By- Dr.Desh Deepak Ladia JR III Radiation Oncology SAIMS

THYROID GLAND Anatomy

Endocrine gland, situated in the lower part of the front and sides of the neck.

Extends : from oblique line of thyroid cartilage to the 5th or 6th tracheal ring.

Lie against C5,C6,C7 & T1.

Consist Right & Left lobes, joined by isthmus.

A 3rd pyramidal lobe may project upwards from the isthmus.

Capsules: two; True & false.

Larger in females than males.

Development: from the endoderm of the floor of primitive oral cavity in the region of the future foramen caecum and ultimobranchial body.

Blood supply:

• Superior and inferior thyroid arteries. (branches of the external carotid arteries)

• Superior, middle and inferior thyroid veins. (branches of the thyrocervical trunk from the subclavian arteries)

• Nerve supply:

• Middle cervical ganglion

• Superior and inferior cervical ganglia

Lymphatic Drainage :The first-echelon nodes for thyroid cancer metastases are level 6 (the central or “visceral” compartment) between the hyoid bone and the thoracic inlet,these include

paralaryngeal,

paratracheal, and

prelaryngeal (Delphian) nodes.

Second-echelon nodal spread is to the

mid- and lower cervical nodes (levels 3 and 4),

supraclavicular nodes, upper mediastinal nodes (level 7), and

to a lesser extent the upper cervical nodes (level 2).

Retropharyngeal node involvement is unusual but can be encountered in the setting of advanced nodal disease.

Level 1 (submental and submandibular) lymph nodes are rarely involved.

PHYSIOLOGY-

The primary physiologic role is the production of thyroid hormone, which plays an important role in metabolic homeostasis.

A secondary role is the production of calcitonin, a hormone involved in calcium homeostasis.

The follicular cells of the thyroid gland synthesize and secrete thyroglobulin(Tg) and thyroid hormone in two biologically active forms,

thyroxine (3,5,3′,5′ iodothyronine or T4) and

triiodothyronine (3,5,3′ iodothyronine or T3).

T4 is considered the storage and transport form of the hormone and T3 is considered the metabolically active form.

Iodine HemostasisThe follicular cells of the thyroid gland possess a unique ability to actively uptake and concentrate iodine. The sodium iodine symporter (NaIS) actively transports sodium and iodine against an electrochemical gradient across the cell membrane in an energy-dependent fashion. This transmembrane protein is stimulated by thyroid-stimulating hormone (TSH or thyrotropin).Functional NaIS is present on malignant follicular cells seen in multiple variants of differentiated thyroid cancer. The unique ability to concentrate iodine within these malignant cells makes radioactive iodine (RAI) a potent targeted therapy.

NaIS is also present in the • parotid glands, • breast tissues, • gastric mucosa, and • nasolacrimal ducts,

placing them at risk for injury from RAI therapy.

PATHOLOGICAL CLASSIFICATIONBASED ON DIFFERENTIATION

WELL DIFFERENTIATED(LOW GRADE MALIGNANCY) POORLY DIFFERENTIATED( HIGH GRADE)• Usual papillary thyroid carcinoma(PTC) Anaplastic (undifferentiated)• Microcarcinoma(lesions <1cm)• Cystic• Follicular variant of PTC• Usual follicular thyroid carcinoma (FTC)• Hurthle cell carcinoma (HCC)INTERMEDIATE DIFFERENTIATION• Medullary thyroid carcinoma(MTC)• Diffuse sclerosing variant of papillary carcinoma• Columnar cell variant of papillary carcinoma• Insular carcinoma• Tall cell variant of papillary carcinoma

INDIAN STATISTICS- 2012

Thyroid cancer is the most commonly diagnosed endocrine cancer.

There will be an estimated 48,000 new thyroid cancer diagnoses and 1,740 thyroid cancer deaths in the United States by the end of 2011.

There is a strong female prevalence.

DTC comprises the overwhelming majority (94%) of new thyroid cancer diagnoses.

Approximately 5% are medullary thyroid carcinoma and 1% are anaplastic thyroid carcinoma.

• Siegel R, Ward E, Brawley O, et al. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011;61:212–236.

