Sections

Thyroid Cancer

Archetype D 41 regimens (Main Regimens) thyroid

Differentiated, medullary, and anaplastic thyroid carcinoma

Management PrinciplesClick to collapse

The management of thyroid carcinoma is guided by histologic type (differentiated [papillary, follicular, oncocytic], medullary, anaplastic), risk stratification (clinicopathologic features, age, tumor size, extension, nodal status, metastases), and response to initial therapy. Differentiated thyroid carcinomas (DTC) have excellent prognosis with 10-year survival exceeding 90-95% [MS-2]. Anaplastic carcinoma is nearly uniformly fatal. Surgery is the primary treatment for most thyroid cancers, with radioactive iodine (RAI) for selected DTC cases, and TSH suppression therapy. For advanced RAI-refractory DTC and medullary carcinoma, kinase inhibitors (lenvatinib, sorafenib, cabozantinib, vandetanib) and targeted therapies (selpercatinib, pralsetinib, larotrectinib) are used. Anaplastic carcinoma requires expedited multidisciplinary care, often with neoadjuvant targeted therapy, surgery, chemoradiation, and palliative measures. The NCCN panel emphasizes a risk-adapted approach and dynamic risk assessment [MS-12-MS-13]. Systemic therapy is reserved for progressive/symptomatic disease, not for stable indolent disease [THYR-B 4 of 5]. All recommendations are category 2A unless otherwise noted.

curative

Most differentiated thyroid carcinomas (low/intermediate risk)

Surgery (lobectomy or total thyroidectomy) ± RAI ablation/adjuvant therapy ± TSH suppression

curative

Medullary carcinoma (localized)

Total thyroidectomy with central neck dissection, ± lateral neck dissection, ± prophylactic thyroidectomy for germline RET carriers

curative

Anaplastic carcinoma (stage IVA/B, potentially resectable)

Consider neoadjuvant targeted therapy (dabrafenib/trametinib for BRAF V600E) then surgery, adjuvant chemoradiation

palliative

Advanced RAI-refractory DTC, medullary, anaplastic with distant metastases

Systemic therapy (targeted, immunotherapy), local therapies (RT, ablation, embolization), best supportive care

Multidisciplinary team management is strongly recommended, especially for anaplastic carcinoma (expedient consultation) and for bulky locoregional disease [PAP-3]. Team should include endocrinology, surgery, radiation oncology, medical oncology, nuclear medicine, pathology, and palliative care. Referral to high-volume centers is advised for anaplastic and complex cases [ONC-2A].

Mdt Requirements

Performance status (ECOG) is considered when selecting systemic therapy; patients with ECOG PS 0 had improved PFS and OS with lenvatinib compared to ECOG PS 1 [MS-27]. For kinase inhibitor therapy, the pace of disease progression and side effect burden must be balanced against quality of life [THYR-B 4 of 5].

Performance Status Guide

Management PathwaysClick to collapse

Papillary Thyroid Carcinoma – Classic Subtype, Low Risk

Branching: Tumor size ≤2 cm (or ≤1 cm for microcarcinoma), Intrathyroidal, Unifocal or multifocal with all foci ≤1 cm, No detectable TgAb, Postoperative unstimulated Tg <1 ng/mL, Negative postoperative ultrasound

All low-risk factors present; patient candidate for active surveillance or surgery
Active surveillance (option); Lobectomy + isthmusectomy (preferred)
Papillary Thyroid Carcinoma – Intermediate Risk (RAI Selectively Recommended)

Branching: Large primary tumor size (>2 cm), High-risk subtypes (tall cell, columnar, hobnail, diffuse sclerosing, solid/trabecular), Lymphatic invasion, Cervical lymph node metastases (millimetric central nodes), Macroscopic multifocality (one focus >1 cm), Postoperative unstimulated Tg 1-10 ng/mL, Microscopic positive margins

