Guidelines for the management of differentiated thyroid carcinomas of vesicular origin

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Annales d’Endocrinologie 69 (2008) 472–486

Guidelines for the management of differentiated thyroidcarcinomas of vesicular origin

Recommandations pour la prise en charge des cancers thyroïdiensdifférenciés de souche vésiculaire

F. Borson-Chazot ∗, S. Bardet , C. Bournaud , B. Conte-Devolx , C. Corone , M. D’Herbomez ,J.-F. Henry , L. Leenhardt , J.-L. Peix , M. Schlumberger , J.-L. Wemeau ,

the expert group for French recommendations for the management of differentiated thyroidcarcinomas of vesicular origin, E. Baudin , N. Berger , M.-H. Bernard , M. Calzada-Nocaudie ,

P. Caron , B. Catargi , G. Chabrier , A. Charrie , B. Franc , D. Hartl , B. Helal , V. Kerlan ,
J.-L. Kraimps , S. Leboulleux , G. Le Clech , F. Menegaux , J. Orgiazzi , S. Perié , I. Raingeard ,
P. Rodien , V. Rohmer , J.-L. Sadoul , C. Schwartz , F. Tenenbaum , M.-E. Toubert , J. Tramalloni ,J.-P. Travagli , C. Vaudrey

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. Introduction

The thyroid cancer scene has changed over the last few years.hyroid cancer is a rare tumor, accounting for only approxi-ately 1% of all cancers. For the last 30 years, however, a clear

ncrease in the incidence of this cancer has become apparent,or the most part in small papillary cancers with good progno-is, resulting from more active screening and changes in medicalractices. Patient survival is very long, as a rule scarcely differ-nt from that of the general population, which explains the highrevalence. The need for long-term follow-up because of theossibility of recurrence, even over the very long-term, ofteneans that non-specialists are involved in the follow-up.Important scientific progress has been achieved. Although

he number of prospective, randomized studies remains limitedrecisely because the prognosis remains globally favorable forhis cancer, large cohort studies have evaluated conventionalherapies and detailed the prognostic factors more precisely.he molecular mechanisms involved in the onset of the cancer
re beginning to be better understood. In particular, new well-valuated, high-performance tools are now available for diagno-is and treatment. Taking these advances into account has made
∗ Corresponding author.E-mail address: [email protected] (F. Borson-Chazot).

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raditional management evolve toward greater interdisciplinaryanagement with a definite chain of skills and new strategies

dapted to the level of patient risk have been developed.This Consensus Conference, based on the initiative

f the French Endocrinology Society (Société francaise’endocrinologie, SFE) and the Thyroid Research Groupgroupe de recherche sur la thyroïde, GRT), was assisted byhe French Society of Nuclear Medicine (Société francaise deédecine nucléaire, SFMN), the French Language Associationf Endocrine Surgeons (Association francophone de chirurgiendocrinienne, AFCE) and the French Ear, Nose and Throatociety (Société francaise d’ORL, SFORL). It responds to twoain objectives:

to propose a rational strategy based on the patients’ risk level,taking into account the scientific advances of recent years andthe need for multidisciplinary care;to adapt the European and American guidelines to the Frenchcontext, thus allowing French clinicians to have a referencesystem available within the framework of the oncology mul-tidisciplinary consultation meetings.

.1. Focus

Differentiated thyroid cancers are the most frequentndocrine cancers: it is currently estimated that 4000–5000 new

mailto:[email protected]

dx.doi.org/10.1016/j.ando.2008.10.002

d’Endocrinologie 69 (2008) 472–486 473

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Table 2UJCC classification stages.

< 45 years ≥ 45 years

Stage I Any T, any N, M0 T1, N0, M0Stage II Any T, any N, M1 T2, N0, M0SS

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ases of thyroid cancer are discovered every year in France.lthough the overall prognosis is good, a total of 5% of patientsie from their cancer and 10–20% of them will present a recur-ence, most often locoregional, sometimes late. This is whyatients should be followed up over the very long-term.

The WHO classification identifies within differentiated can-ers of the thyroid derived from vesicular cells:

well-differentiated, papillary and follicular cancers, the greatmajority and;less well-differentiated forms, whose prognosis is worse.

Recent epidemiological studies report a strong predomi-ance of papillary carcinomas, accounting for 85–90% of cases,hereas follicular cancers account for only 5–8% of the cases

nd the less differentiated forms, mainly oncocyte and insular,–5%.

The unexpected discovery of cancer during thyroid surgeryn nearly 25% of cases is new. In addition, 40–45% of the tumors

easure less than 1 cm. Since 2002, these microcarcinomas noonger belong to a particular TNM category and are incorpo-ated into T1 tumors in the new TNM classification, which nowncompasses tumors that measure 2 cm or less along the longxis (Table 1).

Thyroid cancer treatment should be adapted to the patient’sisk level; it is essential to identify the severe forms, screenecurrences early and treat them appropriately. In parallel, weust avoid imposing heavy treatments that may lead to side

ffects, unnecessary worry and avoidable costs in the largest
roup of patients – those with forms that have a good prognosisparticularly since the risk of recurrence is low.The clearly identified prognostic factors are tumor size, the
egree of extension and the presence of adenopathies. They are

able 1TNM classification, 2002.

pT1 Tumor: < 2 cmpT2 Tumor: 2–4 cmpT3 Tumor: > 4 cm or minimal extrathyroid invasion (muscle

and perithyroid adipose tissue)pT4 pT4a: macroscopic invasion: adipose tissue, larynx, trachea,

esophagus, laryngeal nervepT4b: invasion or prevertebral fascia, the carotids, themediastinal vessels

pN1a Level VI lymph node invasion (recurrent nerve, pretracheal,paratracheal, prelaryngeal lymph nodes)

pN1b Other lymphatic invasion (lateral-cervical and/ormediastinal)

M0 No metastasisM1 Metastasis

Rx Unknown tumor residueR0 No tumor residueR1 Microscopic tumor residueR2 Macroscopic tumor residue

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tage III NA T3, N0, M0 T1–3, N1a, M0tage IV NA T1–3, N1b, M0–1T4, N0–1, M0–1

aken into account in the International Union Against CancerUJCC) classification, which identifies four stages. Althoughurvival in stage I and II patients differs little from that of theeneral population, this is not true for stages III and IV patients,hose prognosis is poor. Among the prognostic factors clearly

dentified, age must be mentioned. Patients less than 45 yearsf age are therefore classified in stage I, whatever the T and N,f they present no metastasis, whereas patients over 45 years ofge are classified in stages I–IV (Table 2).