•   Aschebrook-Kilfoy B, Ward MH, Sabra MM, et al. Thyroid cancer incidence patterns in the United States by histologic type, 1992–2006. Thyroid 2011;21:125–134.

•   Sherman SI. Thyroid carcinoma. Lancet 2003;361:501–511.

EPIDEMIOLOGY

The incidence of thyroid cancer increases with age with a peak incidence at

• 40 to 44 years for women and

• 65 to 69 years for men.

The peak incidence for ATC is at 60 years for both sexes.

CLINICAL MANIFESTATIONS OF THYROID CANCER

The most common presentation

• asymptomatic thyroid nodule found incidentally by the patient, clinicians, or on an imaging study performed for other reasons.

Palpable thyroid nodules occur in 3% to 4% of the normal population, and their incidence at autopsy has been reported as high as 50%

• Mortensen JD, Woolner LB, Bennett WA. Gross and microscopic findings in clinically normal thyroid glands. J Clin Endocrinol Metab 1955;15:1270–1280.

•   Vander JB, Gaston EA, Dawber TR. The significance of nontoxic thyroid nodules. Final report of a 15-year study of the incidence of thyroid malignancy. Ann Intern Med 1968;69:537–540.

•   Nixon IJ, Ganly I, Hann LE, et al. Nomogram for predicting malignancy in thyroid nodules using clinical, biochemical, ultrasonographic, and cytologic features. Surgery 2010;148:1120–1127.

Positive findings on history and physical examination that raise suspicion that a thyroid nodule is malignant include

• rapid growth,

• firmness,

• fixation,

• vocal cord paralysis,

• cervical adenopathy,

• stridor,

• dysphagia.

DIAGNOSTIC EVALUATION OF THYROID CANCER

LABORATORY STUDIES-

serum TSH,

Routine measurement of serum Tg for initial evaluation of thyroid nodules is not recommended.

Serum calcitonin can be measured during the initial evaluation of patients with MTC and is essential during follow-up for these patients.

ULTRASOUND AND ULTRASOUND-GUIDED FINE-NEEDLE ASPIRATE-

characteristics of a thyroid nodule associated with a higher likelihood of malignancy include

• nodule hypoechogenicity compared to the normal thyroid parenchyma,

• increased intranodular vascularity,

• irregular infiltrative margins,

• the presence of microcalcifications,

• an absent halo.

Routine FNA is not recommended for subcentimeter nodules.

Indications for FNA in subcentimeter nodules are

1) family history of PTC 2) history of external beam radiation exposure as a child 3) exposure to ionizing radiation in childhood or adolescence 4) history of prior hemithyroidectomy with discovery of thyroid cancer; and 5)FDG-PET–positive thyroid nodules.

Subcentimeter nodule with a suspicious appearance and when detection of abnormal lymph nodes should lead to FNA of the lymph node.

COMPUTED TOMOGRAPHY AND MAGNETIC RESONANCE IMAGING-

CT and MRI commonly detect otherwise clinically occult thyroid nodules.

MRI is superior to CT for establishing the local extent of a known cancer, because it will more clearly show esophageal or tracheal invasion.

MRI is indicated in the presence of

hoarseness,

stridor,

dysphagia.

The ATA doesn’t recommend the routine preoperative use of imaging studies (CT, MRI, PET).

NUCLEAR MEDICINE STUDIES-

FDG-PET is another nuclear medicine study that is commonly used to detect metastatic disease, but the predictive value of PET in thyroid cancer is not well defined.

TSH stimulation increases the accuracy of FDG-PET in most types of DTC.

PROGNOSTIC FACTORSThe most important prognostic factor for disease recurrence and cancer mortality is the histologic classification.

DTC, when diagnosed in an early stage, has a favorable prognosis.

Tall-cell variant can have a 10-year mortality of up to 25%.

Hürthle cell carcinoma carries a relatively poor prognosis, with a 25% rate of metastatic disease and decreased survival at 10 years of 76%, compared with 93% and 85% for PTC and FC, respectively.

Columnar cell variant and diffuse-sclerosing variants carry a poor prognosis relative to other forms of DTC.

