Northern Cancer Network Guidelines for Management of Thyroid Cancer

Northern Cancer Network Guidelines for Management of Thyroid Cancer

Clinical Oncology Clinical Oncology (2000)12:373±391 # The Royal College of Radiologists Review Article Northern Cancer Network Guidelines for Manag...

229KB Sizes 0 Downloads 18 Views

Clinical Oncology

Clinical Oncology (2000)12:373±391 # The Royal College of Radiologists

Review Article Northern Cancer Network Guidelines for Management of Thyroid Cancer Regional Thyroid Cancer Group* Newcastle upon Tyne, UK

Introduction A regional site-speci®c thyroid cancer group was set up in northeast England in 1993. Following the Calman±Hine report in 1995, this group became part of The Northern Cancer Network, which coordinates cancer services for North Cumbria, Northumberland, Tyne and Wear and North Durham. The Group's remit was to develop regional guidelines for the management of thyroid cancer and a minimum core Correspondence and offprint requests to: Dr U. K. Mallick, Regional Thyroid Cancer Group, Northern Centre for Cancer Treatment, Newcastle General Hospital, Westgate Rd, Newcatle NE4 6BE, UK. Guidelines Group Chairman Dr U. K. Mallick, Consultant Clinical Oncologist, NCCT Members Dr S. Ball, Consultant Endocrinologist, Royal Victoria In®rmary Dr J. D. Fenwick, Consultant Medical Physicist, Regional Medical Physics Department, NGH Dr R. A. James, Consultant Endocrinologist, Royal Victoria In®rmary Dr S. J. Johnson, Consultant Pathologist, Royal Victoria In®rmary Professor P. Kendall-Taylor, Professor of Endocrinology, University of Newcastle upon Tyne Mr T. W. J. Lennard, Consultant Surgeon, Royal Victoria In®rmary Dr H. H. Lucraft, Consultant Clinical Oncologist, NCCT Mr G. Proud, Consultant Surgeon, Royal Victoria In®rmary Dr P. Perros, Consultant Endocrinologist, Freeman Hospital Dr D. R. Weightman, Clinical Biochemist, SAS Laboratory. Medullary Thyroid Cancer Guidelines Group Dr S. Ball, Consultant Endocrinologist, Royal Victoria In®rmary, Dr F. Douglas, Consultant Clinical Geneticist, Regional Genetics Service, Mr T. W. J. Lennard, Consultant Surgeon, Royal Victoria In®rmary Abbreviations CPC, Clinical Pathological Conference FNA, ®ne needle aspiration IRMA, immunoradiometric assay MTC, medullary thyroid carcinoma NCCT, Northern Centre for Cancer Treatment NCN, Northern Cancer Network rhTSH, recombinant human TSH SAS, Supraregional Assay Service SST, somatostatin receptor T4, thyroxine T3, triiodothyronine TSH, thyroid-stimulating hormone WBS, whole-body scan

dataset for regular audit. The main objective was to improve and standardize thyroid cancer management. The thyroid cancer group is multidisciplinary, with representation from relevant clinical subspecialties. A guidelines subgroup was established in 1996. Draft guidelines were prepared by members from the surgical, clinical oncology, endocrinology and medical physics departments. Multidisciplinary guidelines were distilled from these and sent to all members of the group for wider consultation. The search methodology was based on published guidelines, reviews, expert opinions, consensus development conferences, large retrospective and observational studies. Clinical trials are rare in this disease. Evidence is available at levels 2 and 3 of AHCPR 1994. Therefore the recommendations are grades B and C. An extensive literature search following the methodology advised by NICE and SIGN was subsequently carried out. The guidelines were sent to national experts outside the group for comment before preparation of the ®nal version, which is given below. This guideline is scheduled for review in March 2001.

1. Terms of Reference This document provides a summary of the key recommendations for the management of thyroid cancer and medullary thyroid cancer. It is based on several international and national publications. As randomized trials are not available in this setting, evidence is based on large retrospective studies. Therefore, the level of evidence according to AHCPR 1994 is largely II±III This document is intended to provide guidance for all those who are involved in the management of patients with thyroid cancer. The evidence is not

discussed in this document. The full copy of the guidelines with references is available from the Northern Cancer Network. However, the following publications have signi®cant impact on the development of international practice guidelines:

2 Key Recommendations

1. AACE, Clinical Practice Guidelines for the Management of Thyroid Carcinoma, website http://www.aace.com/guidelines/thyroid cancer. html. 2. Mazzaferri E L, Jhiang S M. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97:418±428. 3. Schlumberger M J. Papillary and follicular thyroid carcinoma N Engl J Med 1998;338:297± 306. 4. Van De Velde CJH, Hamming JF, Goslings BM et al. Report of the consensus development conference on the management of differentiated thyroid cancer in the Netherlands. Eur J Cancer Clin Oncol 1988;24:287±292. 5. Robbins J, Merino MJ, Boice JD Jr et al. Thyroid cancer: a lethal endocrine neoplasm. Ann Intern Med 1991;115:133±147. 6. Taylor T, Specker B, Robbins J et al. Outcome after treatment of high risk papillary and nonHurthle-cell follicular thyroid carcinoma. Ann Intern Med 1998;129:622±627. 7. Singer PA, Cooper DS, Daniels GH et al. Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. American Thyroid Association. Arch Intern Med 1996;156:2165±2172. 8. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the US, 1985±1995. Cancer 1998;83:2638± 2648. 9. Wartofsky L, Sherman SI, Gopal J, Schlumberger M, Hay ID. The use of radioactive iodine in patients with papillary and follicular thyroid cancer. J Clin Endocrinol Metab 1998;83:4195± 4203. 10. Hay ID, Grant CS, Bergstralh EJ, Thompson GB, van Herdeen JA, Goellner JR. Unilateral lobectomy: is it suf®cient surgical treatment for patients with AMES low-risk papillary thyroid carcinoma? Surgery 1998;124:958±966. 11. Mazzaferri EL. An overview of the management of papillary and follicular thyroid carcinoma. Thyroid 1999;9:421±427.

The management of differentiated thyroid cancer (a highly curable disease) should be the responsibility of a specialist multidisciplinary team.

Copies of these documents can be obtained through the Northern Cancer Network Of®ce, Derwent Court, Freeman Hospital, Newcastle-upon-Tyne, NE7 7DN, UK. Tel: +191 223 1313. Fax: +191 223 1317. 374

Regional Thyroid Cancer Group

2.1 Access to a Multidisciplinary Thyroid Cancer Team

2.2 Patient Focus Patients should be offered full verbal and written information about their condition and their treatment. They should have continuing access to a member of the core team for guidance and support.

2.3 Surgery Surgery for thyroid cancer should be restricted to selected centres. The surgeons performing the operation should have expertise and interest in the management of thyroid cancers, be members of the multidisciplinary team, and maintain continuing professional development (CPD).

2.4 Radioiodine (I131) Therapy and External Beam Radiotherapy These treatments should be undertaken only in cancer centres where the facilities and expertise are available for administration of high-dose I131 and safe radiotherapy in selected cases. Oncologists with expertise and an interest in the management of differentiated thyroid cancers should supervise this treatment, be members of the multidisciplinary team, and maintain continuing professional development (CPD).

2.5 Follow-up This should be long term, as cure and prolonged survival are common even after tumour recurrence. Regular follow-up is necessary for the detection of early recurrences and appropriate treatment, TSH suppression, treatment of hypocalcaemia, etc. This can be undertaken by the thyroid specialist at the Cancer Unit, according to the network guidelines; results can then be forwarded to the responsible multidisciplinary team. Support and counselling are necessary, particularly for younger patients, and in relation to pregnancy in younger women.

3 Introduction 3.1 Facts and Figures . Cancer of the thyroid is the commonest endocrine malignancy but represents only about 1% of all cancers.

. The overall 10-year survival rate for middle-aged adults with differentiated thyroid carcinoma is about 80%±90%. . 5%±20% of patients develop local or regional recurrences and 10%±15% develop distant metastases. . Despite the general perception that the prognosis is excellent, about 9% of patients with thyroid cancer die of the disease. . Thyroid cancers account for approximately 65% of deaths attributable to malignant endocrine tumours. . In the UK incidence is reported at 0.7 per 100.000 males per year and 1.9 per 100.000 females per year. In the Northern Health Region approximately 40 new cases are likely to present every year.

3.2 Public Health and Prevention . Nuclear fall-out is a well recognized cause of an increase in the risk of thyroid cancer. Following the Chernobyl accident the incidence of thyroid cancer rose severalfold in children in the region. . Therapeutic and diagnostic X-rays are also possible causes. Apart from limiting exposure to radiation, no public health intervention has been shown to be of bene®t.

3.3 Screening At present there is no screening programme for the general population to detect thyroid cancer. Screening is possible for familial medullary thyroid cancers associated with speci®c genomic oncogene mutations. The genetic basis of well differentiated thyroid cancer is being investigated, particularly in the so-called familial cases. The following are considered to be risk factors for thyroid cancer: . . . . . . .

History of neck irradiation in childhood Endemic goitre Hashimoto's thyroiditis Family or personal history of thyroid adenoma Cowden's syndrome Familial adenomatous polyposis Familial thyroid cancer.

Although screening generally is not possible, a family history should be taken in each case of thyroid cancer and, if there is a strong familial incidence of thyroid cancer, or association with other cancers, genetic advice should be considered in appropriate cases from the Regional Genetics Service, at the International Centre for Life, Newcastle upon Tyne.

4 Diagnosis and Referral 4.1 Symptoms or Signs that Warrant Investigation Thyroid cancer usually presents with a lump in the neck. There may be no other symptoms or signs. The presence of associated symptoms may indicate that the tumour is more aggressive or has spread to a distant site.

4.2 The Presence of any of the Following may be Indications for Urgent Referral (Patient Preferably to be Seen within 2 Weeks) . Thyroid lump increasing in size . Unexplained hoarseness or voice change associated with a goitre . History of previous neck irradiation associated with a thyroid lump . Extremes of age . Cervical lymphadenopathy . The presence of stridor should evoke emergency referral.

4.3 Physical Examination The patient should have a full examination of the neck, focusing on inspection and palpation, including the region of the thyroid and lymph node groups in the neck. The pulse and blood pressure should be recorded.

