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Annales d'Endocrinologie
Vol 64, N° 1  - février 2003
pp. 64-67
Doi : AE-02-2003-64-1-0003-4266-101019-ART18
Thyroxine Treatment
 
© Masson, Paris, 2003

Follow-up of thyroid cancer patients with favorable prognostic indicators

Tirés à part :
M.Schlumberger[1] , à l'adresse ci-dessus.

[2] schlumbg@igr.fr

It is estimated that about 60.000 patients are followed in France for papillary and follicular thyroid carcinoma. In these patients the goals of follow-up are to maintain adequate L-thyroxine (L-T4) therapy and to detect persistent or recurrent thyroid carcinoma[13],[20]. Studies have shown that the outcome after recurrent disease depends upon the tumor burden and this emphasizes the critical importance of the early discovery of persistent or recurrent disease[20].

Follow up strategy should be adapted to the risk of recurrence and of cancer-related death that by definition is low in patients with favorable prognostic indicators. Among these patients, an aim of the follow-up is to individualize from the majority of patients without any evidence of disease, the rare patients who may require additional testing and/or treatment.

Most recurrences occur during the first years of follow-up, but some occur late. Therefore, follow-up is necessary throughout the patient's life.

Thyroxine Treatment

The growth of thyroid tumor cells is in part controlled by TSH, and inhibition of TSH secretion with L-T4 improves the recurrence and survival rates. Therefore, L-T4 should be given to all patients with thyroid carcinoma, whatever the extent of thyroid surgery and other treatment. The initial effective dose is about 2.5mg/kg body weight in adults; children require higher doses. The adequacy of therapy is monitored by measuring serum TSH 3 months after it is begun, the initial goal being a serum TSH concentration of <= 0.1mU/ml and a serum free T3 concentration within the normal range that permits to avoid overdosage[2]. When these guidelines are followed, L-T4 therapy does not have deleterious effects on the heart or bone[9].

Early Detection of Recurrent Disease

Several tools can be used to detect persistent or recurrent disease

Clinical and Ultrasonographic Examinations

Palpation of the thyroid bed and lymph node areas should be routinely performed. Ultrasonography is performed in patients at high risk of recurrence and in any patient with suspicious findings. Palpable lymph nodes that are small, thin or oval, in the posterior neck chains, and when they decrease in size after an interval of three months are considered benign; in contrast, absence of central echogenic line, calcifications, cystic component, and hypervascularisation at color Doppler ultrasonography are suspicious findings. Serum Tg is undetectable in 20% of patients receiving L-T4 treatment who have isolated lymph node metastases, and undetectable values do not exclude metastatic lymph node disease. If in doubt, ultrasound-guided fine-needle biopsy of the node for cytology and Tg measurement in the fluid aspirate may be performed[14],[26]. Sensitive RT-PCR to amplify Tg mRNA appeared to be even more sensitive[1].

X-Rays

Bone and chest X-rays are no longer routinely performed in patients with undetectable serum Tg concentration. The reason is that virtually all patients with abnormal X-rays have detectable serum Tg concentrations.

Serum Thyroglobulin Determinations

Thyroglobulin is a glycoprotein that is produced only by normal or neoplastic thyroid follicular cells. It should not be detectable in patients who have had total thyroid ablation, and its detection in them signifies the presence of persistent or recurrent disease.

Modern immunoradiometric assays can detect concentrations as low as ng/ml or even lower. Anti-Tg autoantibodies are found in 15% to 25% of patients with thyroid carcinoma and may lead to underestimation or false negative results. These antibodies should always been screened when measuring serum Tg with a sensitive Tg-antibody immunoassay[10],[24]; as an alternative, interferences can be detected by a recovery test and they are found in 1% of serum when using modern Tg assays[21]. In patients in complete remission after total thyroid ablation, serum Tg antibodies decline gradually to low or undetectable levels. Their persistence or their reappearance during follow-up should be considered as suspicious for persistent or recurrent disease[24].