Follicular-variant PTC and most FC share the same favorable prognosis as classic PTC relative to age and stage at diagnosis.

ATC has an abysmal prognosis. All ATCs are considered stage IV under the current AJCC system and the overall 5-year survival is approximately 5%.

• NCCN guidelines for thyroid carcinoma: National Comprehensive Cancer Network 2011.

• Ruegemer JJ, Hay ID, Bergstralh EJ, et al. Distant metastases in differentiated thyroid carcinoma: a multivariate analysis of prognostic variables. J Clin Endocrinol Metab 1988;67:501–508.

• Samaan NA, Schultz PN, Haynie TP, et al. Pulmonary metastasis of differentiated thyroid carcinoma: treatment results in 101 patients. J Clin Endocrinol Metab 1985;60:376–380.

Within the classification of DTC there are several important prognostic factors, as shown in the table-

STAGING-

SURGICAL MANAGEMENT OF THYROID CANCER

Surgery is the primary treatment of localized thyroid cancer of all histologies.

A total thyroidectomy is the preferred surgery.

Subtotal thyroidectomy, leaving >1 g of tissue with the posterior capsule on the uninvolved side, is an inappropriate operation for thyroid cancer.

It is critical to understand that even a total thyroidectomy leaves residual thyroid tissue that will have major implications for subsequent therapy and disease monitoring.

Total thyroidectomy recommendations-• If the primary thyroid carcinoma is >1 cm• There are contralateral thyroid nodules present or • Regional or distant metastases are present, • The patient has a personal history of radiation

therapy to the head and neck, or • The patient has first-degree family history of DTC.

Bilimoria KY, Bentrem DJ, Ko CY, Stewart AK, Winchester DP, Talamonti MS, Sturgeon C 2007 Extent of surgery affects survival for papillary thyroid cancer. Ann Surg 246:375–381.

Older age (>45 years) may also be a criterion for recommending near-total or total thyroidectomy even with tumors <1–1.5 cm, because of higher recurrence rates in this age group.

Rubino C, de Vathaire F, Dottorini ME, Hall P, Schvartz C, Couette JE, Dondon MG, Abbas MT, Langlois C, Schlumberger M 2003 Second primary malignancies in thyroid cancer patients. Br J Cancer 89:1638–1644.Thyroid lobectomy alone may be sufficient treatment for

Thyroid lobectomy is sufficient when-• small (<1 cm), • low-risk, • unifocal, • intrathyroidal papillary carcinomas in the absence

of • prior head and neck irradiation or • radiologically or clinically involved

cervical nodal metastases.

LYMPH NODE DISSECTION

Therapeutic central-compartment (level VI) neck dissection for patients with clinically involved central or lateral neck lymph nodes should accompany total thyroidectomy to provide clearance of disease from the central neck.

Prophylactic central-compartment neck dissection (ipsilateral or bilateral) may be performed in patients with papillary thyroid carcinoma with clinically uninvolved central neck lymph nodes, especially for advanced primary tumors (T3 or T4).

Near-total or total thyroidectomy without prophylactic central neck dissection may be appropriate for small (T1 or T2), noninvasive, clinically node-negative PTCs and most follicular cancer.

Therapeutic lateral neck compartmental lymph node dissection should be performed for patients with metastatic lateral cervical lymphadenopathy.

White ML, Gauger PG, Doherty GM 2007 Central lymph node dissection in differentiated thyroid cancer. World J Surg 31:895–904 The ATA Surgery Working Group 2009 Consensus Statement on the Terminology and Classification of Central Neck Dissection for Thyroid Cancer. Thyroid 19:1153–1158 .Kupferman ME, Patterson M, Mandel SJ, LiVolsi V, Weber RS 2004 Patterns of lateral neck metastasis in papillary thyroid carcinoma. Arch Otolaryngol Head Neck Surg 130:857–860. Kupferman ME, Patterson DM, Mandel SJ, LiVolsi V, Weber RS 2004 Safety of modified radical neck dissection for differentiated thyroid carcinoma. Laryngoscope 114:403–406.