4.4 Appropriate Investigations Pending Hospital Appointment Ultrasonography or isotope scanning arranged by the GP are likely to cause unnecessary delays in making a diagnosis and are unnecessary. Thyroid function tests should be requested by the GP. Patients with hyper- or hypothyroidism and a nodular goitre are unlikely to have thyroid cancer and should be referred routinely to an endocrinologist.

4.5 Who to Refer to? Patients should be referred to a surgeon or endocrinologist with specialist interest in thyroid cancer.

4.6 Multiprofessional Teams The care of all patients with thyroid cancer should be supervised by a multiprofessional team. The team is composed of professionals who have experience and expertise in the diagnosis and management of patients with thyroid cancer, from the following disciplines: clinical oncology, surgery, endocrinology, pathology, medical physics, clinical biochemistry and nursing. Management of Thyroid Cancer

375

The treatment plan for and care of each newly diagnosed patient should be discussed and supervised by a core team (oncologist, thyroid surgeon and endocrinologist) in consultation with other members of the multiprofessional team. This discussion should be recorded in the patient's records. Close communication between members of the multiprofessional team is key for delivering optimal care, and a joint clinic is the preferred format.

4.7 Hospital investigations Essential Assessments . . . .

Clinical examination Thyroid function studies Thyroid autoantibody status Fine needle aspiration biopsy (FNAB), with or without ultrasound scan guidance . Vocal cord examination (prior to surgery). NB: The measurement of serum thyroglobulin before thyroidectomy has no diagnostic value but may help future monitoring. Additional Investigations . Ultrasound scan: rarely diagnostic but may be of value in aiding ®ne needle biopsy . Respiratory function tests (¯ow±volume loop) if patient has symptoms of upper airway obstruction . MRI or CT: useful in assessing secondary disease . Chest X-ray: useful in assessing secondary disease . Isotope studies: usually non-diagnostic for the thyroid. Best reserved for special circumstances in the preoperative period, and also for postoperative assessment and treatment . Incisional biopsy: should never be carried out for differentiated thyroid carcinoma, for which ®ne needle aspiration should be regarded as the goldstandard diagnostic tool . Plasma calcitonin level may be requested in appropriate cases.

4.8 Communicating the Diagnosis Informing the Primary Care Team . The GP should be informed within 24 hours (by telephone or fax) of the diagnosis being communicated to the patient for the ®rst time. The GP should also be made aware of the information which has been given to the patient and, if possible, an outline of the planned treatment. . Subsequent alterations in prognosis, management or drug treatment of an outpatient should be communicated within 24±48 hours wherever possible. 376

Regional Thyroid Cancer Group

Informing the Patient . The patient should be informed of the diagnosis by a consultant or an appropriately experienced member of staff. . Facilities should be available for the patient to be informed of the diagnosis during a private, uninterrupted consultation. . Whenever possible a trained nurse specialist should be available during the consultation, and should be available to provide additional counselling if required. . Whenever possible a relative or close friend should be present during the consultation and the subsequent journey home. . Written information concerning thyroid cancer and its treatment should be available upon request. . A prognosis should not be offered before adequate staging information is available. . Patients may have dif®culty understanding all this information at a single consultation, and an opportunity for further explanation/discussion should be offered.

5 Timescale of Primary Treatment . All patients with signs suggestive of possible nodular thyroid tumour should be seen within 2 weeks of appropriate referral. . Urgent referrals will be seen sooner in response to speci®c requests. . Where possible the diagnosis and treatment decision should be made within 2 weeks of the ®rst consultation, although this may not be possible when surgery is required. . Appointment to see the clinical oncologist for discussion regarding I131 treatment should be available within 2 weeks of referral from the surgeon.

6 Overview of Treatment of Thyroid Cancer Aims of Treatment . Removal of all tumour and thyroid remnant surgically and by I131 ablation . TSH suppression with thyroxine replacement . Negative 131I scan . Undetectable serum levels of the serum marker thyroglobulin . No clinical or radiological evidence of recurrence . Minimal unwanted effects of treatment.

6.1 Standard Treatment of Differentiated Thyroid Cancer . Most patients will undergo thyroidectomy and I131 ablation. . Uptake in the thyroid bed or elsewhere is an indication for ablation using high-dose 131I. . Patients should be started on suppressive doses of T4 after ablation. . Further surgery or 131I treatment may be required for persistent or recurrent disease. . Reassessment with a challenge scan is indicated 3± 6 months after 131I ablation. . Differentiated thyroid cancer cells express receptors for thyroid-stimulating hormone (TSH), and elevated serum TSH concentrations are thought to have a trophic effect. Suppression of TSH secretion slows down the growth of thyroid cancer, and all patients should receive TSH suppressive thyroxine (T4) therapy. . External-beam radiotherapy and chemotherapy are occasionally used for patients with advanced disease. . Surveillance for recurrence of disease is based on: ± Clinical examination ± Measurement of serum thyroglobulin ± Whole-body scanning. The initial management of differentiated thyroid cancer is summarized in Fig 1.

6.2 Current Recommendations for Postsurgical Management of Differentiated Thyroid Cancers All new cases should be discussed by the multidisciplinary team . All histopathology for thyroid cancer should be reported or reviewed by a pathologist with an interest in thyroid cancers. . All cases should be staged by clinical and pathological TNM staging. Risk group de®nition may be done by the clinicians in addition in appropriate cases. Centres where differentiated thyroid cancer would be managed must have a multidisciplinary team consisting of surgeons, oncologist, pathologist, medical physicist, endocrinologist, biochemist, radiologist, specialist nurses if available, all with expertise and interest in the management of differentiated thyroid cancers. . Triiodothyronine (T3) is preferable thyroid hormone replacement to thyroxine (T4) at this stage, as the former is more likely to allow serum TSH to rise while minimizing hypothyroid symptoms. All patients should start on T3 20 mg tds (normal adult dosage) after the operation. This should be stopped for 2 weeks before an 123I scan is carried out, followed by 131I ablation of thyroid remnant.

. The vast majority of patients, particularly with a tumour size more than 1 cm in diameter, should have 131I remnant ablation. . Exclude pregnancy before administering all radioactive iodine. High-dose I131 would be administered for ablation of thyroid remnant as an inpatient procedure. . Following ablation, patients to start on T4 200 mg daily, 3 days after administration of 131I. Further adjustment of dose may be required depending on the serum TSH concentration. T4 is the preferred form of long-term thyroid hormone replacement. . A further 131I scan (challenge scan) should be performed 6 months after 131I ablation. In patients with very aggressive tumours this can be done after 3 months if clinically necessary. . Before a challenge scan, patients should switch from T4 to T3 replacement. After 2 weeks T3 should be withdrawn. The challenge scan is performed 2 weeks after T3 withdrawal. If signi®cant uptake of the tracer is detectable, a further 131I dose should be given. This is called a `therapy' dose (as opposed to `remnant ablation'), as the assumption is that either residual or recurrent tumour tissue is present (Fig. 2). . A post-treatment scan should be performed 7±10 days later, as this gives a better picture of abnormal tissues taking up 131I. . Following this patients should go back to T4 (same dose as prior to challenge scan). If there is a possibility of residual disease further scans should be carried out, usually 6 months later. If the ®rst challenge scan is negative, one more challenge scan should be done a year later. . Recombinant human TSH (rhTSH) should be used in place of stopping T3 or T4 in special cases where patients cannot tolerate severe hypothyroidism. The suitability of patients for rhTSH use should be determined by the multidisciplinary team. . During follow-up patients would have serum thyroglobulin measurement while on TSH suppression to monitor their progress. In some cases thyroglobulin might have to be measured after stopping thyroxine supplement, or after rhTSH stimulation, as in these situations thyroglobulin measurement is more sensitive. . Serum TSH level should be more than 30 mU/l and serum thyroglobulin level should be checked when the patient has stopped T3 just before a subsequent challenge scan. . Lifelong suppression of serum TSH level below normal is one of the main components of treatment. The level should be kept between 0.01 and 0.1 mU/ l. . In all newly diagnosed cases serum for thyroglobulin measurements should be sent to the Royal Victoria In®rmary in Newcastle, SAS laboratory, after surgery. . Patients should be on lifelong follow-up because: Management of Thyroid Cancer

377

(a) Late recurrences can occur, which can be successfully treated with a view to cure or long-term survival. (b) The disease has a long natural history. (c) Late side-effects of 131I treatment should be monitored. (d) The consequences of supraphysiological T4 replacement need monitoring.

6.3 Management of Other Rare Malignancies of the Thyroid . Hurthle cell carcinoma: all cases should be discussed in the CPC. Routine radioiodine ablation may not be indicated. MIBG or PET scanning may be helpful. Prognosis may be worse than for follicular carcinoma. . Lymphoma will be managed by the Regional Lymphoma Unit. Open biopsy is required. Total thyroidectomy is not indicated. Chemotherapy and radiotherapy or radiotherapy alone are standard treatments. . Medullary thyroid cancer, when diagnosed, is subject to management and investigation according to the protocol (section 19). . Anaplastic thyroid cancer has a very poor prognosis. 131I therapy has no place. Externalbeam radiotherapy and palliative surgery may be useful.

7 Surgery 7.1 Preparation for Surgery . Informed consent should be obtained from all patients; the operating surgeon should obtain the consent. . The possible complications of thyroidectomy should once more be discussed and recorded. At this stage the speci®c complications of thyroid surgery should be discussed, as well as complications that can occur in any surgical procedure. . Thromboembolism prophylaxis should be used in all cases in the form of graduated compression hose (TED stockings) and perioperative calf compression devices. It is usually inappropriate to use heparin preparations. . Vocal cord examination is generally recommended prior to surgery. The need for this is to be audited.

