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Fig. 18-19. Comparison of recurrence-free survival in patients with a "good prognosis" who had a limited (1) versus extensive (0) resection. Survival without recurrence in Group 0 > Group 1, p = 0.05. Patients who had a "good prognosis" were less than age 45 at the time of diagnosis, in Class I or II with intra-thyroidal disease or positive neck nodes, and whose tumors were less than 2.5 cm in diameter. |
While there is fair agreement on initial surgery and consensus on 131-I ablation, it must be noted that there is little agreement on the size of the ablative dose, or on subsequent management with thyroid hormone, or follow-up (512), as reported in a recent survey of thyroidologists. (Fig. 18-17 and Fig. 18-18).
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Figure 18-17. Decisions in deciding the correct dosage of thyroxine in patients who are receiving this medication for various indications, including prior but presumed cured cancer, or who have had recent cancer, or currently have active thyroid malignancy. |
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Figure 18-18. Mean serum thyroglobulin values in patients with thyroid cancer given near-total or total thyroidectomy and radioactive iodide ablation and followed up to ten years. Without further treatment, there is a tendency for the serum thyroglobulin values to decline, suggesting the gradual death of residual normal or cancerous thyroid cells. |
After initial ablation patients are re-placed on hormone therapy. Two-three months later serum TSH, free thyroid hormones and Tg concentrations are measured during l-thyroxine treatment. The strategy of follow-up will rely strongly on the results of the 131-I WBS obtained after the administration of the ablative dose of 131-I (513). This post-therapy WBS should always be performed because it has greater sensitivity them the diagnostic scan (514). As noted above, the diagnostic scan has been abandoned by some in favor of the post-therapy scan.
A suppressed TSH is appropriate when patients have un-cured disease, or high risk, but a "low-normal" TSH level is believed appropriate in cured patients. It has been found that the average TSH level varies inversely with probability of relapse. Hovens et al recently confirmed this relationship usingn Cox regression analysis, which showed a positive association between serum TSH concentrations and risk for thyroid carcinoma-related death and relapse, even in initially cured patients. The median of the individual TSH concentrations was the best indicator for thyroid carcinoma-related death (hazard ratio 2.03; confidence interval 1.22-3.37) and relapse (hazard ratio 1.41; confidence interval 1.03-1.95). A threshold of 2 mU/liter differentiated best between relapse-free survival and thyroid carcinoma-related death or relapse.: This study supports current guidelines, which advise to aim at TSH levels in the low normal range in cured low-risk patients, whereas TSH levels should be suppressed in non-cured or high-risk patients (Hovens GC, Stokkel MP, Kievit J, Corssmit EP, Pereira AM, Romijn JA, Smit JW. Associations of serum thyrotropin concentrations with recurrence and death in differentiated thyroid cancer. J Clin Endocrinol Metab. 2007 Jul;92(7):2610-5. Epub 2007 Apr 10)
If uptake is seen outside the thyroid bed on the post-therapy WBS, further treatment is warranted according to the site of uptake: surgery and/or 131-I therapy in case of lymph node or distant metastases. Serum Tg will be elevated in most of these cases.
If no uptake is seen outside the thyroid bed on the 131-I post-therapy scan, the combination of a diagnostic WBS, with 2 mCi of 131-I, and serum Tg measurement, is recommended by many authors 6-12 months from thyroid ablation after withdrawal of l-thyroxin (alternatively with recombinant human TSH ). This procedure is aimed to ensure that thyroid ablation has been successful and to search for foci of 131-I uptake outside the thyroid bed. At this point the result of serum Tg measurement is the more sensitive predictor of complete remission or persistent disease (provided that anti-Tg autoantibodies are negative) (515-519). Nearly all patients with local or distant disease have detectable or elevated serum Tg levels, while patients in stable remission have undetectable serum Tg concentrations. Compared to serum Tg measurement, the yield of the diagnostic 131-I WBS is lower. A significant proportion of patients may have elevation of serum Tg in the presence of falsely negative diagnostic WBS.