Low-risk patients:

1) No local or distant metastases; 2) All macroscopic tumor has been resected; 3) There is no tumor invasion of locoregional tissues or structures; 4) The tumor does not have aggressive histology (e.g., tall cell, insular, columnar cell carcinoma) or vascular invasion; 5) And, if 131I is given, there is no 131I uptake outside the thyroid bed on the first posttreatment whole-body RAI scan (RxWBS)

Intermediate-risk patients: 1) Microscopic invasion of tumor into the perithyroidal soft tissues at initial surgery; 2) Cervical lymph node metastases or 131I uptake outside the thyroid bed on the RxWBS done after thyroid remnant ablation or 3) Tumor with aggressive histology or vascular invasion.

High-risk patients :1) macroscopic tumor invasion, 2) incomplete tumor resection, 3) distant metastases, and possibly 4) thyroglobulinemia out of proportion to what is seen on the posttreatment scan.

ROLE OF POSTOPERATIVE RAI REMNANT ABLATION

RAI ablation is recommended for all patients • with known distant metastases, • gross extrathyroidal extension of the tumor regardless of tumor size, or • primary tumor size >4 cm even in the absence of other higher risk

features

RAI ablation is recommended for selected patients with • 1–4 cm thyroid cancers confined to the thyroid, • who have documented lymph node metastases, or • other higher risk features when the combination of age, tumor size,

lymph node status, and individual histology predicts an intermediate to high risk of recurrence or death from thyroid cancer

RAI ablation is not recommended for patients with • unifocal cancer <1 cm without other higher risk features• multifocal cancer when all foci are <1 cm in the absence other higher

risk features

HOW SHOULD PATIENTS BE PREPARED FOR RAI ABLATION?

Remnant ablation requires TSH stimulation. TSH of >30 mU/L is associated with increased RAI uptake in tumors , Endogenous TSH elevation can be achieved by two basic approaches to thyroid hormone withdrawal,

• stopping LT4 and switching to LT3 for 2–4 weeks followed by withdrawal of LT3 for 2 weeks, or

• discontinuation of LT4 for 3 weeks without use of LT3. Both methods of preparation can achieve serum TSH levels >30 mU/L in >90% of patientsA low-iodine diet for 1–2 weeks is recommended for patients undergoing RAI remnant ablation, particularly for those patients with high iodine intake.

For most patients, including those unable to tolerate hypothyroidism or unable to generate an elevated TSH, remnant ablation can be achieved with rhTSH.

A recent study has shown that ablation rates were similar with either withdrawal or preparation with rhTSH.

Recombinant human TSH is approved for remnant ablation in the United States, Europe, and many other countries around the world.

Chianelli M, Todino V, Graziano F, Panunzi C, Pace D, Guglielmi R, Signore A, Papini E 2009 Low dose (2.0 GBq; 54 mCi) radioiodine postsurgical remnant ablation in thyroid cancer: comparison between hormone withdrawal and use of rhTSH in low risk patients. Eur J Endocrinol 160:431–436Tuttle RM, Brokhin M, Omry G, Martorella AJ, Larson SM, Grewal RK, Fleisher M, Robbins RJ 2008. Recombinant human TSH-assisted radioactive iodine remnant ablation achieves short-term clinical recurrence rates similar to those of traditional thyroid hormone withdrawal. J Nucl Med 49:764–770

ACTIVITY OF 131I SHOULD BE USED FOR REMNANT ABLATION

The minimum activity (30–100 mCi) necessary to achieve successful remnant ablation and should be utilized, particularly for low-risk patients.

If residual microscopic disease is suspected or documented, or if there is a more aggressive tumor histology (e.g., tall cell, insular, columnar cell carcinoma), then higher activities (100–200 mCi) may be appropriate

Rosario PW, Reis JS, Barroso AL, Rezende LL, Padrao EL, Fagundes TA 2004 Efficacy of low and high 131I doses for thyroid remnant ablation in patients with differentiated thyroid carcinoma based on post-operative cervical uptake. Nucl Med Commun 25:1077–1081Maenpaa HO, Heikkonen J, Vaalavirta L, Tenhunen M, Joensuu H 2008 Low vs. high radioiodine activity to ablate the thyroid after thyroidectomy for cancer: a randomized study. PLoS ONE 3:e1885.