7.2 Elective Surgical Treatment for Thyroid Cancer . Various descriptors are used for thyroid surgery. Only the following will be used in this document. `Lobectomy' and `thyroidectomy' are the only operations described, and the only descriptors applied to these two procedures will be `total' and `subtotal'. 378

Regional Thyroid Cancer Group

. It is recommended that cervical lymph nodes should be searched for during the dissection and all apparently involved nodes removed, particularly those in the pre- and paratracheal region and any lying in the line of the carotid sheath on each side of the neck. Other nodal groups in the neck may require excision, including supraclavicular nodes and occipital nodes when these are involved. Extensive nodal neck dissection by formal block dissection is not normally appropriate. . An adequate ®ne needle aspiration (FNAB) sample of the nodule is required for planning surgery. Reporting Format for FNA of Thyroid AC0 Unsatisfactory ± no epithelial cells AC1 Unsatisfactory ± scanty epithelial cells, no diagnosis possible AC2 Benign ± adequate number of epithelial cells (six or more groups) with no atypia AC3 Equivocal ± atypia of epithelial cells. Written comment will be given AC4 Suspicion of malignancy AC5 Diagnostic of malignancy. Surgery should be planned based on the above ®ndings, as follows: . The unsatisfactory FNA (AC0 or 1) An unsatisfactory FNA obtained from a thyroid nodule should be repeated, perhaps under ultrasound guidance. . Benign (AC2) lesion Where the surgeon has doubt about the cytologically `benign, AC2' lesion because of its clinical performance, then lobectomy is indicated. In general this will be total lobectomy. . AC3 (equivocal) and AC4 (suggestive of malignancy) lesions Lobectomy is indicated: ± if histology of the lobectomy specimen shows malignancy, further surgery may be appropriate according to the type and size of tumour (see below) ± if benign, observe or discharge depending on the pathology report . AC5 (diagnostic of malignancy) lesion De®nitive surgery can be planned for these lesions (see below). De®nitive Surgery Follicular carcinoma . Under 1 cm and minimally invasive: total lobectomy and long-term TSH suppressive thyroxine therapy . Lesion over 1 cm and/or widely invasive, completion total thyroidectomy followed by 123I scan, 131I ablation (if appropriate) and long-term TSH suppression with T4. If showing extrathyroidal spread, removal of all identi®able central neck nodes and any other nodes that may be involved is necessary.

Papillary carcinoma . As with follicular cancer, a small microcancer, i.e. less than 1 cm in diameter, total lobectomy is appropriate followed by TSH suppression with T4. . For larger papillary cancers, for familial papillary microcancers, for multifocal cancers and for extrathyroidal spread, total thyroidectomy with removal of all involved nodes, followed by 123I diagnostic scanning, 131I ablation (if appropriate) and long-term TSH suppression with T4. . Total thyroidectomy is also indicated where there is a history of previous neck irradiation. . The indications for lobectomy only are likely to be exceptional. When a microcancer is suspected, preoperative discussion at either the CPC or the joint clinic is essential prior to operative intervention.

7.3 Emergency Surgery It is rare for emergency surgery to be needed. Usually a careful work-up of patients is achievable. Stridor and airway complications represent the likely need for emergency surgery.

7.4 Surgery for Locally Advanced Disease In locally advanced disease it may not be possible to remove the entire tumour without damaging both recurrent laryngeal nerves. A small residue of tumour may be left behind in these rare instances, to be dealt with by iodine ablation and subsequent TSH suppression with T4, with or without external-beam radiotherapy.

8 Postoperative Care 8.1 Preparation for Pre-ablation Scan A pre-ablation scan will usually be performed after thyroidectomy to assess the presence of thyroid remnant or persistent disease (Fig. 1). For optimal imaging the serum TSH concentration should be allowed to rise to >30 mU/l (this stimulates tracer uptake by thyroid tissue). To achieve this, thyroid hormone withdrawal is necessary (the use of rhTSH is not recommended at this stage in the management of thyroid cancer). The thyroid hormone T3 is used initially for a period of 4±6 weeks (T3 has a lower capacity to suppress TSH than T4, but minimizes hypothyroid symptoms). T3 is withdrawn for a further 2 weeks before the scan. The majority of patients (>90%) demonstrate some uptake in the thyroid bed after surgery which requires 131I ablation. The tracer 123 I (rather than 131I) is used in the ®rst scan as it is less likely to compromise subsequent 131I ablative therapy (`stunning' effect). Subsequent scans will normally utilize 131I tracer (much cheaper, and

possibly yielding a more sensitive scan than 123I), given that the likelihood of further treatment is low. . Immediately after surgery thyroid hormone replacement with T3 (20 mg tid) should be initiated and the patient should be referred to the oncologist for a pre-ablation scan. . The patient should be seen by the oncologist (preferably in the joint clinic) for assessment and full discussion about radioiodine studies and treatment. Informed consent to be given by the patient before treatment. . A pre-ablation scan will be arranged and a cubicle booked in the radiotherapy department prospectively for the week after the scan, in anticipation of 131 I ablation. . A pre-ablation 123I scan will be performed 6±8 weeks after thyroidectomy in order to assess the completeness of the procedure and the need for ablative 131I therapy (Fig. 1). . In the rare instance of patients undergoing a lobectomy only (i.e. radioiodine ablation not being contemplated), a postoperative scan is unnecessary; however, these patients should receive suppressive T4 therapy.

8.2 Postoperative

131

I Ablation

Rationale . Destroys microscopic foci of carcinoma cells within the thyroid remnant, thereby reducing the risk of local recurrence in the neck. . Aids the interpretation of serum thyroglobulin measurements during follow-up, as patients become totally athyrotic. . Aids detection of persistent or metastatic disease by destruction of remaining normal tissue. Remnant Ablation with

131

I

. Routine postoperative ablation of thyroid remnant with 131I has been shown to reduce local recurrence and improve survival in the vast majority of differentiated thyroid cancers, particularly tumours more than 1 cm in diameter. . There is controversy as to whether thyroid cancers should be divided into high-risk and low-risk groups. Proponents of selective 131I ablation advise that only high-risk groups should be given 131 I ablation routinely, and in the low-risk group optimal surgery with full TSH suppression might be suf®cient. . Because of the safety and tolerability of 131I ablation it is recommended that well differentiated thyroid cancers greater than 1.0 cm should receive postoperative 131I ablation if a thyroid remnant is demonstrated on scanning. . The usual ablation dose is 3000 MBq. Management of Thyroid Cancer

379

Procedure for

131

I Therapy and Aftercare 131

I therapy, ward . After admission to NCCT for procedures should be followed and the patient discharged after medical physics assessment. At the time of discharge, advice should be given to restart T4 as appropriate and a handwritten letter to the GP must go with the patient. . Following this patients will be seen in the joint clinic usually after 6 weeks, for assessment, TSH suppression adjustment and arrangements for further follow-up thyroglobulin and scans. . Information lea¯ets (Appendix II) and appropriate support from specialist nurses should be provided.

8.3 Challenge Scan (131I 150 MBq) WBSs postablation are referred to as `challenge scans'. After ablation a challenge scan should be done between 3 and 6 months. If this is negative, one more challenge scan should be done a year later. If this is also negative no further routine challenge scans need be done unless there are other indications of disease progression, such as rising thyroglobulin (provided there is no antibody interference and it has been undetectable previously), clinical signs of progression or radiological evidence of progression. Chest X-ray should be done only occasionally after routine challenge scans are stopped, keeping in mind that this is less sensitive for detecting early disease than are iodine studies. During active treatment, particularly with radioiodine, patients would have open access to the clinic, the ward where iodine treatment was given, specialist nurses or the clinician's secretary.

8.4 Management of Hypocalcaemia . Ionized calcium should be checked the day after surgery, and daily until stable. . If hypocalcaemia develops (ionized calcium <1.0 mmol/l) or the patient becomes symptomatic at a higher calcium level, commence calcium supplementation, i.e. Titralac, 9 6 420 mg tablets per day in divided doses, or its equivalent in alternative preparations. . If hypocalcaemia does not improve, or worsens, introduce a-calcidol at suggested starting dose of 3 mg per day, adjusting up or down according to response. . Close monitoring of ionized calcium is needed to ensure hypercalcaemia does not develop. . Monitoring of calcium should be done in the specialist clinic, with assistance by the GP if appropriate. . After total thyroidectomy 30% of patients will need calcium supplementation + a-calcidol; by 3 months only 2% of patients will still require calcium supplementation. 380

Regional Thyroid Cancer Group

8.5 Long-term Thyroid-Stimulating Hormone (TSH) Suppression . T4 should be used in preference to T3 for long-term suppression. . The initial dose of T4 should be 200 mg daily. . The dose of T4 should be adjusted by 25 mg every 6 weeks until the target serum TSH concentration is reached (concentration 0.01±0.1 mU/l). . Suppressive T4 therapy is best supervised by an endocrinologist.

8.6 Measurement of Serum Thyroglobulin . Thyroglobulin is a speci®c and extremely useful tumour marker that is secreted by both normal and cancerous thyroid cells. In patients who have not had a total thyroidectomy and 131I ablation the interpretation of serum thyroglobulin measurements is limited by the inability to differentiate between a tumour and a thyroid remnant source. . In patients who have been treated with total thyroidectomy and 131I ablation detectable serum thyroglobulin is highly suggestive of residual or recurrent tumour. . The diagnostic sensitivity of serum thyroglobulin measurements is enhanced by an elevated TSH concentration. It is therefore imperative that thyroglobulin is measured in conjunction with challenge scans, when T4 therapy has been withdrawn. . Thyroglobulin has a long serum half-life and should not usually be measured more frequently than 3-monthly during routine follow-up. . Serum thyroglobulin should be measured by a sensitive assay which includes assessment of autoantibody interference. The current IRMA adopted by the SAS laboratory in Newcastle should preferably be used.

8.7 Short- and Long-Term Side-Effects of 131 I Therapy . Neck discomfort with swelling immediately after treatment can rarely occur. It is more common when a large thyroid remnant is present. A short course of steroids may be necessary. . Nausea, sialoadenitis, radiation cystitis, radiation gastritis, bleeding in secondary deposits, oedema in cerebral secondaries are extremely rare. . Pregnancy should be deferred for 1 year after highdose 131I. There is no risk to fertility or normal pregnancies as long as the pregnancy is deferred beyond 1 year. . Pretreatment sperm banking should be considered in patients likely to have repeated treatments. . The incidence of leukaemia and second cancers is extremely low (0%-0.4% in published series).

9 External-Beam Radiotherapy

12 Pregnancy and Thyroid Cancer

This is used infrequently. The main indications are:

12.1 Diagnosis of Thyroid Cancer in Pregnancy

. High-grade tumours that do not concentrate radioactive iodine. . Gross evidence of local invasion at surgery and presumed to have signi®cant macro- or microscopic residual disease after operation, particularly if it does not take up radioactive iodine. . For recurrent disease in neck which is not amenable to 131I therapy or further surgery. . For palliation of recurrent disease or metastatic disease in bone, cerebrum, spine and other areas. . For locally advanced tumours which are inoperable for a variety of reasons it can be used for palliation along with TSH suppression.