This classification, as with most of the prognostic scoresAGES, AMES, MACIS), does not take into account the his-ological type or other factors, the most important of whichnclude tumor necrosis, whether the tumor is infiltrating, mani-est angioinvasion of the medium- and large-caliber vessels anduclear atypias. These criteria may nevertheless be authenticrognostic factors.

The operational definition of the level of risk used in theonsensus is the following:

very low level of risk: single-focus intrathyroid microcarci-nomas less than 1 cm;low level of risk: T1–T2, N0, M0 well-differentiated follicularand papillary carcinomas;high level of risk: T3–T4 carcinomas, lymph node extension(any T, N1), metastasis (any T, any N, M1), unfavorable histol-ogy: tall cell, diffuse sclerosing, oncocyte, insular and poorlydifferentiated follicular epitheliomas.

New diagnostic tools have been developed over the last fewears that have radically changed patient management, partic-larly the follow-up modalities, notably the development ofltrasound, now playing a central role, the advent of recombi-ant thyrotropin stimulating hormone (TSH), the developmentf new high-performance imaging technologies, most notablyositron-emission tomography (PET). These methods facilitatearly screening for recurrences that occur most often within therst 5 years, although they can occur much later. The range of

herapeutic tools is currently growing with the development ofigh-performance locoregional treatments and the hope raisedy targeted therapies.

In this context, it is essential to review the different diagnosticnd therapeutic approaches so that all patients can be offered the
est-adapted strategy. This is directly in line with the nationalancer plan, which recommends that each patient be offered areatment protocol with local reference points after examina-ion or recording of the patient’s file in the multidisciplinaryncology consultation meeting.

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.2. Working method

The basis for reflection was logically the European andmerican Consensuses published in June and February 2006,

espectively (Pacine F. et al., The American Thyroid, Associ-tion Guidelines Taskforce). The work was carried out withinix multidisciplinary groups involving endocrinologists, nuclearedicine physicians, endocrine and ENT surgeons, pathologists,

iologists, oncologists and radiologists, in hospital or privateractice settings, working under the aegis of rapporteurs andiven the responsibility of writing a preliminary text respondingo the questions asked. The presentation and discussion of thereliminary texts took place during two meetings of the workingroup during the SFE meeting in Montpellier in September 2006nd in Paris at the SFE headquarters in December 2006. Theseeetings produced a final document made up of a summary text

f recommendations with technical annexes, published in Frenchn its entirety in a supplement of the Annales d’endocrinologie.he recommendations are in good agreement with those of theuropean Consensus. After standardization, they were presentedt the SFE–ALFEDIAM, on 23 March 2007 at Marseille, thenisseminated from March to June 2007 on the SFE website to allf the society’s members and to the members of the other inter-sted societies in a forum. The final text, presented hereafter ints English version without the annexes, takes into account theomments made on the website as well as the contribution ofxperts designated secondarily by the SFORL.

. Initial surgery

.1. Objectives of surgery

Surgery is the only curative treatment for thyroid cancer. Itims to:

remove all macroscopic tumor tissue;limit morbidity caused by treatment of the disease as muchas possible;stage the disease;facilitate postoperative treatments and monitoring;limit risk of recurrence.

Surgery is part of a global disease management strategy andts extent conditions later disease management (radioiodine abla-ion therapy, Levothyroxine [LT4] suppressive treatment).

.2. Preoperative assessment

Surgical management of a nodule considered suspicious oralignant after fine-needle aspiration biopsy requires systematic

reoperative cervical ultrasound evaluation of the lymph nodesarried out by an experienced specialist. The performance of this
xamination is better than that of simple cervical palpation inssessing possible lateral lymph node chain involvement. Exceptn particular cases, other imaging exams are not indicated. Areoperative dosage of thyroglobulin (Tg) is not recommended.
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docrinologie 69 (2008) 472–486

When preoperative cytology is suspicious, the surgical teamhould be able to carry out an intraoperative extemporaneousest. When preoperative cytological examination supports malig-ancy, the surgical treatment is the same as for cancer.

.3. Extent of surgery

When the diagnosis of malignity is known pre- or intraoper-tively, surgery for thyroid cancer is total thyroidectomy.

Lobo-isthmectomy cannot be proposed considering theecessity to monitor the remaining lobe and the frequency of theontralateral micronodules that may encourage revision surgerygiven the precision of the ultrasound follow-up). In addition,obo-isthmectomy complicates later follow-up of the Tg levelnd precludes the administration of a complementary radioactivereatment.

.4. When should surgical treatment be proposed ifiagnosis has been differed?

When the extemporaneous pathological exam or the lack ofn exam has made it impossible to obtain the diagnosis of malig-ity and a simple lobectomy or lobo-isthmectomy has beenone, total surgical removal of the thyroid is indicated whenhyroidectomy would have been done if the diagnosis of cancerad been reached before the initial surgery. This is a prerequisiteor administration of later radioactive treatment.

With a single-focus tumor less than 1 cm in size (pT1),ecurrence is very rare, which allows more limited thy-oidectomies such as lobectomy. However, in practice it ismpossible to diagnose multifocality or microscopic tumorxtension in the extrathyroid tissue based only on the macro-copic aspect. Total thyroidectomy therefore remains the choiceurgery unless the histological diagnosis has not been madextemporaneously.

Therefore, there is no indication for a second surgery for aingle tumor measuring less than 1 cm, with no tumor extensionn the perithyroid tissue (pT1), discovered on a thyroidectomypecimen.

In young subjects (under 45 years) with a single-focus pT1umor 10–20 mm in diameter, less than total surgical excisionan be discussed subject to:

the absence of detectable thyroid anomaly in the contralaterallobe;the absence of suspicion of lymph node involvement on ultra-sound;the possibility of long-term follow-up.

If the patient presents recurrent paralysis soon after thenitial surgery, the patient should achieve full recuperationefore proposing total resection. If laryngeal mobility cannot
e recuperated, the indication for total resection should be dis-ussed on a case-by-case basis, depending on the risk–benefitatio and the dramatic complication of recurring bilateralaralysis.