The production of Tg by both normal and neoplastic thyroid tissue is in part TSH-dependent. When serum Tg is detectable during L-T4 treatment, it will increase after TSH stimulation obtained either after the thyroid hormone treatment is discontinued or with injections of recombinant human TSH (rhTSH). Following rhTSH stimulation (0.9mg im for 2 consecutive days), the peak of serum Tg is usually obtained 2 to 3 days after the second injection; in most patients, the maximal serum Tg is lower after rhTSH than following thyroid hormone withdrawal[8],[23].

At discovery of persistent or recurrent disease, serum Tg level during L-T4 treatment is elevated in nearly all patients with large distant metastases, but is undetectable in about 5% of patients with small lung metastases that are not visible on standard chest X-rays, and in about 20% of patients with isolated lymph node metastases in the neck[20]. Following TSH stimulation, serum Tg level will become detectable in almost all patients with persistent or recurrent disease; it may remain undetectable in rare patients with small distant metastases and in about 5% of patients with isolated lymph node metastases in the neck.

The serum Tg concentration is an excellent prognostic indicator, even in patients without any other evidence of disease. Most of the patients not receiving L-T4 with undetectable serum Tg concentrations have been free of relapse after more than 15 years of follow-up, and only 1-2% had a recurrence, mainly in neck lymph nodes. Conversely, 60 to 80% of patients with serum Tg concentrations above 10ng/ml after LT4 withdrawal and with no other evidence of disease, have detectable foci of 131½ uptake in the neck or at distant sites after administration of a large dose (3700 MBq, 100mCi) of 13½[22].

In low risk patients who have had a total thyroidectomy and no 131½ ablation, serum Tg is undetectable in 93% during LT4 treatment and in about 70% following thyroid hormone withdrawal[20],[22]. However, when only a lobectomy has been performed, serum Tg remains detectable in about 40% of patients during LT4 treatment, even when serum TSH is suppressed.

Recently, several researchers have developed sensitive RT-PCR assays to amplify Tg messenger mRNA. The technique appeared sensitive, being positive in most patients with thyroid tissue but results were not related to the extent of the disease[17],[18]. This technique may be useful in patients with interferences in the Tg assay.

131½-Total Body Scan

The results of 131½ total body scan depend on the ability of neoplastic thyroid tissue to take up 131½ in the presence of high serum TSH concentrations, which are achieved by withdrawing LT4 for 4 to 6 weeks[6],[12]. However, the resulting hypothyroidism is poorly tolerated by some patients. This can be attenuated by substituting the more rapidly metabolized L-T3 for L-T4 for 3 weeks and withdrawing it for 2 weeks or by simply reducing the dose of thyroxine to about half[7]. The serum TSH concentration should be above some arbitrary value (25-30mU/ml) in patients managed in this way; if it is not, 131½ administration should be delayed until it is. Intra-muscular injections of recombinant human thyrotropin (rhTSH, 0.9mg im, for 2 consecutive days) is an alternative, because L-T4 treatment needs not be discontinued and side effects are minimal. When combining serum Tg measurement and 131½ otal body scanning, its efficiency is comparable to that of L-T4 withdrawal in most patients[8],[19],[23].

When 131½ scanning is planned, patients should be instructed to avoid iodine-containing medications and iodine-rich foods, and urinary iodine should be measured in doubtful cases. Pregnancy must be excluded in women of childbearing age. For routine diagnostic scans, from 2 to 5mCi (74 to 185MBq) 131½ is given; higher doses may reduce the uptake of a subsequent therapeutic dose of 131½[16]. The scan is done and uptake, if any, is measured 48 to 72 h after the dose using a double-head gamma camera equipped with high energy collimators. When rhTSH is used, a dose of 148 MBq (4mCi) is recommended with a TBS performed 2 days later. False-positive results are rare and are usually easily recognized.