Any of the above intermediate-risk factors after total thyroidectomy
Total thyroidectomy (if not already done) (recommended); RAI therapy (selectively recommended)
RAI is selectively recommended. TSH suppression to 0.1-0.5 mU/L for patients with biochemical evidence of disease but no structural disease; otherwise to normal range if disease-free after several years (THYR-A).
Papillary Thyroid Carcinoma – High Risk (RAI Typically Recommended)

Branching: Significant N1b disease, Gross extrathyroidal extension (ETE), Postoperative unstimulated Tg >10 ng/mL, Bulky or >5 positive lymph nodes, Vascular invasion, Differentiated high-grade carcinoma (≥5 mitoses/2 mm² and/or tumor necrosis), Known or suspected distant metastases at presentation, Gross residual disease

Any high-risk factor after total thyroidectomy
RAI therapy (recommended); Resect clinically significant structural disease if possible (recommended); EBRT (consider)
RAI is typically recommended. TSH suppression to <0.1 mU/L for patients with known structural residual disease or high risk of recurrence (THYR-A).
Papillary Thyroid Carcinoma – RAI-Refractory Locally Recurrent/Advanced/Metastatic

Branching: Unresectable locoregional recurrent/persistent disease, Distant metastases (soft tissue, bone, CNS), RAI-refractory (no uptake on scan, progression despite RAI, or cumulative >600 mCi), Progressive and/or symptomatic disease

RAI-refractory, progressive/symptomatic, or threatening disease
Clinical trial (consider); Systemic therapy (see Principles of Systemic Therapy) (consider); Resection of distant metastases and/or RT/other local therapies (consider); EBRT for local symptoms (consider)
Papillary Thyroid Carcinoma – Bone Metastases (RAI-Refractory)

Branching: Bone metastases from RAI-refractory DTC

Symptomatic or asymptomatic in weight-bearing sites
Surgical palliation and/or RT/other local therapies (consider); Embolization or other interventional procedures (alternatives); Intravenous bisphosphonate or denosumab (consider); Systemic therapy for progressive/symptomatic disease (consider)
Papillary Thyroid Carcinoma – CNS Metastases (RAI-Refractory)

Branching: CNS metastases from RAI-refractory DTC

Solitary CNS lesion
Neurosurgical resection (preferred); Stereotactic radiosurgery (SRS) (preferred)
Multiple CNS lesions
Radiotherapy (WBRT or SRS) ± resection in select cases (consider); Systemic therapy for progressive/symptomatic disease (consider)
Follicular Carcinoma – Post-Lobectomy Results

Branching: Final pathology after lobectomy for follicular neoplasm (Bethesda IV)

Benign or NIFTP
Levothyroxine to keep TSH normal (recommended)
Papillary carcinoma
See PAP-3 (recommended)
Invasive follicular carcinoma (widely invasive or angioinvasive with ≥4 vessels)
Completion thyroidectomy (recommended)
Postsurgical evaluation includes TSH, Tg, TgAb, and RAI considerations per FOLL-3.
Encapsulated angioinvasive with <4 vessels, or Minimally invasive FTC
Completion thyroidectomy or disease monitoring (monitoring preferred)
Follicular Carcinoma – RAI Selection after Total Thyroidectomy

Branching: Clinicopathologic factors: tumor size, vascular invasion, ETE, lymph node metastases, postoperative Tg, etc.

RAI not typically recommended: all present (tumor ≤4 cm, intrathyroidal, no vascular invasion, clinical N0, unstimulated Tg <1 ng/mL, negative US, no TgAb)
Disease monitoring (recommended)
RAI selectively recommended: any of large primary tumor size, minor vascular invasion (<4 foci), cervical lymph node metastases (millimetric central), postoperative Tg 1-10 ng/mL, microscopic positive margins
RAI therapy (selectively recommended)
RAI considered based on clinicopathologic features. TSH suppression per risk.
RAI recommended: differentiated high-grade carcinoma, significant N1b, gross ETE, extensive vascular invasion (≥4 foci), postoperative Tg >10 ng/mL, bulky or >5 positive lymph nodes, known/suspected distant metastases, gross residual disease
RAI therapy (recommended)
RAI recommended. TSH suppression to <0.1 mU/L for high-risk.
Oncocytic Carcinoma (Hurthle Cell) – Management