10 Palliative Chemotherapy Chemotherapy has no role in the routine management of early differentiated thyroid carcinoma. Its role is restricted to end-stage disease uncontrolled by surgery, radioiodine or external-beam radiotherapy for palliation. Effective agents are doxorubicin and cisplatinum. The partial response rates are, at best, 20%±30%. It should only be used in very select cases, in the context of a clinical trial.

11 Recurrent Disease . For recurrences in the neck in particular surgical reexploration is the preferred method of management, usually in combination with 131I or externalbeam radiotherapy. . Metastatic disease involving lung and other soft tissue areas not amenable to surgery should be treated with 131I if the tumour readily takes up radioactive iodine. Long-term survival is still possible. . Further therapy for metastatic disease is usually 5000 MBq. . Bone metastases should be treated by a combination of external beam radiotherapy, 131I or orthopaedic intervention. . In patients with rising thyroglobulin in the absence of a positive radioiodine scan the treatment options are: (a) Further imaging with MRI, CT or PET scanning (b) Empirical treatment with 131I followed by post-treatment scan.

Women of childbearing age with thyroid cancer generally have a very good prognosis. A thyroid nodule presenting during pregnancy should be investigated by FNAB. Radionuclide scans are contraindicated. If thyroid cancer is diagnosed or suspected, the following options should be considered: . Defer thyroidectomy and 131I studies and treatment until the postpartum period. . Suppressive T4 therapy during the remaining pregnancy, and thyroidectomy and 131I studies and treatment in the postpartum period. . Thyroidectomy during pregnancy, followed by 131I studies in the postpartum period. . Termination of pregnancy followed by thyroidectomy and 131I studies and treatment. (The last two options are very rarely necessary.) The management of these cases requires careful consideration of risks to mother and fetus. Discussion of the case by the multidisciplinary team and joint clinic, as well as counselling of the couple, is imperative. In most cases the tumour is not aggressive and it is reasonable to allow the pregnancy to continue. Thyroidectomy in the ®rst trimester of pregnancy carries a very high risk of abortion. Suppressive thyroxine therapy may be considered until surgery. In cases of advanced or aggressive disease delays in treatment would be undesirable and termination of the pregnancy must be discussed with the couple. Radioiodine therapy must be avoided in pregnancy.

12.2 Pregnancy in the Treated Patient . Pregnancy should be avoided for 1 year after 131I ablation and treatment. . Suppressive T4 therapy should continue during pregnancy. . Thyroid function tests should be monitored regularly to ensure that TSH remains suppressed, as T4 requirements may change during pregnancy.

13 Thyroid Cancer in Childhood Thyroid cancer in childhood is rare and the prognosis may be slightly worse. The principles of diagnosis and management are similar to those for adult thyroid cancer, but the team looking after the child should include a paediatric endocrinologist and the paediatric oncologist. Management of Thyroid Cancer

381

14 Record Keeping The information required for the Northern Thyroid Cancer Audit and Cancer Registry must be clearly recorded in the patient's notes. The following should be recorded: . . . . . . . . .

Family history Surgeon, assistant, anaesthetist Extent of surgery Side-effects of surgery The presence or absence of metastases FNA, histology and pTNM staging Curative or palliative intent Details of radioiodine therapy and side-effects Follow-up arrangements.

15 Histopathology Requirements for Histopathological Reports of Differentiated Neoplasms Pending publication of minimum datasets for thyroid carcinoma reporting by the Royal College of Pathologists, it is recommended that local reports in cases of differentiated thyroid neoplasms contain the following points. Many of these features affect staging and prognosis and may therefore in¯uence clinical management decisions. Macroscopic Report Nature of specimen ± lobectomy

± partial, .subtotal or .total left or .right .+ isthmus ± thyroidectomy.± subtotal or total

Weight of specimen Dimensions of specimen Description of ± single or multifocal lesion(s) ± dimensions ± left or right location ± solid or cystic ± con®ned to gland or invasion of adjacent structures Accompanying sites ± site (if stated) of lymph nodes ± number ± macroscopic involvement? Microscopic Report For all tumour types ± single or multiple ± greatest dimensions (of largest lesion if multiple) ± con®ned to gland or invasion of extrathyroidal structures ± completeness of local excision ± any lymph node involvement 382

Regional Thyroid Cancer Group

Additional points for speci®c types Papillary carcinoma ± typical or variant type ± presence or not of lymphatic or vascular invasion Follicular neoplasm ± presence or not of capsular invasion (8±10 blocks ± presence or not of vascular including capsule) invasion ± presence or not of invasion of adjacent thyroid tissue ± minimally invasive or widely invasive type ± presence and proportion of Hurthle cell change Medullary ± presence of amyloid carcinoma ± uniformity of labelling on immunohistochemistry for calcitonin

Staging pTl 1±<4 cm pT3 >4 cm pT4 extension N0 N1

no nodes involved regional nodes involved (cervical or .upper mediastinal) NX .cannot assess nodal involvement M0 .no distant metastases M1 .distant metastases MX cannot assess distant metastases

Adjacent Thyroid . Presence of any additional disease process (eg. nodular goitre, thyroiditis, Graves' disease) . Presence of C-cell hyperplasia in cases of medullary carcinoma . Any parathyroids included?

16 Long-term Follow-up . Regular follow-up is necessary for the detection of early recurrences and appropriate treatment, TSH suppression, treatment of hypocalcaemia etc. This can be undertaken by the thyroid specialist at the Cancer Unit, according to the network guidelines; results can then be forwarded to the responsible multidisciplinary team. Support and counselling are necessary, particularly for younger patients, and in relation to pregnancy in younger women. . Frequency of attendance to be decided in each case: usually 3-monthly for the ®rst 2 years, decreasing to 6-monthly for 3 years, and annually thereafter.

At each visit: . Clinical examination . Assessment of adequacy of TSH suppression . Measurement of thyroglobulin as a marker of tumour recurrence . Measurement of serum calcium if indicated . If tumour recurs, 131I scanning, and other modalities of investigation, i.e. MRI, implemented, but on an individually planned basis.

17 Palliative Care Palliative care is not necessary in the vast majority of patients with differentiated thyroid cancer because they are cured. However, in a very small proportion of patients with recurrent and end-stage disease, and also in anaplastic thyroid cancers, specialist palliative care help would be necessary. A consultant in palliative medicine with a special interest in treating this should also liaise with the multidisciplinary team. The special symptoms of stridor and fear of choking are very distressing and can be alleviated by pharmacological means, palliative surgery and counselling. These patients should be referred early to the local palliative care team.

18 Audit The NCN Thyroid Cancer Group is engaged in discussion with other groups in the country to decide on a uniform dataset for thyroid cancer registration and audit nationally.

19 Guidelines for Management of Medullary Thyroid Cancer (MTC) MTC is a rare disease (accounts for 5%-10% of all thyroid cancers) that requires a dedicated multidisciplinary regional service. Developments in the molecular genetics of MTC have facilitated a rational framework for management. However, the use and interpretation of molecular diagnostics is dif®cult, requiring application to the individual patient context. The biology of MTC has unique implications for the development and structure of clinical services and management of this unusual disease. The factors that contribute to this are: . 25% of MTC is familial, necessitating a comprehensive and integrated approach to both the patient and their family. . MTC may arise as part of a familial endocrine cancer syndrome, requiring additional monitoring and management.

. Patient survival may be many years, even with signi®cant tumour burdens, making the risk/bene®t decisions for additional intervention dif®cult. . Clinical services for MTC should dovetail with those for MEN-1 and MEN-2, which require similar services, and address common issues.

19.1 History . MTC may present with a lump in the neck or metastasis, or with the systemic effects resulting from the coincident secretion of calcitonin (frequent loose stools and vasomotor ¯ushing) or, less commonly, adrenocorticotrophin (ACTH). . The diagnosis may be made following ®ne needle aspiration (FNAB) of a thyroid nodule or lymph node, in the absence of previous clinical suspicion. Unsuspected MTC can be found at surgery. . In all cases a comprehensive family history must be taken for other members of the kindred with features of MTC or other endocrinopathies of the MEN-2 spectrum. This should include a history of unexpected sudden death, which should raise the suspicion of occult phaeochromocytoma.

19.2 Hospital Investigation The aims of investigation are: . Establish a baseline value for tumour markers that will aid longer-term follow-up. . Monitor for coincident, linked endocrinopathies that may be part of a wider familial endocrine cancer syndrome. . Potentially establish the molecular basis for the disease within an individual or kindred, aiding in designating the index as a sporadic or familial case, and forming the basis of a future genetic screening programme. . Preoperative diagnosis should include baseline values for calcitonin and carcinoembryonic antigen. . Even in the absence of a positive family history or symptoms, all patients should have coincident phaeochromocytoma and hyperparathyroidism excluded by appropriate biochemical investigation. . A preoperative diagnosis of MTC should trigger appropriate staging of the disease with abdominal, thoracic and neck CT. Whether this should be performed when the diagnosis is made or postoperatively should be guided by the value of tumour markers. Some MTCs are positive on MIBG scanning. . Pentavalent 99mTc DMSA scan also has a place in detecting recurrent disease. Management of Thyroid Cancer

383

19.3 Treatment

19.5 Molecular Genetics

Surgery

. 25% of MTC is familial, inherited as autosomal dominant traits within the spectrum of MEN. . The presence of a family history suggestive of MEN-2 should prompt referral for RET gene analysis and genetic screening. However, given that any case may represent the herald case of a new kindred, the absence of a family history should not be taken as reassurance that a familial cancer syndrome is excluded. . Due consideration should be given to referral to a consultant in cancer genetics with expertise in contact tracing and genetic counselling. Ideally, this should be in close relationship with an endocrine surgery/endocrinology team with appropriate skills. . Features suggestive of a familial cause in the absence of a family history are: ± early age at presentation (less than 40) ± multifocal disease within the thyroid ± the presence of C-cell hyperplasia on histological examination. . The interpretation of both somatic and germline molecular genetic data needs to be made with caution, and with appropriate reference to the clinical context. This is particularly important when the data have implications for the continued screening, either biochemical or genetic, of the index patient and/or other members of the family.