Post-131½ Therapy Total Body Scans

Assuming equivalent fractional uptake after administration of a diagnostic and a therapeutic dose of 131½, uptake too low to be detected with 2 to 5mCi (74-185MBq) may be detectable after the administration of 100mCi (3700MBq). Thus, a total body scan should be routinely performed 4 to 7 days after a high dose. This is also the rationale for administering a large dose of 131½ in patients with elevated Tg levels (>10ng/ml off L-T4 treatment), even if the diagnostic scan is negative[22]. However, this attitude remains controversial for main reasons: firstly, favorable responses have not been observed in all cases; secondly, serum Tg normalized in some patients without any treatment[15], and thirdly, due to the absence of randomized controlled trial, there is no demonstrated effect on survival[11].

Other tests

They should be performed only in selected cases and may include spiral computed tomography or magnetic resonance imaging of the neck and chest, bone scintigraphy, positron emission tomography (PET) scan with (18F) fluorodeoxyglucose (FDG), and scintigraphy using a less specific tracer (e.g., thallium, MIBI, tetrofosmin). FDG PET scan is more frequently positive in patients with no detectable 131½ uptake in the metastases, and is particularly sensitive for the discovery of neck lymph nodes; spiral CT scan is more sensitive than FDG PET scan for the discovery of small lung metastases[5],[27].

Follow-up strategy

If the total body scan performed after administration of 131½ to destroy the thyroid remnants does not show any uptake outside the thyroid bed, physical examination is performed and serum TSH and Tg are measured during L-T4 treatment 3 months later. A diagnostic 131½ total body scan is done after thyroid hormone withdrawal or rhTSH stimulation, 6 to 12 months later. A visible uptake in the thyroid bed that is too low to be quantified should not be considered as evidence of disease in the absence of any other abnormality. If any significant uptake is detected, 100mCi (3700MBq) 131½ is given. Studies have shown that diagnostic 131½ total body scan is negative in almost all these patients, and serum Tg level after TSH stimulation obtained after either thyroid hormone withdrawal or injections of rhTSH stimulation, will become detectable in rare patients[3]. Serum Tg level obtained following TSH stimulation may decrease and even normalize at subsequent follow up evaluation[15]; therefore, another rhTSH stimulation or thyroid hormone withdrawal is performed some months or years later in those patients with detectable serum Tg; at that time, when serum Tg increases or remains elevated, a total body scan is performed with a large amount of 131½.

Among low-risk patients, 85% are considered cured (undetectable serum Tg and negative 131½ total body scan), and the risk of recurrence is less than 1-2%. The dose of L-T4 is decreased to maintain a low but detectable serum TSH concentration (0.1 to 0.5mU/ml). In high-risk patients, higher doses of L-T4 are given, the goal being a serum TSH concentration of <= 0.1mU/ml[4]. Clinical and biochemical evaluation is performed annually; any other testing is unnecessary as long as the patient's serum Tg concentration is undetectable.

In patients receiving L-T4 in whom serum Tg becomes detectable, neck ultrasonography is performed and serum Tg should be measured again after either LT4 is discontinued or after rhTSH stimulation. If the serum Tg concentration increases above 10ng/ml, and even if no uptake is seen on the 131½ total body scan performed with 2-5mCi, 100mCi 131½ should be given. In the absence of 131½ uptake, spiral CT of the neck and lungs, bone scintigraphy, and PET scan using 18F-fluorodeoxyglucose can be useful.

In low-risk patients who have had a near total thyroidectomy but who were not given 131½ post-operatively, a 131½ total body scan is performed 6 to 12 months after surgery. Indeed, an ablative 131½ treatment may be given in those patients with an elevated serum Tg level or with abnormal findings on 131½ total body scanning. The follow-up protocol described above is then applied, based on serum Tg determinations.