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bconsensus and the activity to administer and the best adaptedstimulation method have not been defined. These cases are beingdiscussed in the Multidisciplinary Oncology Consultation Meet-ing (Réunion concertation pluridisciplinaire en oncologie).

Table 3Indications for radioiodine remnant ablation.

Consensus: no radioiodine remnant ablation because no demonstratedbenefitPatients with very low risk of progression: pT1 ≤ 10 mm, unifocal,

N0–Nx, M0–Mx

Consensus: radioiodine remnant ablation with at least 3700 MBq(100 mCi) of 131I after thyroid hormone therapy withdrawal

Patients with a high risk of disease progression: incomplete tumorexcision that cannot be reoperated or complete tumor excision buthigh risk of recurrence or mortality: large tumor and/orextrathyroid extension (T3 and T4), lymph node extension (any T,N1), metastasis (any T, any N, M1)

Fig. 1. The neck compartments, adapted from Robbins (2001).

.5. Lymphadenectomy

Papillary thyroid cancer is characterized by the frequencyf lymph node invasion found on microscopic examination inore than 50% of cases, but it has little influence on patient

urvival. This paradox explains the absence of a consensus on thereatment of the lymph nodes and the possibility of very differentttitudes, in particular on prophylactic lymph node dissection.

When suspicious cervical adenopathies are demonstratedreoperatively or during surgery, consensus exists for rec-mmending lymph node dissection associated with thehyroidectomy. First-intention therapeutic lymph node removalhen there is lymph node metastasis can reduce the risk for

ecurrence in low-risk patients and improve the survival of high-isk patients.

At a minimum, the dissection will include central dissectionsually corresponding to the first group of lymph nodes (level VIr the central compartment of the neck), possibly completed byither ipsilateral or bilateral dissection depending on the resultsf the workup and intraoperative exploration (Fig. 1). Lymphode picking is not recommended.

On the other hand, there is no consensus on the advantages ofrophylactic dissection in the absence of suspicious adenopathydentified during the preoperative workup. Its main advantage isroviding precise staging of the disease, which can be useful inuiding complementary treatment indications (radioiodine) andpecifying the monitoring techniques to use.

In cases of revision surgery for total excision after lobo-sthmectomy, the indications for lymph node dissection are the
ame as for initial surgery, but the repeated approach to the ini-ially dissected thyroid region exposes the patient to a higher ratef recurrent parathyroid morbidity. In these cases, the indicationshould be carefully specified in relation to the risk–benefit ratio.
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. Radioiodine thyroid remnant ablation therapy

.1. Objectives of iodine 131 (131I) treatment

Administration of postsurgical 131I for differentiated thyroidarcinoma (internal radiotherapy with 131I, radioactive iodineemnant ablation therapy, or radioiodine ablation) aims to:

destroy the remaining normal thyroid tissue (or thyroid rem-nants) to facilitate later monitoring using serum Tg level,neck ultrasound and, if necessary, diagnostic 131I whole-bodyscintigraphy;treat any macro- or microscopic postoperative tumor foci;complete staging by posttherapy whole body scintigraphy, ahighly sensitive examination when the thyroid remnants aresmall in size.

.2. Indications

Thyroid remnant ablation is not systematic. It is indi-ated after total or near-total thyroidectomy, when the patient’sge, tumor extension as evaluated by the pTNM classifica-ion (Table 3), histological type and/or multiple tumors suggestostoperative residual disease, metastasis or a risk of later pro-ression.

The indications for radioiodine thyroid remnant ablationepend on the patient’s risk level.

Three prognosis groups (or recurrence and mortality risktratification groups) are defined. In patients with a very lowisk of progression, radioactive iodine therapy has demonstratedo benefit and therefore is not indicated. In patients with a highisk of progression, 131I treatment reduces the risk of recurrence,acilitates the early detection of residual tumors and may reduceancer-related mortality.

In the other cases, the benefits of radioactive iodine have noteen demonstrated, radioactive iodine therapy has not met with

o consensus: radioiodine remnant ablation necessary? Which activitylevel? Which stimulation method?

atients at low risk: all other cases

4 d’Endocrinologie 69 (2008) 472–486

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Table 4Suggested patient information sheet (SFMN procedure guide).

Madame, Monsieur,

You will be receiving radioactive iodine treatment for your thyroid disease.This treatment is simple, painless and necessary to treat your disease aseffectively as possible. It has considerable advantages in relation to theprecautions described below

This treatment is strictly contraindicated in patients who are pregnant, whosuspect pregnancy, or who are breastfeeding

For several days, your body will retain a part of the radioactive iodinenecessary to this treatment. The iodine that has not been taken up will benaturally and progressively eliminated by the body in the stool, salivaand in urine

Because radioactive iodine is present, you risk subjecting the peoplearound you to low irradiation, which presents no real danger, but it is notuseful and should therefore be avoided. The very general principles forlimiting this irradiation is to limit as much as possible the time spentwith other people by remaining 1–2 m from them. The following are afew precautions to observe

For your family and friendsLimit contact with children and pregnant women for. . .. . .. . .daysLimit contact with your spouse and sleep alone if possible for. . .. . .days

For yourselfDrink abundantly, if possible water with lemon juiceTake a shower and change your clothes every dayUrine frequently, in a seated position and flush the toilet twiceWash your hands well after going to the bathroom or before preparingmealsUse paper tissues

Both men and women are advised not to conceive a child in the year

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Stimulation of thyrocytes by hormone suppression or recom-binant human TSH (rh TSH):

Table 5Medications to interrupt before radioactive iodine therapy.

Medications Recommended Period ofsuspension

Thyroid hormones 2 weeks for L-T3(tri-iodothyronine)3–6 weeks for L-T4(tetra-iodo-thyronine)

Syrup, vitamins, nutritivepreparations containing sodiumiodide, seafood

1–2 weeks depending on iodinelevel

Medications containing iodide(amiodarone)

Several months or several years

Iodized topical medications(Betadine, eyedrops, etc.)

1–2 weeks

Radiological contrast agents


.3. Contraindications

Absolute contraindications:

pregnancy: if the thyroid cancer is diagnosed during preg-nancy, radioactive iodine treatment should be postponed untilthe end of pregnancy;breastfeeding: if the decision for 131I treatment is made duringbreastfeeding, it should be stopped before administration ofthe iodine and will not be resumed afterward (but remainspossible after later pregnancies);medical emergency warranting specific treatment beforeradioactive iodine treatment.