. The primary treatment modality is total thyroidectomy and central node dissection. In the presence of disseminated disease surgery can still be considered for palliative purposes. The same approach is appropriate for persistent or recurrent disease. . Prophylactic surgery must be considered for disease-free carriers of germline RET mutations, identi®ed by genetic screening programmes of affected kindred. Data would indicate that this is optimally performed before the age of 7, though the decision is balanced by the dif®culty of the procedure and associated morbidity in younger patients. Radiotherapy and Chemotherapy . Routine adjuvant external-beam radiotherapy has not been shown to improve survival. . Radiotherapy may have limited role in controlling local symptoms in cases of inoperable or secondary disease. . Chemotherapy is generally ineffective and is used very rarely for disseminated disease. . Therapeutic MIBG might be useful in a small number of cases. . Treatment with any of these modalities should preferably be within a clinical trial. Palliative Care . In the absence of an evidence base for improvements in survival, medical therapy should concentrate on symptom control. . Gastrointestinal symptoms often respond well to Lomotil and/or codeine phosphate. Somatostatin receptor analogues are an attractive alternative which can decrease tumour peptide release.

19.4 Follow-up Long-term follow-up is recommended: . The response to primary surgery can be assessed clinically, and by the measurement of tumour markers. . The presence of an elevated but stable calcitonin level postoperatively may be managed conservatively. Progressively rising levels should trigger imaging for further staging. In the absence of recurrent symptoms, appropriate intervals are 6±12 months. . Because of the long natural history of the disease the optimum duration of follow-up and evidencebased criteria for a de®nition of `cure' and discharge remain to be clari®ed. 384

Regional Thyroid Cancer Group

In appropriate cases tumour samples can be analysed for the presence of somatic RET mutations, found in some 30%±40% of sporadic MTC. This is best done in close liaison with an experienced endocrine pathologist, who can aid in de®ning samples likely to contain only tumour DNA. A request for this analysis should be accompanied by a peripheral blood sample, to allow comparison of genetic and germline genotypes. As this technology and application to the management of MTC has only recently been developed, is labour intensive and expensive, its value requires close monitoring. The following are suggested pragmatic guidelines for the management of the family of an isolated case of MTC without a family history: . First-degree relatives should be offered clinical and biochemical screening. The logistics of family tracing and the ethics of contacting need careful consideration and coordination. Ethical guidelines currently used by clinical genetics units are clear in this area. . The presence of multifocal disease within the thyroid at presentation, and/or the presence of Ccell hyperplasia in the index case, should prompt referral for germline RET analysis.

. A sample of the tumour should be analysed for the presence of speci®c codon mutations involving the RET gene. . Absence of biochemical expression in the relative of an index case after the age of 40, together with both the absence of germline RET mutations and the presence of a somatic mutation in the tumour of the index case of the kindred, is suggestive of sporadic disease. The incidence of MTC in such individuals approaches that of the background population. . In the absence of such data, clinical and biochemical screening of ®rst-degree relatives of an index case can be extended to the age of 50. Fig. 2. Summary of procedure for challenge scan.

20 Patient Support Groups BACUP 3 Bath Place Rivington Street London EC2A 3JR UK British Thyroid Foundation PO Box 97 Clifford Wetherby West Yorkshire LS23 6XD UK

21 Patient Information Lea¯ets Thyroid Cancer What is Cancer? The tissues of the body are made up of cells. Cells repair and reproduce in the same way. Sometimes the growth of cells gets out of control. Then cells create a lump known as a tumour. Tumours are either benign or malignant. Benign tumours do not spread to other parts of the body. Malignant tumours are made up of cancer cells. Cancer can spread to other parts of the body, causing a `secondary tumour' or `metastasis'. Cancer is not one disease. There are more than 200 different types of cancer. Each type has a different name and requires different treatment. Thyroid Cancer Cancer of the thyroid usually grows very slowly. Modern treatment is very successful. Most patients are completely cured even if the cancer has spread outside the thyroid gland. Types of Thyroid Cancer . Papillary ± this is the most common, particularly in women and younger people. . Follicular ± this is a less common cancer and is more often found in older people. . Medullary - this is a rare type known to run in some families. If your family is affected your relatives may have to be screened to ensure they show no signs of the disease. . Anaplastic ± this type of cancer is usually found in older people. It tends to grow more rapidly. The Thyroid Gland

Fig. 1. Summary of therapeutic and diagnostic procedures in ®rst 2 months from diagnosis of thyroid cancer.

The thyroid is a small gland in the front of the neck just below the voice box (larynx). It produces two hormones, thyroxine (T4) and triiodothyronine (T3). These are required to keep the body functioning Management of Thyroid Cancer

385

normally. This gland requires a regular supply of iodine. If your thyroid does not produce enough hormones you will feel lethargic and gain weight easily (hypothyroidism). If there is overproduction of the hormone the opposite will occur.

useful for you to know what to expect. You will feel normal again when you start taking thyroxine, although this may take a few weeks. The following are frequent symptoms of hypothyroidism (an underactive thyroid gland).

Causes of Thyroid Cancer

. . . . . . .

The cause of this cancer is unknown. Cancer of the thyroid is sometimes found in people who have had radiotherapy to the neck 10±20 years previously. Also, following the Chernobyl accident its incidence has increased signi®cantly in nearby areas. Surgery The ®rst treatment for thyroid cancer is an operation. People whose cancer is diagnosed and removed early have an excellent chance of being cured. Sometimes surgery is the only treatment necessary. Most patients will also need radioactive iodine treatment.

Radioactive Iodine Treatment (Internal radiotherapy, iodine-131, radioiodine) Introduction In order to destroy all cancer cells after the operation, you may need treatment with radioactive iodine. This is the same as that used in the thyroid scan, but given in a larger dose. It is a way of giving radiotherapy internally. Thyroid cells absorb the iodine very quickly. Thyroid cancer cells receive a high dose of radiation which destroys them. Radioactive iodine does not affect other parts of your body. For this treatment you will be admitted to Ward 37 at the Northern Centre for Cancer Treatment, Newcastle General Hospital. Admission days are Tuesdays and Fridays, usually. Preparation for Radioiodine Scan and Treatment Before treatment with radioactive iodine a scan will be done. This will help decide whether radioactive iodine treatment is needed. To prepare you for your scan you will have to follow a set schedule. If you are taking thyroxine (or `T4') tablets, they will have to be stopped. Instead, you will be given another thyroid hormone tablet called `T3' (it is also known as `triiodothyronine' or `liothyronine'). T3 is usually prescribed for 2 weeks. Then no thyroid hormone medication is allowed for 2 weeks. Your scan will be done at the end of this 4-week period. If it shows that no radioactive iodine treatment is needed, the thyroxine tablets will be restarted. If radioactive iodine treatment is needed thyroxine will be started again after the radioactive iodine treatment. During the 4-week period before your scan, your thyroid will become underactive (`hypothyroid'). Most people develop some symptoms of hypothyroidism, particularly in the last 2 weeks before the scan. In some cases the symptoms can be severe. It may be 386

Regional Thyroid Cancer Group

Weight gain Constipation Tiredness Dry skin and hair Cold hands and feet Mood changes Physical and mental slowness.

It is advisable to eat a diet high in ®bre. Taking a laxative such as senna to avoid constipation will also help. While you are hypothyroid your re¯exes may slow down. If you drive, you should be more careful than usual. You should avoid long journeys and high speeds. You should consider taking time off work if: . you hold a professional driving licence . your job involves operating heavy machinery . your work requires rapid decision making. You should avoid leisure or other activities that: . are dangerous . demand high physical and mental stamina. You should put off making very important decisions (either in your personal life or at work) until you have recovered. If the symptoms are very severe please discuss this with your general practitioner or consultant. Admission On the day of admission you will have nothing to eat or drink for 3 hours before the radioactive iodine capsule. After swallowing the radioactive capsule you will not be allowed to drink for 1 hour. No eating is allowed for another 212 hours. You may want to bring in books or magazines to occupy your time. You will be shown to one of two cubicles. One has an en suite bathroom. If there are two patients in for this treatment the bathroom is shared. The furniture will be covered with polythene. This is to prevent absorbing radioactivity from sweat. The cubicles have televisions and access to a coin-operated telephone. Side-effects This treatment makes you slightly radioactive for about 4±5 days. During this time the radioactivity will be lost from your body in your urine, blood, saliva and sweat. While you are in hospital your level of radioactivity will be measured. You will be discharged when the levels are safe. You are unlikely to feel any symptoms from this treatment. Your property will NOT be radioactive at the time of discharge. Radioactive iodine treatment does not interfere with a normal pregnancy. Pregnancy should be delayed for

about a year from having radioactive iodine treatment. The risk of leukaemia or other cancers following radioactive iodine treatment is extremely small. Food Foods which have a high iodine content (seafood, watercress, and foods containing red food colouring) should be avoided during your stay in hospital. Iodine in the food can interfere with radioactive iodine treatment. You are expected to wash up your own crockery, which will stay in the room. Hospital Stay The length of your stay is decided by the level of radioactivity. It is usually 4±5 days. Strict Visiting For the visitors' own safety visiting is restricted to half an hour per person per day. Anyone 18 years and under, or pregnant women, must NOT visit.

Thyroid Cancer: A Guide for the Primary Care Physician Raising Awareness . Thyroid nodules, particularly when solitary and clinically obvious, should be investigated as they carry a small but signi®cant malignant potential (about 10%).

Prevention Apart from limiting exposure to radiation, no public health intervention has been shown to be of bene®t. . Nuclear fall-out is a well recognized cause of increased risk of thyroid cancer. . Therapeutic and diagnostic X-rays are possible causes.

Screening General screening: no screening programme for general population Risk-directed screening should be considered (by referral to the specialist secondary team) when the primary care physician identi®es patients with: . Familial medullary thyroid cancers . History of neck irradiation in childhood . Familial thyroid cancer. The following carry a statistically increased risk of thyroid malignancy but no screening is recommended:

. . . . .

Endemic goitre Hashimoto's Thyroiditis Family or personal history of thyroid adenoma Cowden's syndrome Familial adenomatous polyposis.