In low-risk patients who underwent a lobectomy, yearly follow-up consists of a neck examination and of serum Tg determination during LT4 treatment. Ultrasonography will show abnormalities in the remaining lobe in most patients with detectable Tg concentrations. If their size is small, fine needle biopsy may be impossible, and surgery is frequently the only option although abnormalities are benign in most cases.

In conclusion, follow-up of patients with papillary and follicular carcinoma is based on serum Tg determination. Among low-risk patients, more than 85% appeared to have no evidence of disease, and they require only substitutive L-T4 treatment and no other testing. This has permitted an improvement of the quality of life by decreasing the number of 131½-TBS, that will be further improved with the use of rhTSH.

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[2] Bartalena L, Martino E, Pacchiarotti A, et al. Factors affecting suppression of endogenous thyrotropin secretion by thyroxine treatment: retrospective analysis in athyreotic and goitrous patients. J Clin Endocrinol Metab 1987; 64: 849-855.

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[9] Marcocci C, Golia F, Bruno-Bossio C, et al. Carefully monitoring levothyroxine suppressive therapy is not associated with bone loss in premenopausal women. J Clin Endocrinol Metab 1994; 78: 818-823.

[10] Mariotti S, Barbesino G, Caturegli P, et al. Assay of thyroglobulin in serum with thyroglobulin autoantibodies: an unobtainable goal? J Clin Endocrinol Metab 1995; 80: 468-472.

[11] Mc Dougall IR. 131½ treatment of 131½ negative whole body scan and positive thyroglobulin in differentiated thyroid carcinoma: what is being treated? Thyroid 1997; 7: 669-672.

[12] Maxon HR, Smith HS. Radioiodine-131 in the diagnosis and treatment of metastatic well differentiated thyroid cancer. Endocrinol Metab Clin North Am 1990; 19: 685-718.

[13] Mazzaferri EL. Carcinoma of follicular epithelium: radioiodine and other treatment and outcomes. In The thyroid: a fundamental and clinical text, 8th Edition. Braverman LE, Utiger RD (Eds). Lippincott Williams Wilkins; 2000: 904-929.

[14] Pacini F, Fugazzola L, Lippi F, et al. Detection of thyroglobulin in fine needle aspirates of nonthyroidal neck masses: a clue to the diagnosis of metastatic differentiated thyroid cancer. J Clin Endocrinol Metab 1992; 74: 1401-1404.

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[16] Park HM, Perkins OW, Edmondson JW, Schnute RB, Manatunga A. Influence of diagnostic radioiodines on the uptake of ablative dose of iodine-131. Thyroid 1994; 4: 49-54.

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[18] Ringel MD, Balducci-Silano PL, Anderson JS, et al. Quantitative reverse transcription-chain reaction of circulating thyroglobulin messenger ribonucleic acid for monitoring patients with thyroid carcinoma. J Clin Endocrinol Metab 1999; 84: 4037-4042.

[19] Robbins RJ, Tuttle RM, Sharaf RN, et al. Preparation by recombinant human thyrotropin or thyroid hormone withdrawal are comparable for the detection of residual differentiated thyroid carcinoma. J Clin Endocrinol Metab 2001; 86: 619-925.

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[21] Schlumberger M, Baudin E. Serum thyroglobulin determination in the follow-up of patients with differentiated thyroid carcinoma. Eur J Endocrinol 1998; 138: 249-252.

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[23] Schlumberger M, Ricard M, Pacini F. Clinical use of recombinant human TSH (rhTSH) in thyroid cancer patients. Eur J Endocrinol 2000; 143: 557-563.

[24] Spencer CA, Takeuchi M, Kazarosyan M, et al. Serum thyroglobulin autoantibodies: prevalence, influence on serum thyroglobulin measurement, and prognostic significance in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 1998; 83: 1121-1127.

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[27] Wang W, Macapinlac H, Larson SM et al. 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography localizes residual thyroid cancer in patients with negative diagnostic 131½ whole body scans and elevated serum thyroglobulin levels. J Clin Endocrinol Metab 1999; 84: 2291-2302.


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