Relative contraindications or those requiring precautions:

dysphagia;esophageal stenosis;gastritis and/or progressive gastroduodenal ulcer;urinary incontinence;iodine overload;kidney failure;cerebral metastasis and untreated, symptomatic medullarycompression;life expectancy less than 6 months;loss of independence.

.4. Methods

In France, the 131I treatment methods have been studied inrocedure guidelines aimed at nuclear physicians (published in006 by the SFMN), inspired by the 2003 European guidelinesnd take into account the French legislation on radioprotectionintegrating the European directives) and management of canceratients (Cancer Plan).

In France, the accreditation to perform internal radio-herapy vectored by 131I is granted by the Authority foruclear Safety (ASN) and its local divisions (formerly

he DGSNR/DSNR) to departments or units with L1Approval.

.4.1. Informing the patientThe patient or the patient’s legal guardian must be informed

y the physician who proposes the treatment and the physi-ian responsible for carrying out the treatment (decree of1 January 2004, called the Kouchner Law, Journal Officiel,February 2004, p. 2586). This information must include thebjectives, the examination methods, the expected benefits, theossible side effects, as well as the means to limit exposure tohe persons in contact with the patient after leaving the nuclear

edicine unit (Table 4).

.4.2. Preparation for 131I treatment
Any food or medication iodine overload must be avoided in
he 2 weeks preceding the administration of radioactive iodine.able 5 presents an example of the main sources of iodinend the recommended period for interrupting these sources.

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ydrosolubles 3–4 weeksiposolubles per os (cholecystography) 3 monthsily products (e.g., bronchography) 6–12 monthsyelography 2–10 years

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Table 6Artifacts and sources of 131I posttherapy scintigraphy error.

Thyroid remnants with intense uptake masking neighboring lymph nodefoci

Salivary glands near metastatic lymph nodesAlveolar-dental cyst and other cysts (pleuropericardial, renal), that have

trapped radioactive idodideContamination by vomit, urine, nasal secretions, saliva, perspiration on the

skin, hair and clothingLung uptake because of infectious lung disease or chronic inflammatory

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preparation by hormone suppression should provide a TSHlevel greater than 30 mU/l (empirical value) and requires stop-ping T4 for at least 3 weeks or from 4 to 5 weeks, with thepossibility of relay with T3, and stopping T3 for 2 weekswith the consequences in terms of hypothyroidism. Thyroidhormone treatment is resumed 2–4 days after taking iodine;preparation with rh TSH (IM injection of 0.9 mg ofThyrogen© 48 and 24 h before administration of 131I) isauthorized by a European approval to market for radioio-dine thyroid remnant ablation in forms with a good prognosis(pT1–T2, N0–N1) with 3700 MBq of 131I.

Corticotherapy: the inflammatory phenomena that are some-imes observed during treatment of voluminous remnants arereated with corticotherapy.

A blood sample is taken before administration of the treat-ent to measure the Tg level (with the TSH and anti-Tg antibody

evels) and for beta hCG levels in women of childbearing age.

.4.3. 131I activity administeredAfter total or nearly total thyroidectomy, the activity to

dminister in view of eliminating the normal thyroid tissue rem-ants is between 1100 and 3700 MBq (30 and 100 mCi) of 131I.his level is assessed for a given patient in relation to the initialrognostic factors:

the minimal activity necessary to obtain destruction of rem-nants has not yet been defined consensually;there is no significant difference in efficacy in terms of abla-tion between 100 and 30 mCi after hormone suppressionpreparation;there is no difference in efficacy in terms of ablation betweenhormone suppression and rh TSH after administration of100 mCi 131I;given today’s knowledge, if tumors persist, after known orpresumed incomplete excision or if metastasis is present, thetumors should be treated with an activity of at least 100 mCi,administered after hormone suppression.

The EANM guidelines provide activity levels by weightapproximately 1 mCi or 37 MBq/kg).

.4.4. Scintigraphy

.4.4.1. Pretreatment scintigraphy. Pretreatment scintigraphys not recommended because it has low sensitivity and mayeduce the efficacy of the radioactive iodine therapy by atunning effect. For teams that wish to carry out this examina-ion because the quantity of remnants could not be evaluateduring surgery or on postoperative sonography, a low 131Ictivity (< 37 MBq or 1 mCi) is recommended, or 123 iodine,hich provides better image quality and a more standardizeduantification.

.4.4.2. Posttreatment scintigraphy. Scintigraphy is done–8 days after treatment with 131I and provides information onhe thyroid remnants left in place during surgical thyroidectomynd particularly on the possible presence of metastases taking

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astroesophageal reflux, stagnation of radioactive saliva in the esophagussophageal metaplasiasophageal diverticula

p iodine in regional lymph nodes or extracervical sites. Thexamination is informative if uptake of thyroid remnants is lowless than 2% of the activity administered), although it is subjecto artifacts and diagnostic pitfalls (Table 6). If the examinations informative and shows no anomaly, whole-body scintigraphys useful.

.4.5. Measurement of residual activity and/or dose rateResidual activity is measured before the patient leaves the

nit and allows for adapting the recommendations for the radio-rotection of those caring for the patient.

. Thyroid hormonotherapy after surgery

.1. Which patients are best suited?

Thyroid hormone therapy is necessary for all patients oper-ted for thyroid cancer whatever the extension of the excision,hether or not there has been complementary radioactive

reatment.

.2. What outcome can be expected?

Hormone treatment is intended to:

meet thyroid hormone needs;brake possible residual cancerous tissue that persists despitesurgery and 131I administration.

Even if only slightly differentiated, malignant thyroid cellsossess receptors for TSH. It is therefore important to reducehe TSH level, a major factor in the multiplication of thy-ocytes. Experimental models and clinical evaluations havelearly established the hormonal dependence of thyroid cancernd the improvement in the prognosis of cancer patients whondergo therapy to inhibit TSH secretion (TSH ≤ 0.1 mU/l).he role of thyroid hormone therapy at doses that suppressSH in preventing major undesirable clinical events was
onfirmed by a recent meta-analysis (RR = 0.73; confidencenterval = 0.60–0.88; p < 0.05). However, there has been no evi-ence that hormone treatment should be recommended at dosesnhibiting TSH in cases with a good prognosis when remission

4 d’Endocrinologie 69 (2008) 472–486

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Table 7Factors modifying thyroid hormone needs.