Diagnosis and Referral Usual presentation is of a complaint of a lump in the neck. There may be no other symptoms or signs. . The presence of associated symptoms may indicate a more aggressive or advanced disease. Such symptoms include, hoarseness due to vocal cord palsy, distant bone pain, cervical lymphadenopathy (usually deep cervical or supraclavicular region) or airway obstruction causing stridor. . Patients should be referred to a surgeon or endocrinologist who are members of the regional thyroid cancer multidisciplinary team.

Physical Examination . Full examination focusing on inspection and palpation of the thyroid and neck, movement of the nodule with swallowing, and palpation of the deep cervical nodes and all other node groups in the neck, especially supraclavicular nodes.

Appropriate Investigations Pending Hospital Appointment . Initiation of investigations (such as ultrasound scanning or autoantibodies) by the primary care physician is unnecessary and is likely to cause a delay in making a diagnosis. . Thyroid function tests should be obtained and appended in the referral letter. Hyper- or hypothyroidism associated with a nodular goitre is unlikely to be thyroid cancer. Patients with thyroid dysfunction and a nodular goitre should be referred routinely to an endocrinologist.

Follow-up Whether the general practitioner is directly involved with the clinical follow-up or not he/she should ensure: . Multidisciplinary follow-up ± necessary for the detection of early recurrences and complications and their appropriate treatment . Patient has continuing access to a member of the core team for guidance and support. Management of Thyroid Cancer

387

Algorithm for Diagnosis & Management of Thyroid Cancer

Bibliography AACE, Clinical Practice Guidelines for the Management of Thyroid Carcinoma, website http://www.aace.com/guidelines/thyroid cancer.html. Akslen L, LiVolsi VA. Prognostic signi®cance of histologic grading compared with subclassi®cation of papillary thyroid carcinoma. Cancer 2000;88:1902±1908. Ayala C, Navarro E, Rodriguez JR, Silva H, Venegas E, Astorga R. Conception after I131 therapy for differentiated thyroid cancer. Thyroid 1998;8:1009±1011. Bal C, Padhy AK Jana S et al., Prospective randomised clinical trial to evaluate the optimal dose of I131, for remnant ablation in patients with differentiated thyroid carcinoma. Cancer 1996;77:2575±2580. Baudin E, Travagli JP, Ropers J et al. Microcarcinoma of the thyroid gland: the Gustave-Roussy Inst experience. Cancer 1998;83:553±559. Bi J, Lu B. Advances in diagnosis and management of thyroid neoplasms. Curr Opin Oncol 2000;12:54±59. Brennan MD, Bergstralh EH, Heerden JA, McConahey WM. Follicular thyroid cancer treated at the Mayo Clinic 1946± 1970. Initial manifestation, pathologic ®ndings, therapy and outcome. Mayo Clin Proc 1991;66:11±22, Brierley J, Tsang R, Simpson WJ. Medullary thyroid cancer: analyses of survival and prognostic factors and the role of radiation therapy in local control. Thyroid 1996;6;305±311. Britton KE, Foley RR, Siddiqi HJ, Canizales A et al. I123 Imaging for the prediction of I131 therapy for recurrent differentiated thyroid cancer, RDTC when I131 tracer is negative but raised thyroglobulin. Eur J Nucl Med 1999;26:Abstract 09±212. Brown AP, Greening WP, McCready VR, Shaw HJ et al. Radioiodine treatment of metastatic thyroid cancer. Royal Marsden Experience. Br J Radiol 1984;57:324±27. Cady B. Presidential address: Beyond risk group ± a new look at differentiated thyroid cancer. Surgery 1998;124;947±957. Cailleux AF, Baudin E, Travagli JP, Ricard M, Schlumberger

388

Regional Thyroid Cancer Group

M. Is diagnostic I131 scanning useful after total thyroid ablation for differentiated thyroid cancer? J Clin Endocrinol Metab 2000;85:175±178. Canadian Task Force on the Periodic Health Examination. Screening for thyroid disorders and thyroid cancer in asymptomatic adults. Health Canada; Jan 1994;612±618. Casara D, Rubello D, Saladini G et al. Pregnancy after high therapeutic doses of iodine-131 in differentiated thyroid cancer: potential risks and recommendations. Eur J Nucl Med 1993;20:192±194. Cavalieri RR. Nuclear imaging in the management of thyroid carcinoma. Thyroid 1996;6:385±391. Chigot JP. Management of thyroid metastasis. Ann Endocrinol 1997;58:335±337. Chopra S, Wastie ML, Chan S et al. Assessment of completeness of thyroid ablation by estimation of neck uptake of I131 on whole body scans: comparison of quanti®cation and visual assessment of thyroid bed uptake. Nucl Med Commun 1996;17:687±691. Chung JK, So Y, Lee JS et al. Value of FDG PET in papillary thyroid carcinoma with negative I131 whole body scan. J Nucl Med 1999;40:986±992 Clark OH, Hoelting T. Management of patients with differentiated thyroid cancer who have positive serum thyroglobulin levels and negative radioiodine scans. Thyroid 1994;4:501±505. Coburn M, Teates D, Wanebo HJ. Recurrent thyroid cancer ± role of surgery versus radioactive iodine I131. Ann Surg 1994;219:587±595. Coleman PM, Babb P, Damiecki P et al. Cancer survival trends in England and Wales 1971±1995: deprivation and NHS region London: Stationery Of®ce, 1999 (Series SMPS No. 61); 471±478. Cooper DS, Specker B, Ho M et al. Thyrotropin suppression and disease progression in patients with differentiated thyroid cancer: results from the National Thyroid Cancer Treatment Cooperative Registry. Thyroid 1998;8:737±744. De-Groot LJ, Kaplan EL, McCormick M, Straus FH. Natural history, treatment and course of papillary thyroid cancer. J Clin Endocrinol Metab 1990;71:414±424. Di-Russo G, Kern KA. Comparative analysis of complications from I131 radioiodine ablation for well-differentiated thyroid cancer. Surgery 1993;116:1024±1030. Dottorini ME, Lomuscio G, Mazzuchelli L et al. Assessment of female fertility and carcinogenesis after iodine I131 therapy for differentiated thyroid carcinoma. J Nucl Med 1995;36:21±27. Dulgeroff JA, Hershman JM, Medical therapy for differentiated thyroid carcinoma. Endocr Rev 1994;15:500±515. Edmonds CJ, Smith T. The long term hazards of treatment of thyroid cancer with radioiodine. Br J Radiol 1986;59:45±51. Emerick GT, Duh QY, Siperstein AE et al. Diagnosis, treatment and outcome of follicular thyroid carcinoma. Cancer 1993;72:3287±3295. Eng Charis. Editorial: Familial papillary thyroid cancer ± many syndromes, too many genes? J Endocrinol Metab 2000;85:1755±1757. Evans DB, Fleming JB Lee JE et al. The surgical treatment of medullary thyroid carcinoma. Semin Surg Oncol 1999;16:50±63. Falk SA, McCaffrey TV. Management of recurrent laryngeal nerve in suspected and proven thyroid cancer. Otolaryngology Head Neck Surg 1995;113:42±48. Flower MA, Schlesinger T, Hinton P J et al, Radiation dose assessment in radioiodine therapy to practical implementation using quantitative scanning and PET with initial results of thyroid carcinoma. Radiother Oncol 1989;15:345±357. Gilliland Frank D, Hunt WC, Morris DM et al. Prognostic factors for thyroid carcinoma. A population based study of 15,698 cases from the surveillance, epidemiology and end results (SEER) Programme 1973±1991, Cancer 1997;79:564±573. Grigsby PW, Baglan K, Siegel. Surveillance of patients to detect recurrent thyroid carcinoma. Cancer 1999;85;945± 951.

Grunwald F, Menzel C, Bender H et al. Re-differentiation therapy-induced radioiodine uptake in thyroid cancer. J Nucl Med 1998;39:1903±1906. Guimaraes V, DeGroot LJ. Moderate hypothyroidism in preparation for whole body I131 scintiscans and thyroglobulin testing. Thyroid 1996;6:69±73. Harkness JK, Norman, Thompson W et al. Differentiated thyroid carcinoma in children and adolescents. World J Surg 1992;16:547±554, Harmer CF, MacReady VR. Thyroid cancer: differentiated carcinoma. Cancer Treat Rev 1996;22:161±177 Harmer C, Bidmead M, Shepherd S et al. Radiotherapy planning techniques for thyroid cancer. Br J Radiol 1998;71;1069±1075. Haugen BR, Pacini F, Reiners C et al. A comparison of recombinant human thyrotropin and thyroid hormone withdrawal for the detection of thyroid remnant or cancer. J Clin Endocrinol Metab 1999;84:3877±3855. Hay ID, Bergstralh EJ, Grant CS et al. Impact of primary surgery on outcome in 300 patients with a pathologic tumour-node-metastasis stage III papillary thyroid carcinoma treated at on institution from 1940±1989. Surgery 1999;126:1741±1782 Hay ID, Bergstralh EJ, Goellner JR, Bersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: Development of reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940±1989. Surgery 1993;114:1050±1058. Hay ID, Grant CS, Van Heerden JA, et al. Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50 year period. Surgery 1992;112:1139±1147. Hay ID, Papillary thyroid carcinoma. In: Sheares R, Jenkins PJ, Wass JAH, eds. Clinical endocrine oncology, Oxford 1997;117±122. Hay ID, Grant CS, Bergstralh EJ, Thompson GB, van Herdeen JA, Goellner JR. Unilateral lobectomy: is it suf®cient surgical treatment for patients with AMES low-risk papillary thyroid carcinoma? Surgery 1998;124:958±966. Hay, ID. Papillary thyroid carcinoma. Endocrinol Metab Clin North Am 1990;19:545±576. Henry WD, Humm JL, Larson SM. Radioiodine uptake in thyroid remnants during therapy after tracer dosimetry. J Nucl Med 2000;41:1082±1085. Heptulla R A, Schwartz R P, Bale A E et al. Familial medullary thyroid carcinoma: pre symptomatic diagnosis and management in children. J Pediatr 1999;135:327±331. Hodgson DC, Brierley JD, Tsang RW et al. Prescribing 131 iodine based on neck uptake produces effective thyroid ablation and reduced hospital stay. Radiother Oncol 1998;47:325±330. Hoskins PJ, Harmer CL. Chemotherapy for thyroid cancer. Radiother Oncol 1987;10:187±194. Houlston SA, Stratton MR. Genetics of non-medullary thyroid cancer. Q J Med 1995;88:685±693. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the US, 1985±1995. Cancer 1998;83:2638±2648. Ivanov VK, Tsyb AF, Gorsky AI et al. Leukaemia and thyroid cancer in emergency workers of the Chernobyl accident: estimation of radiation risks (1986±1995). Radiat Envir Biophys 1997;35:9±16. Jana S, Dayem H M, Young I. Nuclear medicine and thyroid cancer. Eur J Nucl Med 1999;26:1528±1532. Johansen K, Woodhouse NJY, Odugbesan O. Comparison of 1073 MBq and 3700 MBq iodine 131 in post operative ablation of residual thyroid tissue in patients with differentiated thyroid cancer. J Nucl Med 1991;32:252±254 Kaplan EL. Endocrine surgery. J Am Coll Surg 1999;188:118± 126. Kebebew E, Ituarte PH, Siperstein AE, Duh QY, Clark OH. Medullary thyroid carcinoma: clinical characteristics, treatment, prognostic factors, and a comparison of staging systems. Cancer 2000;88:1139±1148.