POSTSURGERY AND ‘RAI’ THERAPY EARLY MANAGEMENT OF DTC

Initial TSH suppression to below 0.1 mU/L is recommended for high-risk and intermediate-risk thyroid cancer patients.

Maintenance of the TSH at or slightly below the lower limit of normal (0.1–0.5 mU/L) is appropriate for low-risk patients.

McGriff NJ, Csako G, Gourgiotis L, Lori CG, Pucino F, Sarlis NJ 2002 Effects of thyroid hormone suppression therapy on adverse clinical outcomes in thyroid cancer. Ann Med 34:554–564.Brabant G 2008 Thyrotropin suppressive therapy in thyroid carcinoma: what are the targets? J Clin Endocrinol Metab 93:1167–1169

RADIATION SAFETY AFTER TREATMENT WITH 131I OF PATIENTS

To release a patient treated with 131I from physician’s control

• The radiation exposure to any other individual (generally, a family member) encountering the patient will likely not exceed 5 mSv (500 mrem) per annum,

• The radiation dose to a child, a pregnant woman, or an individual not involved in the care of the patient will not exceed 1 mSv (100 mrem) per annum

• Patients should avoid public transportation.

• The patient must be capable of self-care, cannot live in a nursing home or communal living facility.

• Patients must be given radiation safety instructions.

Women receiving RAI therapy should avoid pregnancy for 6–12 months.

Patients receiving therapeutic doses of RAI should have baseline CBC and assessment of renal function.

Patients should sleep alone and at least 6 feet away from any other individual throughout the nighttime restricted period. Use of a separate bedroom or sleeping area would be best.

Urine is the primary excretion route for RAI and is maximal during the first 48 hours after treatment. Sufficient fluid (3–4 L/day) should be consumed to enable frequent urination.

Emptying of the bowel moderately reduces radiation to the patient and also to individuals nearby.

Since RAI concentrations are present in the saliva for as long as 7 days, patients should avoid kissing, especially of children, for the period

ADVERSE EFFECTS OF IODINE-131

EXTERNAL BEAM RADIOTHERAPY FOR THYROID CANCER

There are no randomized control trials defining the indications for external beam radiotherapy (EBRT) in thyroid cancer.

In general, only patients with unresectable tumor are treated with primary EBRT.

ATA recommends EBRT

• age</=18 yr- metastasis(symptomatic), critical locations that are otherwise untreatable.

• age 19 to 45 yr-metastasis(symptomatic), critical locations that are otherwise untreatable.

• age> 45yr- gross ETE, gross residual tumour not amenable to further surgery.

EXTERNAL BEAM RADIOTHERAPY TECHNIQUE

CT simulation is used for treatment planning with patients positioned supine with arms at their side and the neck extended such that the mandible is at 90 degrees with respect to the treatment couch.

Axial CT images are acquired from above the skull base to the middle of the chest.

conventional anterior posterior/posterior anterior or lateral fields have been described to treat thyroid cancer, often requiring custom bolus materials to ensure homogenous dose distributions.

Because the target volume straddles the level of the shoulder and, in nearly all cases, contains concavities with envaginated critical normal tissues, therefore it useful to treat patients with intensity-modulated radiotherapy (IMRT).

AP-PA photon fields

▪superior border at level of mastoid processes, shield mandible▪ lateral borders covering medial 2/3 of clavicles▪ inferior border usually just below carina

TARGET VOLUMES AND DOSE-

The gross tumor volume (GTV) will be any residual gross disease.

Two CTVs: (Clinical Target Volume)

• the high-risk CTV corresponds to the region at highest risk for residual disease (positive margin, ETE, lymph node with extracapsular disease, or gross residual disease) and

• the standard-risk CTV, which is the region at moderate risk for residual disease (electively irradiated nodal stations).(upper mediastinal nodes should also be included)

The dose prescribed is 66 to 70 Gy to the high-risk PTV(Planning target volume) and 54 to 56 Gy to the standard-risk PTV in 33 to 35 fractions using a single IMRT plan with a simultaneous integrated boost.

