheral vascularization has the best sensitivity-specificity compromise. Round shape, hypoechogenicity, and the loss of hilum taken as single criteria are not specific enough to suspect malignancy. (Leboulleux S, Girard E, Rose M, Travagli JP, Sabbah N, Caillou B, Hartl DM, Lassau N, Baudin E, Schlumberger M Ultrasound criteria of malignancy for cervical lymph nodes in patients followed up for differentiated thyroid cancer. J Clin Endocrinol Metab. 2007 Sep;92(9):3590-4)

Follow- up scans (Table 18-7,8)

It is usual to perform whole body imaging with the gamma scintillation camera at 48 and 72 hours after administration of 2-4 mCi 131I. The 48-hour study is done so that metastases showing a relatively active turnover of iodine will not be missed, to shorten the study if possible, and to allow early ordering of isotope. The 72-hour imaging is technically superior, since the background iodide is almost entirely excreted by this time. Isotope typically remains in the sinuses even at the 72 hour scan, and usually some is seen in stomach, intestine, and bladder. Accumulation outside the thyroid bed, and not in one of the areas noted, indicates metastatic disease. However occasionally false positive uptake is seen in esophagus, various cysts, Meckel’s diverticuli, and elsewhere (463). In whole body scanning there is a definite advantage to the use of the gamma camera with multiaperture parallel holes, over a diverging collimator. By comparing the counting rate over a metastasis with a known standard, the percentage uptake of the dose can be computed. The gamma camera is essential for this procedure since, with the multiaperture parallel collimation described, the counting rate is essentially distance independent, as compared to the usual broad-field thyroid uptake collimator in which distance is critical. Using this technique, it is possible to measure easily the exact percentage of dose retention in specific areas at 48-72 hours. The method is much simpler and more accurate than measuring isotope retention by collecting urinary 131I, and for this writer, constitutes an essential part of every whole body scan.

STUNNING FROM "TRACER" RAI-
The amount of 131I used for scanning varies from 2-10 mCi, in various clinics, or even larger amounts. Clearly the larger doses detect more lesions, but this rarely alters treatment plans. More importantly, doses of 5-10 mCi have been shown to decrease tumor uptake of the subsequent treatment dose -- to "stun" the tumor (464). The exact importance of this phenomena is uncertain, but  use of a 2 mCi dose has seemed to be a reasonable compromise.  A recent study by Lassmann et al (464a) call this assumption into question, since they found that even a 2mCi  scan dose reduced RAIU by up to 50% in a second procedure done 6 weeks later. This study was carefully performed on a few patients, but it is possible that prolonged stimulation of the thyroid by elevated TSH  may have adversely altered iodide kinetics in the remnants during the second RAIU proceedure. Although a reduction of uptake after prior low dose scans has been reported, it is uncertain that this limits the effectiveness of treatment. It was recently reported that ablation rates were equal in individuals who had, or had not, received scans prior to their treatment dose of 131-I (465). Elevation of TSH above 25-30uU/ml by hormone withdrawal or rhTSH is the prime determinate in successful scanning.
    Ingestion of large amounts of iodide, or exposure to contrast dye within 6 (or more) weeks, can prevent RAIU. Uptake can be enhanced by prescribing a low iodine diet, and this should be employed for at least two weeks before scanning and therapy. (Table 18-7). It is useful to give magnesium citrate to induce bowel emptying prior to the scan .
    As discussed above, the value of routine follow-up diagnostic scans has been challenged by Cailleux et al, who suggest that such scans rarely give information of value in patients who have TG < 1 after thyroid ablation (465.1) They suggest testing TG after thyroid hormone withdrawal or rhTSH, and directly treating those with TG above 10 by administration of 100mCi 131-I. This concept is of interest and awaits further examination, but has obvious problems as noted.

HIGH DOSE RAI THERAPY FOR INVASIVE OR METASTATIC DISEASE
Efficacy and morbidity of high activity I therapy was assessed in  38 patients with locally advanced or metastatic differentiated thyroid cancer (16 follicular, 20 papillary, one Hurthle cell, one insular)(465a). Patients were treated with high activity radioiodine therapy (9 GBq, 243 mCi) as the cancers had previously not responded to standard activities (5.5 GBq). After high activity treatment, 9.7% of patients suffered grade 3 and 3.2% suffered grade 4 WHO haematological toxicity. Significant salivary gland morbidity was observed (30% dry mouth, 27% salivary swelling).  In this study repeated treatment with high activity (9 GBq) 131-I in patients with advanced differentiated thyroid carcinoma appeared to be of no apparent benefit and  lead to late morbidity.
However, other investigators have differing results. A retrospective analysis was  conducted by orn et al (465b) on 124 differentiated thyroid cancer patients who underwent dosimetric evaluation using MIRD methodology over a period of 15 y. One hundred four RAI treatments were performed. A complete response at metastatic deposits was attained with absorbed doses of >100 Gy. No permanent BM suppression was observed in patients who received absorbed doses of <3 Gy to BM. The maximum administered dose was 38.5 GBq (1,040 mCi) with the BM dose limitation. Dosimetry-guided RAI treatment allowed administration of the maximum possible RAI dose to achieve the maximum therapeutic benefit. Estimation of tumor dose rates helped to determine the curative versus the palliative intent of the therapy.