Keh-Chuan Loh. Familial non-medullary thyroid carcinoma: a meta-review of case series. Thyroid 1997;7:107±113. Kim JH, Leiber RD. Treatment of locally advanced thyroid carcinoma with combination doxorubicin and radiation therapy. Cancer 1987;60:2372±2375. Koong SS, Reynolds JC, Movius EG et al. Lithium as a potential adjuvant to I131 therapy of metastatic, well differentiated thyroid carcinoma. J Clin Endocrinol Metab 1999;84:912±916. Kuhel WI, Ward RF. Thyroid cancer in children. Lancet 1995;346:719±720. Kuijpens JL, Hansen B, Hamming JF et al. Trends in treatment and long-term survival of thyroid cancer in southeastern Netherlands, 1960±1992. Eur J Cancer 1998;34:1235±1241. Ladenson PW, Braverman LE, Mazzaferri MD et al. Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma. N Engl J Med 1997;337:888±895. Laundau D, Vini L, Hern R A, Harmer C. Thyroid cancer in children: the Royal Marsden Hospital experience. Eur J Cancer 2000;36:214±220. Leeper RD. Thyroid cancer. Med Clin North Am 1990;19:1079±1096. Leger FA, Izembart M, Dagousset F et al. Decreased uptake of therapeutic doses of iodine 131 after 185 MBq iodine 131 diagnostic imaging for thyroid remnants in differentiated thyroid carcinoma. Eur J Nucl Med 1998;25:242±246. Lerch H, Schober O, Kuwert T, Saur HB. Survival of differentiated thyroid carcinoma studied in 500 patients. J Clin Oncol 1997;15:2067±2075. Lin JD, Huang MJ, Juan JH, Chao TC et al. Factors related to the survival of papillary and follicular thyroid carcinoma patient with distant metastases. Thyroid 1999;9:1227±1235. Lin JD, Kao PF, Chao TC. The effects of radioactive iodine in thyroid remnant ablation and treatment of well differentiated thyroid carcinoma. Br J Radiol 1998;71:307±313. LiVolsi VA. Well differentiated thyroid carcinoma. Clin Oncol 1996;8:281±288. Loh KC, Greenspan FS, Gee L et al. PTNM staging for papillary and follicular thyroid carcinoma: a retrospective analysis of 700 patients. J Clin Endocrinol Metab 1997;82:3553±3562. Lukinac L, Francheschi M, Nothig-Hus D et al. Endogenously labelled thyroid hormones (I131±T3±T4) in sera of patients with differentiated thyroid carcinoma. Thyroid 1996;6:201± 206. Lupoli G, Vitale G, Craglia M et al. Familial papillary thyroid microcarcinoma: a new clinical entity. Lancet 1999; 353:637±639. Massin JP, Savoie JC, Garnier H et al. Pulmonary metastases in differentiated thyroid carcinoma±study of 58 cases with implications for the primary tumour treatment. Cancer 1984;53:982±992. Maxon HR, Englaro EE, Thomas SR et al. Radioiodine-131 therapy for well differentiated thyroid cancer ± a quantitative radiation dosimetric approach: outcome and validation in 85 patients. J Nucl Med 1992;33:1132±1136. Maxon HR. Quantitative radioiodine therapy in the treatment of differentiated thyroid cancer. Q J Nucl Med 1999;43:313± 323. Maxon HR, Thomas SR, Hertzberg VS et al. Relation between effective radiation dose and outcome of radioiodine therapy for thyroid cancer. N Engl J Med 1983;309:937±941. Maxon HR, Thomas SR, Samaratunga RC et al. Dosimetric considerations in the radio iodine treatment of macro metastases and micro metastases from differentiated thyroid cancer. Thyroid 1997;7:183±187. Maxon HR. Detection of residual and recurrent thyroid cancer by radionuclide imaging. Thyroid 1999;9:443±446. Mazzaferri EL. Thyroid remnant I131 ablation for papillary and follicular thyroid carcinoma. Thyroid 1997;7:265±271. Mazzaferri EL, Jhiang SM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 1994;97:418±428. Management of Thyroid Cancer

389

Mazzaferri EL. An overview of the management of papillary and follicular thyroid carcinoma. Thyroid 1999;9:421±427. Mellemgaard A, From G, Jorgensen T et al. Cancer risk in individuals with benign thyroid disorders. Thyroid 1998;8:751±754. Morris JC, Kim CK, Padilla ML, Mechanick JI. Conversion of non-iodine-concentrating differentiated thyroid carcinoma metastases into iodine concentrating foci after anticancer chemotherapy. Thyroid 1997;7:63±66. Nishida T, Nakao K, Hamaji M et al. Preservation of recurrent laryngeal nerve invaded by differentiated thyroid cancer. Ann Surg 1997;22:85±91. Noguchi S, Murakami N, Yamashita H, et al. Papillary thyroid carcinoma: modi®ed radical neck dissection improves prognosis. Arch Surg 1998;133:276±280. Norstrand D, Neutze J, Atkins F. Side effects of rational dose iodine I131 therapy for metastatic well-differentiated thyroid carcinoma. J Nucl Med 1986;27:1519±1527. O'Connell MEA, Flower MA, Hinton PJ, et al. Radiation dose assessment in radioiodine therapy. Dose-response relationships in differentiated thyroid carcinoma using quantitative scanning and PET. Radiother Oncol 1993;28:16±26. Pittas A G, Adler M, Fazzari M et al. Bone metastases from thyroid carcinoma. Clinical characteristics and prognostic variable in 146 patients. Thyroid 2000;10:261±268. Pacini F, Gasper M, Fugazzola L et al. Testicular function in patients with differentiated thyroid carcinoma treated with radio iodine. J Nucl Med 1994;35:1418±1422. Pacini F, Cetani F, Miccoli P et al. Outcome of 309 patients with metastatic differentiated thyroid carcinoma treated with radioiodine. World J Surg. 1994;18;600±604. Park HM, Park YA, Jhow X H Detection of thyroid remnant/ metastases with stunning ± an ongoing dilemma. Thyroid 1997;7:277±280. Pochin EE. Prospects of treatment of thyroid carcinoma with radioiodine. Clin Radiol 1967;18:113±125. Pochin EE. Radioiodine therapy of thyroid cancer. Semin Nucl Med 1971;1:503±515. Rall J E, Alpers J B, Lewallen C G, Sonenberg M, Berman M, Rawson R W. Radiation pneumonitis and ®brosis: a complication of radioiodine treatment of pulmonary metastases from cancer of the thyroid. J Clin Endocrinol Metab 1997;17:1263±1276. Ramanna L, Waxman A, Braunstein G. Thallium-201 scintigraphy in differentiated thyroid cancer: comparison with radioiodine scintigraphy and serum thyroglobulin determinations. J Nucl Med 1991;32:1441±1446. Reiners C, Farahatti J. I131 therapy of thyroid cancer patient. Q J Nucl Med 1999;43:324±335. Reston (VA) Society of Nuclear Medicine: Procedure guideline for extended scintigraphy for differentiated thyroid cancer. 1999. (Society of Nuclear Medicine Procedure Guidelines: version 2.0 Reston VA Society of Nuclear Medicine. Procedure guideline for thyroid scintigraphy. 1999. Society of Nuclear Medicine Procedure Guidelines; version 2.0 Richards MA, Stockton D, Babb P, Coleman MP. How many deaths have been avoided through improvements in cancer survival. Br Med J 2000;320:895±898. Riddell VH. Injury to recurrent laryngeal nerves during thyroidectomy. Lancet 1956;2:608. Ringel MD, Balducci-Silano PL, Anderson JS et al. Quantitative reverse transcription polymerase chain reaction of circulating thyroglobulin messenger ribonucleic acid for monitoring patients with thyroid carcinoma. J Clin Endocrinol Metab 1999;84:4037±4040. Ringel MD, Ladenson PW, Levine MA. Molecular diagnosis of residual and recurrent thyroid cancer by ampli®cation of thyroglobulin messenger ribonucleic acid in peripheral blood. J Clin Endocrinol Metab 1998;83:4435±4442. Robbins J, Merino MJ, Boice JD Jr et al. Thyroid cancer: a lethal endocrine neoplasm. Ann Intern Med 1991;115:133± 147. Robbins RJ, Hill RH, Wang W, Macapinlac HH, Larson S.