Increase in thyroid hormone needs

Caused by a reduction in intestinal absorptionIntestinal malabsorption: celiac diseaseMedications: colestestyramine

Digestive remediesIron, calcium, magnesium saltsUrsodeoxycholic acid, proton-pump inhibitors

Caused by an increase in metabolic clearanceEnzyme inducers: phenobarbital, phenytoins, rifampicin, imatinib3rd trimester of pregnancy (placental deiodinase)Tumors producing deiodase (hemangiomas)

Caused by an increase in the diffusion spaceWeight gainPregnancy

Caused by hormonal lossNephrotic syndromeHemodialysis

Caused by acquired resistance to thyroid hormonesAmiodarone

Decrease in thyroid hormone needs

Elderly subjectWeight loss

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as been obtained. In such case, the recommendation is, thus,or hormone replacement therapy.

.3. What form should it take?

LT4 is the most common, the most convenient and theost logical treatment. Its action is mild and its long half-life

6–8 days) provides good stability in T4 and TSH levels, therebyequiring only one intake per day. Thyrotropic cells of the ante-ypophysis only have T3 receptors, but T3 is produced in situy deiodination of circulating T4. Thus, in vivo, the TSH lev-ls are better correlated with circulating T4 levels than with T3evels.

Triiodothyronine (LT3) has only marginal indications, forxample during the phase of LT4 withdrawal before radioac-ive therapy to reduce the hormone shortage phase or as it isropping for rapid correction of hypothyroidism. Supplementsf triiodothyroacetic acid have not been sufficiently evaluated.he use of thyroid hormone analogs (GC1) that respect the car-iac and bone receptors relatively well could be promising inhe future for poor prognosis situations.

.4. What dosage is best suited?

Treatment is ideally initiated and monitored by a team orpecialized physicians.

The LT4 doses are on the order of 2–2.5 �g/kg per day inSH suppression therapy, from 1.6 to 2 �g/kg per day in replace-ent therapy. Thyroid hormone needs are proportional to weight

more precisely, lean mass), slightly less in women and olderubjects. The medication should be taken daily, always in theame conditions.

The factors that may raise or lower hormone needs should benown (Table 7).

.5. How should dosage be adapted?

Adaptation is based on the TSH level measured 6 weeks tomonths after initiating the dosage. The T4 measurement is

ess informative than TSH level and it should be measured onlyf there is doubt as to whether the patient is complying withherapy. An increase in the T3 level normally indicates that theosage is too high. Adaptation should be done in increments of2.5–25 �g of LT4. Once the replacement or suppression dosageas been determined, monitoring every year or every 6 monthss sufficient.

For patients who are not cured, the progression of circulatingg under TSH suppressive therapy has to be taken into account.

.6. What tolerance level should be sought?

The tolerance level is assessed by data derived from question-ng the patient and the clinical examination. Cardiac and bone
isks are apparent particularly in prolonged or poorly adaptedSH inhibition treatments and in older subjects. They should berevented by beta-blockers or diphosphonates. Monitoring boneealth is particularly recommended in postmenopausal women
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AndrogensDevelopment of endogenous production: functional metastases

ho are taking TSH inhibition therapy. Specific monitoring ofhe heart is necessary in frail or elderly subjects.

.7. Recommendations

.7.1. Initial hormone therapyAfter surgery, treatment is started immediately with a dosage

ear 2 �g/kg per day and adapted after 6 weeks to 2 months toring TSH:

to a value close to the lower limit of normal (between 0.1 and0.5 mU/l) in cases where the cancer has a good prognosis (T1and 2, N0–Nx, M0, well-differentiated papillary or vesicularepitheliomas);to a value less than or equal to 0.1 mU/l in cases of cancer withless good prognosis (T3 and 4, lymph node extension (anyT, N1), metastasis (any T, any N, M1), unfavorable histol-ogy (epitheliomas with poorly differentiated vesicular cells,oncocytes, diffuse sclerosing cells and tall cells).

.7.2. Later hormone therapyCervical ultrasound and Tg evaluation with recombinant TSH

hould be done between the 6th and 12th month:

in patients who are in remission and at low risk of recur-

0.3–2 mU/l;in patients in remission but with cancer that shows less goodprognosis, maintain hormone therapy at a value close to thelower levels of normal (0.1–0.5 mU/l) for 5–10 years;

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in patients who are not cured, TSH is permanently maintainedat a value less than 0.1 mU/l.

. Monitoring during follow-up

.1. Biological monitoring: Tg level

Tg level is an essential parameter in the follow-up of patientsresenting with differentiated papillary thyroid and/or vesicularancer. It is a sensitive and specific marker whose measured levelainly reflects the differentiation of tumor tissue, the thyroid

issue mass and the degree to which the TSH receptors are stim-lated. Serum Tg should be measured with an immunometricssay (Tg-IMA) using a radioactive, enzymatic, or luminescentracer, standardized by the European reference standard (CRM57) that has a functional sensitivity less than 1 ng/ml (or �g/l).he assay variability remains notably high (recently estimatedt 37%), meaning that a patient should be followed up withhe same Tg reagent. The majority of the tests marketed todayave a functional sensitivity between 0.5 and 1 ng/ml. Certainew reagents propose a functional sensitivity close to 0.2 ng/ml,hich provides a precise measurement of low Tg concentrations.he functional sensitivity tests less than 0.1 ng/ml have a lowerpecificity, which may induce false-positive results.

Depending on the Tg test used, the presence of anti-Tg anti-odies in the blood induces a more or less substantial reduction.he systematic search for interferences using anti-Tg antibodies

s therefore necessary. There is no restriction as to the methodo use, as long as a quantitative method is used. The anti-Tgntibodies are reduced and disappear in patients in completeemission, but the time between the disappearance of the anti-en and the disappearance of the antibodies can be 2–3 years.hus, the persistence or the reappearance of circulating anti-Tgntibodies with an undetectable Tg level can be considered anndicator of disease persistence.

Tg is produced by both normal and cancerous thyroid cellsnd its production is controlled by TSH. Serum TSH shouldlways be measured when Tg is tested.