Intensity-modulated radiation therapy clinical target volume contouring atlas for a patient with T2N0M0 insular thyroid carcinoma status post total thyroidectomy and radioactive iodine.

EXTERNAL BEAM RADIOTHERAPY TOXICITY-

The acute toxicities reported include

mucositis,

pharyngitis,

dysphagia,

hoarseness,

radiation dermatitis,

weight loss, and malnutrition.

Late complications include fibrosis and atrophy of the skin, lung apices, and neck musculature and tracheal and esophageal stenosis.

The most commonly reported severe late complication is esophageal stenosis.

FOLLOW UP OF DTC-

CHEMOTHERAPY AND TARGETED AGENTS FOR DIFFERENTIATED THYROID CARCINOMA-

As per the present ATA guidelines there is no role for the routine adjunctive use of chemotherapy in patients with DTC.

Agents currently under investigation target specific pathways involving inhibition of tyrosine kinase (TKI) receptors ,inhibition of vascular endothelial growth factor receptors (VEGFR).

• Axitinib

• Motesanib

• Sorafenib and sunitinib

Motesanib, an oral TKI, was studied in a phase II trial and demonstrated an 81% rate of disease control with a median progression-free survival of 9.3 months.

A recent phase III, randomized, double blind trial for patients with RAI refractory DTC published in Lancet.

Patients received either sorafenib or placebo.

There was an improvement in the PFS of 10.8 months vs 5.8 months in the placebo arm.

• Brose MS, Nutting CM, Jazrab B et al., Lancet 2014 Jul. PMID 24768112.

MTC comprises less that 5% to 10% of all thyroid cancers.

Medullary thyroid carcinoma (MTC) does not originate from the follicular epithelial cells, but from the parafollicular C cells, which are neural crest-derived cells whose function is to produce calcitonin.

Cases are seen sporadically (80%) or in association with familial multiple endocrine neoplasia (MEN IIa, MEN IIb, and pure familial MTC) syndromes.

Multifocal and bilateral MTC are usually seen in patients with MEN, but, otherwise, familial and sporadic MTCs are indistinguishable.

Grossly, these tumors are well circumscribed and nonencapsulated.

MEDULLARY THYROID CARCINOMA

Microscopically, tumors can have different appearances, including patterns that mimic other types of thyroid tumors.

The most common pattern is of solid growth or nests similar to insular carcinoma.

Amyloid, which is present in approximately 80% of cases, is a characteristic feature of MTC.

Calcitonin stains are usually positive and specific for MTC, but up to 20% of cases may not stain for calcitonin;

therefore, other neuroendocrine markers such as chromogrannin may be useful.

MANAGEMENT OF MEDULLARY THYROID CARCINOMA

All patients with MTC should be tested for RET mutations, including sporadic cases. Genetic screening and testing is also indicated.

Initial primary management of localized MTC is total thyroidectomy, which is the only completely effective therapy.

Central neck dissection should be performed in all cases and compartment-oriented lateral neck dissection is indicated when clinically involved.

There is no role for adjuvant RAI therapy.

All patients should be followed with serum calcitonin levels as this presents a sensitive and specific marker for extent of residual disease.

The indications for EBRT in a patient with MTC depend on the patient’s age.

In children (<18 years old), EBRT is reserved for

• palliation of symptoms from tumors not amenable to other treatment or

• when tumor progression is likely to cause normal tissue damage.

For adults, EBRT is indicated

• unresectable gross disease or

• when there is a high risk of residual microscopic disease after total thyroidectomy based on pathologic evaluation revealing positive margins,

• T4 primary tumors, or

• nodal metastases with extensive extracapsular extension.

Traditional cytotoxic systemic therapies have largely been ineffective in the management of metastatic or recurrent MTC.

Recently two TKIs have been approved for treatment of MTC:

In 2012 USFDA Approval for Cabozantinib was based on the EXAM clinical trial, an

international, multicenter, randomized study ,cabozantinib(tyrosine kinase inhibitor of MET, VEGF2 and RET) vs placebo in medullary thyroid cancer were recent published. The study found a 28% response rate in those receiving the study drug vs 0% in the placebo arm. There was an associated improvement in median PFS 4 month in placebo vs. 11.2 months in the cabozantinib (140mg) arm.Partial response were observed only in active treatment arm(27% vs. 0% p< 0.0001)

Elisei R, Schlumberger MJ, Muller SP, et al.,J clin Oncol.2013oct. PMID 24002501.