390

Regional Thyroid Cancer Group

Inhibition of metabolic activity in papillary thyroid carcinoma by a somatostatin analogue. Thyroid 2000;10:177±183. Robie DK, Dinauer CW, Tuttle RM, et al. The impact of initial surgical management on outcome in young patients with differentiated thyroid cancer. J Pediatr Surg 1998;33:1134± 1140. Ron E, Lubin JH, Shore RE et al. Thyroid cancer after exposure of external radiation: a pooled analysis of seven studies. Radiat Res 1995;141:259±277. Ronga G, Fiorentino A, Paserio E, Signore A, Todino V. Can I131 whole body scan be replaced by thyroglobulin measurement in the post-surgical follow-up of differentiated thyroid carcinoma. J Nucl Med 1990;31:1766±1771. Roos DE. Randomised trials on radiactive iodine ablation of thyroid remnants for thyroid carcinoma ± a critique. Int J Radiat Oncol Biol Phys 1999;44:493±495. Rosen HN, Moses AC, Garber J et al. Randomised trial of pamidronate in patients with thyroid cancer. Bone density is not reduced by suppressive doses of thyroxine but is increased by cyclic intravenous pamidronate. J Clin Endocrinol Metab 1998;83:2324±2330. Rossi RL, Majlis S, Rossi RM; Thyroid cancer. Surg Clin North Am 2000;80:571±580. Ryu KY, Senokozlieff ME, Smanik PA et al. Development of reverse transcription-competitive polymerase chain reaction method to quantitate the expression levels of human sodium iodide symporter. Thyroid 1999;9:405±409. Samaan NA, Schultz PN, Hickey RC et al. The results of various modalities of treatment of well differentiated thyroid carcinomas: a retrospective review of 1599 patients. J Clin Endocrinol Metab 1992;75:714±720. Sanders LE, Cady B. Re-examination of risk group and outcome of treatment. Arch Surg 1998;1332:419±425. Sanders LE, Cady B. Differentiated thyroid cancer. Arch Surg 1998;133:419±425. Sanders LE, Silverman M. Follicular and Hurthle Cell carcinoma ± predicting outcome and directing therapy. Surgery 1998;124:967±974. Schlumberger MJ, Mancusi F, Baudin E, Pacini F. I131 therapy for elevated thyroglobulin levels. Thyroid 1997;7:273±275. Schlumberger MJ. Papillary and follicular thyroid carcinoma. N Engl J Med 1998;338:297±306. Schlumberger M, Challeton C, De Vathaire F et al. Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma. J Nucl Med 1995;37:598±605. Schlumberger M, Parmentier G, Delisle MJ et al. Combination therapy for anaplastic giant cell thyroid carcinoma. Cancer 1991;67:564±566. Schlumberger JP Travagli P, Fragu P et al. Follow-up of patients with differentiated thyroid carcinoma. Experience at Institut Gustave-Roussy, Villejuif. Eur J Cancer Clin Oncol 1988;24:315±350. Schlumberger M, De Vathaire F, Ceccarelli C et al. Exposure to radioiodine (I131) for scintigraphy or therapy does not preclude pregnancy in thyroid cancer patients. J Nucl Med 1996;37:606±612. Schmutzler C, Kohrle J. Retinoic acid redifferentiation therapy for thyroid cancer. Thyroid 2000;10:393±406. Shaha AR. Natural history, management strategies (surgery, XRT and RADI and outcomes. ASTRO presentation October 1998, Phoenix, Arizona. Shaha AR, Shah JP, Loree TR. Low risk differentiated thyroid cancer: the need for selective treatment. Ann Surg Oncol 1997;4:328±333. Sherman SI, Brierly JD, Spurling M et al. Prospective multicentre study of thyroid carcinoma treatment, initial analysis of staging and outcome. Cancer 1998;83:1012±21. Shimaoka K, Schoenfeld DA, Dewyes WD et al. A randomised trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 1985;56:2155±2160. Shi W, Johnston CF, Buchanan KD et al. Localisation of

neuroendocrine tumours with (111In) DTPA octreotide scintigraphy (Octreoscan): a comparative study with CT and MR imaging. Q J Med 1999;91:295±301. Simoes MS. Hail to the histologic grading of papillary thyroid carcinoma? Cancer 2000;88:1902±8. Simpson WJ, Panzarelli TSE, Carruthers JS et al. Papillary and follicular thyroid cancer. Impact of treatment in 1578 patients. Int J Radiat Oncol Biol Phys 1988;14:1063±1075. Singer PA, Cooper DS, Daniels GH et al. Treatment guidelines for patients with thyroid nodules and well-differentiated thyroid cancer. Arch Intern Med 1996;156:2165±2172. Sisson JC, Giordano TJ, Jamadar DA, et al. Treatment of micronodular pulmonary metastases from papillary thyroid carcinoma. Cancer 1996;78:2184±2192. Smithers DW. Some varied applications of radioactive isotopes to the localisation and treatment of tumours. Acta Radiol 1951;35:49±61. Spencer CA, Takeuchi M, Kazarosyan M et al. Serum thyroglobulin autoantibodies: prevalence, in¯uence on serum thyroglobulin measurement and prognostic signi®cance in patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab 1998;83:1121±1127. Staunton M D, Bourne H. Malignant thyroid tumours 1932± 1972: the outcome of 492 patients. Eur J Surg Oncol 1992;18:469±474. Staunton MD. Thyroid cancer, a multivariate analysis on in¯uence of treatment on long-term survival. Eur J Surg Oncol 1994;20:613-621. Surveillance, Epidemiology and End Results (SEER) programme of the National Cancer Institute. J Nat Cancer Inst 1997;89:1753. Sweeney DC, Johnston GS. Radioiodine therapy for thyroid cancer. Endocrinol Metab Clin North Am 1995;24:803±839. Taylor T, Specker B, Robbins J et al. Outcome after treatment of high risk papillary and non-Hurthle-cell follicular thyroid carcinoma. Ann Intern Med 1998;129:622±627. Tennvall MD, Lundell G, Hallquist A, et al. Combined doxorubicin, hyperfractionated radiotherapy, and surgery in anaplastic thyroid carcinoma. Cancer 1994;74:1348±1354. Teppo L, Hakulinen and Eurocare Working Group. Variation in survival of adult patients with thyroid cancer in Europe. Eur J Cancer 1998;34:2238±2252. Thompson NW. Thyroidectomy: indications for its use in welldifferentiated thyroid carcinoma. Abstracts from the Proceedings of the International Symposium on Thyroid and Parathyroid Tumours, 24±27 March 1999, Pisa, Italy. Angusti T, Codegone A, Pellerito R, Favero A. Thyroid cancer prevalence after radioiodine treatment of hyperthyroidism. J Nucl Med 2000;41:1006±1009. Tronone L, Ru®ni V. 131I-MIBG therapy of neural crest tumours (review). Anticancer Res 1997;17:1823±1831. Tsang RW, Brierley JD, Simpson WJ, Panzarella T, Gospodarowiczz MK, Sutcliffe SB. The effects of surgery, radioiodine and external radiation therapy on the clinical outcome of patients with differentiated thyroid carcinoma. Cancer 1998;82:375±388. Tubiana M, Hadad E, Schlumberger M et al. External radiotherapy in thyroid cancers. Cancer 1985;55:2062±2071. Udelsman R, Iakatos E, Larenson P. Optimal surgery for papillary thyroid carcinoma. World J Surg 1996;20:88±93. US Dept of Health Human Services. Agency for Health Care Policy and Research. Acute pain management: operative or

medical procedures and trauma. Rockville (MD): The Agency, 1992. Clinical Practice Guideline No. 1 AHCPR Publication No. 92-0023 p. 107. Van De Velde CJH, Hamming JF, Goslings BM et al. Report of the consensus development conference on the management of differentiated thyroid cancer in the Netherlands. Eur J Cancer Clin Oncol 1988;24:287±292. Vassilopoulou-Sellin R, Palmer L, Taylor S, Cooksley CS. Incidence of breast carcinoma in women with thyroid carcinoma. Cancer 1999;85:696±705. Vassilopoulou-Sellin R, Schultz N, Haynie TP. Clinical outcome of patients with papillary thyroid carcinoma who have recurrence after initial radioactive iodine therapy. Cancer 1996;78:493±501. Vathaire de F, Schlumberger M, Delisle M J et al. Leukaemia and cancers following iodine 131 administration for thyroid cancer. Br J Cancer 1997;75:734±739. Vermiglio F, Violi MA, Finochiaro MD, et al. Short-term effectiveness of low dose radioiodine ablative treatment for thyroid remnants after thyroidectomy for differentiated thyroid cancer. Thyroid 1999;9:387±391. Vialli N, Catargi B, Ronci N, Guyot M. Evaluation of indium111 pentetreotide somatostatin receptor scintigraphy to detect recurrent thyroid carcinoma in patients with negative radioiodine scintigraphy. Thyroid 1999;9:583±589. Vitale G, Tagliaferri P, Caraglia M, Rampone E et al. Slow release lanreotide in combination with interferon-alpha 2b in the treatment of symptomatic advanced medullary thyroid carcinoma. J Clin Endocrinol Metab 2000;85:983±988. Walsh RM, Watkinson JC, Franklyn J. The management of solitary thyroid nodule: a review. Clin Otolaryngol 1999;24:388±397. Wanebo H, Coburn M, Teates D, Cole B. Total thyroidectomy does not enhance disease control or survival even in highrisk patients with differentiated thyroid cancer. Ann Surg 1998;227:912±921. Wang W, Larson S, Fazzari M et al. Prognostic value of 18 F ¯uorodeoxyglucose positron emission tomographic scanning in patients with thyroid cancer. J Clin Endocrinol Metab 2000;85:1107±1113. Wartofsky L, Sherman SI, Gopal J, Schlumberger M, Hay ID. The use of radioactive iodine in patients with papillary and follicular thyroid cancer. J Clin Endocrinol Metab 1998;83:4195±4203. Westbury C, Vini L, Fisher C, Harmer C. Recurrent differentiated thyroid cancer without elevation of serum thyroglobulin. Thyroid 2000;10:171±176. Wong JV, Kaplan MM, Meyer KB, Pauker SG. ablative radioactive iodine therapy for apparently localised thyroid carcinoma ± a decision analysis perspective. Endocrinol Metab Clin North Am 1990;19:741±756. Wong CO, Dworkin AJ. Role of FDG PET in metastatic thyroid cancer. J Nucl Med 1999;40:993±994. Yaakob W, Gordon L, Spicer KM, Nitke SJ. The usefulness of iodine-123 whole-body scans in evaluating thyroid carcinoma and metastases. J Nucl Med 1999;27;279±281. Yamashita H, Noguchi S, Murakami N et al. Extracapsular invasion of lymph node metastasis. Cancer 1999;86:842± 849. Yamashita S, Nagataki S. Chernobyl and thyroid. Thyroid 1995;5:153±154.

Management of Thyroid Cancer

391