After complete surgical ablation and radioactive iodine treat-ent, the Tg level should be undetectable and any detectable

evel should alert the clinician. However, serum Tg can remainetectable for several months after surgery or radioactive iodinereatment. Therefore, Tg should not be measured less than

months after initial treatment. Assessment should take intoccount the Tg level and the progression of this level for theonsecutive tests.

The rare false-negative serum Tg results after TSH stimula-ion are for the most part attributable to small metastatic lymphodes that are demonstrated on cervical sonography.

Radioactive iodine ablation improves the specificity of theerum Tg test. In these patients, TSH stimulation improves sen-itivity without reducing specificity.

The stimulated Tg level is usually lower, by a factor of 1.5–2,
fter rh TSH than after TSH withdrawal.
Few data exist in the literature on the response thresholds toh TSH, that is, the level beyond which relapse can be demon-trated. An institutional threshold should be determined by each

5

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docrinologie 69 (2008) 472–486 479

enter in relation to the method used. The clinical significationf minimal rises in Tg with rh TSH are as yet unknown and needo be studied. In presence of anti-Tg Ac, the absence of a Tgesponse with rh TSH should be interpreted cautiously.

After the initial treatment, Tg and the search for associatednti-Tg antibodies should be tested every 6–12 months.

.2. Neck ultrasound

Neck ultrasound has become a key test in the initial workupnd follow-up of operated thyroid cancers. The procedure andhe results of this test should be standardized so as to limitubjectivity.

Neck ultrasound is an operator-dependent examination and aearning period can improve individual performance. It is moreensitive than palpation and is routinely used to verify lymphode chains and the thyroid bed. It can detect lymph nodes asmall as 2–3 mm in diameter. Benign lymph node hyperplasias frequent. For a lymph node that persists longer than severalonths, the specificity of cervical sonography is improved by

he study of the sonographic characteristics (shape, structure,ascularization, size). Lymph nodes that do not have worrisomeharacteristics warrant only one detailed description, with peri-dic ultrasound verification to reassure the patient. If a lymphode is sonographically suspicious, with a therapeutic decisiono make (notably surgical revision), the sonographic character-stics are not sufficiently discriminatory and ultrasound-guidedne-needle aspiration biopsy is required. If within a single areaeveral lymph nodes are considered suspicious, biopsy of one ofhese nodes is sufficient. A Tg test should be done on the washoutuid of any biopsy performed on lymph nodes suspected of

hyroid cancer metastasis.Six to 12 months after surgery, neck ultrasound should be

erformed to examine the thyroid bed and its central and lateralymph node compartments, whether or not there has been iodineblation treatment. It should be done again depending on the riskf relapse and the Tg level.

In low-risk patients, an annual ultrasound follow-up exami-ation after the first follow-up at 6–12 months is not warranted.hen the ultrasound results are normal, when the Tg level is

ndetectable after TSH stimulation, the risk of relapse is lesshan 1% at 10 years. Neck ultrasound is recommended if the Tgevel rises during follow-up. If ultrasound shows a lymph nodehat is clearly pathological, fine-needle aspiration biopsy and Tgesting on washout fluid are indicated.

In high-risk patients, ultrasound monitoring is advised buthere is no consensus as to the frequency of testing (1, 3, oryears?).

In lobectomies after chance discovery of a microcarcinoma,ltrasound monitoring of the remaining lobe and the lymph nodereas is proposed at 1 year, 3 years and 7 years if there are noigns of progression.

.3. 131I scintigraphy

131I is used as sodium iodide. Images are acquired throughcamera equipped with a high-energy collimator. The exam

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onsists in whole-body sweeping with static images centered onhe neck region and the thorax or any other region that has shown

pathological focus, with anterior and posterior incidence, ifecessary lateral images, with anatomic landmarks if possible.ameras equipped with SPECT/CT can be used; their fusion

mages can precisely localize pathological sites.Interpretation is visual. The abnormal uptake foci are defined

y the fact that this is not physiological uptake or artifacts. Theptake rate can be calculated.

The physiological uptake corresponds to tissue capable ofaking up and excreting sodium iodide. This is true in the sali-ary glands, the mouth and the nose, the stomach, the bladder,he thymus and, for certain young women, the mammary glands.rtifacts can stem from the test conditions or pathological situ-

tions (Table 5).131I uptake is low or absent during TSH suppression and

SH should be stimulated before every diagnostic or therapeu-ic 131I administration, obtained either during thyroid hormoneithdrawal or after exogenous rh TSH stimulation.

131I scintigraphy has long been one of the pillars of differenti-ted thyroid cancer monitoring, along with Tg level monitoring.ver the last few years, several studies have shown that the sen-

itivity was poor, on the order of 20% for diagnosis of relapse,uch lower than the sensitivity of Tg with TSH stimulation and

eck ultrasound. Furthermore, practically all patients with anbnormal whole-body scintigraphy have a detectable Tg levelfter TSH stimulation. Currently, the best definition of suc-essful ablation is an undetectable serum Tg level after TSHtimulation and a normal neck ultrasound.

Whole-body diagnostic scintigraphy is therefore not indi-ated for monitoring low-risk patients with an undetectableg level with TSH stimulation and normal neck ultrasound

esults, but can be used for patients at high risk of residualisease.

Scintigraphy remains useful for high-risk patients (pT3 orT4 tumor, adenopathy, or immediate metastasis) and when Tgs detectable and increases at successive testing. In these cases,he examination is done after administration of a high activityf 131I.

If anti-Tg antibodies persist at significant levels, monitor-ng is based on scintigraphy with a diagnostic activity and onltrasound.

.4. PET

PET is done with a dedicated PET camera and combined withmorpho-PET or PET–CT. The tracer used today is 18-FDG,

n analog of glucose marked by a positron transmitter, fluor-8. FDG uptake is not specific of the cancer. Inflammatory ornfectious lesions or granulomatosis lesions (e.g., sarcoidosis)lso take up FDG intensely.

Given the approximately 5-mm spatial resolution of PET,umors smaller than 5 mm cannot be visualized. For this rea-
on, PET performs less well than CT during forced inspirationr posttreatment scintigraphy with 131I in micronodular lungetastases or miliary-type metastases. The quality of the detec-
ion also depends on the FDG uptake by the tumor. Aggressive

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r poorly differentiated tumors generally take up more thanell-differentiated tumors.Interpretation of FDG-PET is foremost visual and qualitative.

n FDG exam is considered normal if there is no hypermetabolicocus considered as significant, in particular on regions at risk ofocal relapse (neck) or metastasis (lungs, bones). Quantificationy calculating the standard uptake value can be advantageous inrognosis or therapy follow-up.