A recent retrospective study by Cailleaux et al. (520) has shown that when serum Tg off therapy is undetectable, routine diagnostic WBS does not add any further information on the clinical status of the patient. Similar results have been obtained at the Department of Endocrinology, University of Pisa, by Capezzone et al. (521) in a retrospective series of 315 patients who had undetectable serum Tg off l-thyroxine at the time of the first control after thyroid ablation. None of these patients had evidence of disease activity at WBS, and 99.4% were in complete and stable remission after 12 years of follow-up. Only two patients (0.6%) had recurrence of lymph node metastases which were treated with radioiodine therapy. Based on these studies it is possible that in the future the need for 131-I scanning may be dictated by the results of serum TG during hypothyroidism or by rhTSH-stimulated serum Tg results (522). A practical problem using this approach is that it may take days or even weeks for the TG analysis to become available, while the patient remains off hormone. Although with added expense, it may be expeditious to have both scan and TG available as soon as possible at the time of the first post-ablation scan, and the combination does give the highest degree of certainty in diagnosis. Some authors point out that the prognostic value of serum TG, independent of other known prognostic variables, has not been demonstrated, and may be over emphasized.
After the follow up scan (or possibly a second negative scan), low-risk patients (those with an undetectable serum Tg off l-thyroxine and negative WBS) considered as cured may be followed with periodic serum Tg measurement during l-thyroxine therapy. Thyroxine therapy may be decreased to maintain a low but not suppressed serum TSH concentration (0.1-0.4 µU/ml; Figures 18-17 and 18-18, above). The risk of recurrence is in fact so low in these patients (representing more than 80% of the total) that overdosage of l-thyroxine is unjustified.
As noted the problem of antibody interference in the TG assay makes this test unreliable in 10-15% of patients. However another aspect of the antibodies should be remembered. If patients are free of thyroid cancer and the thyroid has been ablated, it appears that the antigenic stimulation necessary to maintain an anti-TG titer is gradually lost, and these antibodies disappear with a 3-6 year half-life (523a). Recent introduction of mRNA analysis offers a method for circumventing this problem, although TG mRNA assays are not generally available as yet, and have many false positives. Fugazzola et al (524) point out that the combination of TG RIA and TG mRNA assay offer better positive and negative predictive value than TG alone. In some studies TG mRNA analysis has proven much less reliable than serum TG assay.
In high risk patients, even if considered cured, suppressive doses of l-thyroxine should be continued, because the risk of relapse is greater. Pujol et al evaluated a series of patients over an average of 95 months and compared those who had TSH values constantly under 0.05 mU/l to those who had all TSH values greater than 1 mU/l. A lesser degree of TSH suppression was associated with an increased incidence of relapse, with a shorter average relapse-free survival (525). This observation was not sustained in another study (526).
The objective of suppressive therapy in these patients should be to attain a serum TSH level of 0.1 µU/ml or less with normal free T3. In this situation, side effects such as osteoporosis, are not observed (527). Clinical and biochemical evaluation is performed annually. If serum Tg becomes detectable during follow-up, l-thyroxine should be withdrawn to perform a diagnostic WBS with 131-I. Some authors prefer to avoid this procedure and give directly a therapeutic dose of 131-I followed by a post-therapy scan. In the absence of uptake after therapeutic doses of 131-I, any further administration of 131-I is not justified, and the site of Tg production should be searched for by other imaging techniques. A schematic summery of the post-surgical follow-up is represented in Table 18-10.
If 131-I thyroid ablation has not been performed or if the patient has undergone only partial thyroid surgery (subtotal or lobectomy), follow-up should consist of clinical and ultrasound examination and serum Tg measurement. However, in this case, the sensitivity and specificity of serum Tg assay is lost.
Patients may develop recurrences or isolated metastases that can be approached surgically. Intra-operative gamma probe examination is sometimes helpful in localizing and excising minute remnants of cancer tissue. Osseous metastases, especially from follicular cancer, may require radiotherapy or operative procedures for stabilization. Progressive growth of soft tissue or osseous metastases that are not amenable to thyroid hormone, 131I therapy, or radiotherapy should lead to consideration of chemotherapy.