USFDA in 2011 approved Vandetanib(CAPRELSA) based on the results of the ZETA study.

A phase III, double-blind trial that randomized 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer to vandetanib 300 mg (n=231) or placebo (n=100).

Participants randomized to vandetanib showed a statistically significant improvement in progression-free survival (PFS) when compared to those randomized to placebo (p< 0.0001).

This difference reflects a 65% reduction in risk for disease progression. Median progression-free survival was 19.3 months in the placebo arm and at least 30.5 months in the vandetanib arm. At the primary PFS analysis, no significant overall survival difference was noted.Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012 Jan 10. 30(2):134-41.

MANAGEMENT OF ANAPLASTIC THYROID CARCINOMA

Most ATC presents with extraglandular disease and it is not clear that any form of therapy improves outcomes.

Complete surgical excision should be the goal of initial therapy, when feasible.

However, surgery should be avoided when complete excision is not possible as debulking does not improve outcomes.

There is no therapeutic role for RAI.

EBRT is the standard of care for palliation of local symptoms from unresectable disease or as adjuvant therapy in the rare case of a completely resected tumor.

NCCN Guidelines Version 2.2015Thyroid Carcinoma – Anaplastic Carcinoma

FNA OR CORE BIOPSY FINDINGa

DIAGNOSTIC PROCEDURES

Anaplastic thyroid

carcinoma (ATC)

• CBC with differential• Comprehensive

chemistry• TSH• Neck

ultrasound• CT head, neck, chest, abdomen, pelvis• Laryngoscopy•18FDG PET/CT

• In case of airway invasion, bronchoscopy

ESTABLISH GOALS OF THERAPYb

• Consultation with multi- disciplinary

management team

• Discuss prognosis

• Discuss risks/ benefits of

treatment options• Discuss palliative

care options

STAGEc

Stage IVA or IVBa,b

(Locoregional disease)

R0/R1resectiond

achieved (usually as incidentally discovered, very small

ATC)

Unresectabled

(R2 resection)

Observation or

Adjuvant EBRT/IMRT

± Chemothera

pye

EBRT/IMRT±

Chemotherapy

Surgery can be reconsidered

after neoadjuvant

therapy depending

on response

Stage IVC (metastatic disease)

METASTATIC DISEASE

Stage IVCc

Aggressive therapy

Palliative care

• Total thyroidectomy with therapeutic lymph node dissection if resectable

(R0/R1)• Locoregional radiation

therapy• Systemic therapy

• Cross-sectional imaging of brain, neck, chest, abdomen, and pelvis

at frequent intervals as clinically

indicated.• Consider 18FDG-PET-CT

3–6 months after initial therapy.

• Continued observation

• Palliative locoregional

radiation therapy• Focal lesion control

(eg, bonef, brain metastases)

• Second-line systemic

therapy or clinical trial

• Hospice/Best supportive care

NCCN Guidelines Version 2.2015Thyroid Carcinoma – Anaplastic Carcinoma

TREATMENT SURVEILLANCE AND MANAGEMENT

• Palliative locoregional radiation therapy

• Focal lesion controlwith surgery or

radiation (eg, bonef, brain metastases)

• Hospice/Best supportive care

Regimen Agents/Dosages Frequency

Paclitaxel/carboplatin Paclitaxel 60–100 mg/m2, carboplatin AUC 2 mg/m2 IV Weekly

Paclitaxel/carboplatin Paclitaxel 135–175 mg/m2, carboplatin AUC 5–6 mg/m2 IV

Every 3–4 weeks

Docetaxel/doxorubicinDocetaxel 60 mg/m2 IV, doxorubicin 60 mg/m2 IV (with pegfilgrastim) or

Docetaxel 20 mg/m2 IV, doxorubicin 20 mg/m2 IV

Every 3-4 weeks

WeeklyPaclitaxel 60–90 mg/m2 IV Weekly

Systemic Ther-apy