FDG-PET is recommended after initial treatment of dif-erentiated thyroid cancer (surgery followed by 131I ablationreatment) when there is a confirmed and significant rise inhe Tg level and when scintigraphy with tracer or 131I therapys negative. FDG-PET can demonstrate neck or extracervicalesions, which are sometimes operable. Therefore, in these cir-umstances, it can be of interest for establishing diagnosisnd prognosis. It usefully completes the other imaging exams,ainly neck ultrasound, neck and thorax CT and MRI of the

ones or brain. Bone scintigraphy has low sensitivity.The advantages of FDG-PET are debated:

in establishing prognosis when there are metastases at theoutset (revealing cancer or diagnosed at the time of ablation),whether or not they take up 131I;when during monitoring, there is a confirmed high Tg level,whatever the results of the scintigraphy after tracer injectionor 131I therapy.

. Follow-up

.1. Objective

The objective of follow-up is early detection of recurrence.fter relapse, complete remission is obtained in two-thirds of1 patients and one third of M1 patients; the results depend on

he extension of the relapse. It is necessary to have availableensitive tests that allow early detection. Since relapses are notery frequent, the tests should have a high negative predictivealue to avoid unnecessary acts in cured patients.

.2. Follow-up procedure

.2.1. Short-term follow-up

.2.1.1. Patients treated with surgery alone. In very low-riskatients who did not have complementary treatment withadioactive iodine, the risk of persistent disease is by defini-ion very low. TSH stimulation, either with thyroid hormoneithdrawal or administration of rh TSH, is not recommended,articularly since, when radioiodine thyroid remnant ablationas not been done, the results are difficult to interpret. Follow-p is based on the serum Tg level during LT4 treatment and neckltrasound.

The same procedure is followed for patients treated withobectomy.

.2.1.2. Patients treated with total thyroidectomy and radioac-ive iodine. The strategy is summarized in the decision treeelow (Fig. 2).

F. Borson-Chazot et al. / Annales d’Endocrinologie 69 (2008) 472–486 481

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If whole-body scintigraphy done a few days after postsur-ical administration of radioactive iodine shows small thyroidemnants and no uptake other than in the thyroid bed, patientsre seen at 3 months (on LT4 treatment) for neck palpation andSH and Tg tests.

At 6–12 months, the disease condition is verified by clinicalxamination, neck ultrasound and serum Tg testing obtainedfter rh TSH stimulation (undertaken 3 days after the secondnjection of rh TSH).

Diagnostic radioactive iodine scintigraphy after administra-ion of rh TSH is only done in very special cases:

high-risk patients;postablation whole-body scintigraphy providing insufficientinformation (because of high uptake in the thyroid remnants)or showing suspicious uptake foci;persistence of anti-Tg antibodies.

A 150- to 185-MBq (4–5 mCi) 131I activity is administerednd the scintigraphy is done 2 days later. It is preferable to usecoincidence dual-head gamma camera equipped with high-

nergy collimators and thick crystals. Sweeping should be atlow speed (6–8 cm/min, for at least 30 min or 140,000 sweeps),ith images centered on each uptake focus. Thyroid hormone isithdrawn only if rh TSH is not available or cannot be purchased.Low-risk patients with normal neck ultrasound results and

ndetectable Tg after rh TSH are considered cured, because laterelapses are very rare (1% at 10 years).

When the neck ultrasound evidences anomalies, other testsre necessary, depending on the ultrasound characteristics: either

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ssociating total thyroidectomy and radioactive iodine.

follow-up ultrasound a few months later or ultrasound-guidedne-needle aspiration biopsy for cytology and Tg level in theiopsy product.

Patients with detectable serum Tg after rh TSH stimulationut a level lower than the institutional threshold (generallyetween 5 and 7 ng/ml) should undergo another rh TSH stimula-ion test 6–12 months later. If serum Tg becomes undetectable,he patient is considered to be cured. If the serum Tg levelncreases beyond its preceding level, disease relapse should benvestigated (see above).

.2.1.3. Patients with positive Tg. Serum Tg can remainetectable for a few months after the initial treatment and a highctivity of 131I should be administered only in patients whose Tgevel is over a certain threshold and has a tendency to increase.

In patients with high Tg levels after endogenous or exogenoush TSH stimulation or when Tg levels increase at successive testsn the same metabolic condition (during LT4 treatment or afterh TSH stimulation) and when there is no other evidence of dis-ase, a neck ultrasound and a CT scan of the neck and thorax areone and a therapeutic activity of 131I is administered. Whole-ody scintigraphy done 3–5 days after administration of a highctivity of radioactive iodine can identify neoplastic foci that hadot yet been revealed. Identification of the site of Tg productionan indicate appropriate therapeutic measures (surgery if there

In patients with negative posttherapy whole-body scintigra-hy, the administration of a high activity of 131I should not beepeated. Other diagnostic imaging tests should be done, notablyhoracic CT, MRI of the axial skeleton and FDG–PET.

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.2.1.4. Patients with anti-Tg antibodies. In patients withetectable levels of anti-Tg antibodies, undetectable serum Tgannot be interpreted as proof of remission. These patientshould be monitored periodically using diagnostic 131I scintig-aphy and neck ultrasound. Every time there is a suspicion ofetastasized disease, these patients should be explored by imag-

ng techniques such as cervicomediastinal CT, MRI of the axialkeleton and FDG–PET. Disappearance of anti-Tg antibodiesuring follow-up can itself be considered proof of remission.

.2.2. Long-term follow-upIn low-risk patients with no evidence of disease at follow-up

t 9–12 months, the LT4 dose is reduced (section 4). In patientsonsidered initially to be high risk, it seems more prudent toaintain serum TSH at a low level for several years. Even in

hese patients, the risk of relapse is low when there is no evidencef disease after a few years and they can then be reclassified asow risk.

Follow-up includes determining TSH and serum Tg levelsuring LT4 treatment with an annual clinical examination, pro-ided that there is no evidence of disease. Neck ultrasound is notystematic in patients who present no suspicions (section 5.2).

The utility of checking Tg after rh TSH stimulation and neckltrasound at 3–5 years requires confirmation. Follow-up shoulde maintained throughout life either in a specialized center ory an outside specialist depending on the local collaborativeetwork.

. Relapse treatment

.1. Managing locoregional recurrences and distantetastases

Three prognostic parameters predict survival at the relapsetage (locoregional recurrences and metastases): tumor volume,istological differentiation and age. Another factor should bedded to these three parameters – the tumor location – whichonditions the possibility of surgical excision and 131I uptake,llowing radioiodine treatment.

Remission can be obtained in approximately 60% of cases ofeck recurrence and 30 of distant metastases. The smaller theumors, the more complete these remissions are. This reflectshe importance of the initial management of the initial cancer athe locoregional level and of the monitoring thereafter to detecteck and metastatic recurrence early.

.2. Locoregional recurrences

The locoregional progression of the cancer can occur onymph node chains or in the thyroid bed. Lymph node recur-ences can be approached surgically with a low mortality rate,ontrary to surgical revision in the thyroid bed. Tumor massesre localized using imaging techniques (for the most part ultra-
ound, 131I and CT). Treatment is based on surgical revisionf the risk of morbidity related to the intervention is minimalompared to the expected benefit (eradication or reduction ofumor volume). In certain cases, surgery can be improved by
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ntraoperative use of detection probes (after administration of aose of 131I tracer). A therapeutic dose of 131I is indicated afterurgery as long as uptake persists or if surgical revision has noteen retained either because of the small size of the tumors orecause the location precludes any hope for satisfactory excisionithout complications. If surgery could not be macroscopically

omplete, radiotherapy can be used.

.3. Invasion of the visceral axis

Invasion of the neck’s visceral axis is rare. Surgical treatmenthould be considered because of the morbidity associated withrogression of this type of invasion and because of the absence ofon-surgical curative treatment in these cases. The indication forurgery depends on the weighted analysis of the morbidity andortality associated with surgery, the patient’s general health

nd the local progressive potential of the disease. Completeacroscopic resection (R0) is desirable. Certain cases can be

ffectively treated with superficial limited resections (shaving),hereas other cases require more or less extensive resections

nd/or reconstructions. These indications should be discussed inhe multidisciplinary consultation meeting. This surgery shoulde practiced by an experienced team.

.4. Metastases

.4.1. Lung metastasesIf the metastases take up 131I, conventional treatment is itera-

ive administration, under endogenous TSH stimulation (rh TSHoes not currently have approval to market for this indication),f 131I doses between 3.7 and 7.4 GBq every 4–12 months for therst 2 years, then with a longer interval depending on treatmentesponse.

Posttreatment whole-body scintigraphy done 2 to 5 days afterdministration of 131I and the monitoring of Tg values after TSHtimulation and under LT4 suppressive therapy can allow forollowing the treatment’s efficacy.

There is no maximum cumulative dose recommended for 131If lung metastases persist. However, remission is obtained in the

ajority of cases with cumulative doses less than or equal to2 GBq. Administration of a higher dose should be evaluatedn a case-by-case basis depending on the context (age, size ofetastases, existence of other associated metastases, speed of

rogression, etc.) and, in particular, the existence of lung fibrosishat limits the possibility of using 131I.

In certain special cases, other therapies can be considered:etastasectomy, endobronchial laser, or pleural or pericardiac

rainage.

.4.2. Bone metastasesThe therapy discussion should first and foremost take into

ccount the risk of fracture (in particular in weight-bearingones), the risk of neurological complications (location in the
ertebrae) and/or the existence of pain.
Whenever possible, bone metastases should first be eradi-ated or reduced (and consolidated for weight-bearing zones)ith surgery or other local treatments (injections of cement,

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adiofrequency, embolization). The 131I (5.5–11.1 GBq) isdministered after these local interventions if the metastatic 131Iptake. The use of corticosteroids at the time of 131I treatmenthould be taken into consideration, notably when there is local-zed pain or a neurological risk. External radiotherapy can bendicated in cases of no uptake for antalgic reasons. Wheneverossible, it should be done after the therapeutic administrationf 131I.

As a complement, a bisphosphonate treatment can be pro-osed.

.4.3. Brain metastasesBrain metastases are rare and carry a poor prognosis. Treat-

ent consists in surgical excision when possible. If surgery ismpossible and the target lesion is clearly limited, radiosurgeryγ unit) can be undertaken. If the metastases take up 131I aherapeutic administration can be given after surgery or in isola-ion if surgery is impossible. However, administration of 131I isoorly codified in this indication and should be done with cor-icotherapy, aiming to reduce the neurological risk. If surgery ismpossible and if there is no 131I uptake, conventional externaladiotherapy can be provided.

.5. Limits of therapeutic 131I use

It is not useful to continue (or undertake) 131I administrationsf locoregional recurrences and metastases do not take up 131Ind if Tg is undetectable. This indicates dedifferentiation of theumor masses.

.6. Conventional external radiotherapy

External radiotherapy is not a first-intention treatment sinceifferentiated cancers of the thyroid are not very radiosensitive.ts indication should be assessed in relation to the context (age,ain, metastasis size and progression). It can only be proposeds a complementary and palliative treatment on residual lesionsr locoregional recurrences and metastases that are not acces-ible to surgery and/or that do not take up 131I. It is done in5–30 sessions with five sessions per week for a total dose of0–60 Gy.

.7. Chemotherapies

Chemotherapies have not proved their efficacy in treating dif-erentiated thyroid cancers and their benefit on survival has noteen demonstrated. This type of treatment should be discussednly in cases of uncontrollable development after all other treat-ent possibilities have failed. The response hoped for is at best a

artial and transitory response in 20% of the cases using doxoru-icin alone or in association with cisplatin, with no lengthening
f survival shown.
A certain number of therapeutic trials using antiangiogenicrugs or anti-tyrosine kinase are being evaluated for this indica-ion.

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docrinologie 69 (2008) 472–486 483

External radiotherapy and/or chemotherapy should be dis-ussed on a case-by-case basis, on progressing lesions that areot accessible to surgery and 131I. In this type of tumor, usingDG-PET in staging is useful to select patients who could ben-fit from alternative therapies (or therapeutic trials): with tumorasses that take up 18-FDG considered more aggressive than

umors that are negative to 18-FDG.

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Guidelines for the management of differentiated thyroid carcinomas of vesicular origin

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