Branching: FNA shows oncocytic neoplasm (Bethesda IV), Clinical and radiographic features: evidence of locoregional spread vs. reassuring features

Benign or minimally invasive oncocytic carcinoma (encapsulated, no vascular invasion) after diagnostic lobectomy
Disease monitoring (preferred)
Invasive oncocytic carcinoma (widely invasive or angioinvasive with ≥4 vessels) after lobectomy
Completion thyroidectomy (recommended)
RAI considerations per ONC-3. Note: majority of oncocytic carcinomas are non–iodine-avid. Postsurgical evaluation includes neck CT, chest CT, FDG-PET if indicated.
Gross residual disease in neck after thyroidectomy
Resect if possible (recommended); EBRT (consider); RAI therapy if uptake present (preferred if avid)
TSH suppression. Disease monitoring per ONC-6/7.
Medullary Thyroid Carcinoma – Sporadic

Branching: FNA or molecular analysis suggests medullary thyroid cancer, Screening for pheochromocytoma, hyperparathyroidism, germline RET PV

Confirmed MTC, no clinical evidence of pheochromocytoma
Total thyroidectomy with central neck dissection (level VI) (recommended); Therapeutic EBRT (rarely recommended as adjuvant)
Postoperative levothyroxine to normalize TSH (not suppress). Calcitonin and CEA monitoring at 2-3 months postop (MEDU-5).
Medullary Thyroid Carcinoma – Germline RET PV (MEN2A/2B/FMTC)

Branching: Identification of germline RET pathogenic variant through screening or family history

MEN2B (RET PV, typically M918T or A883F)
Total thyroidectomy during childhood or at diagnosis (recommended)
MEN2A/FMTC – No primary hyperparathyroidism
Risk-adapted surgery based on mutation (recommended)
MEN2A/FMTC – With primary hyperparathyroidism
Total thyroidectomy + parathyroid exploration (recommended)
Medullary Thyroid Carcinoma – Recurrent or Persistent Locoregional Disease or Distant Metastases

Branching: Somatic molecular testing for RET, Symptomatic vs. asymptomatic disease

Locoregional recurrence, resectable
Surgical resection (preferred) (preferred)
Asymptomatic distant metastases
Disease monitoring (recommended)
Symptomatic disease or progression
Systemic therapy (Principles of Systemic Therapy) or clinical trial (recommended); EBRT for local symptoms (consider); Intravenous bisphosphonate or denosumab for bone metastases (consider); Palliative resection, ablation (RFA, embolization), other regional treatment (consider)
Anaplastic Thyroid Carcinoma – Stage IVA or IVB (Locoregional Disease)

Branching: Resectability assessment (potentially curable with surgery vs. borderline/unresectable)

Resectable (potentially curable with surgery)
Total thyroidectomy with therapeutic lymph node dissection (recommended); Neoadjuvant dabrafenib/trametinib for BRAF V600E-mutated disease (category 2B)
Adjuvant EBRT with radiosensitizing chemotherapy (THYR-B 3 of 5) when clinically appropriate. For R0/R1: consider adjuvant chemoradiation; for R2: EBRT with chemotherapy. Disease monitoring after treatment (ANAP-3).
Unresectable or borderline resectable
Targeted neoadjuvant therapy (dabrafenib/trametinib for BRAF V600E, pralsetinib/selpercatinib for RET fusion, entrectinib/larotrectinib/repotrectinib for NTRK fusion) (consider); EBRT with chemotherapy (consider)
Anaplastic Thyroid Carcinoma – Stage IVC (Metastatic Disease)

Branching: Metastatic disease at presentation

Stage IVC, aggressive therapy candidate
Total thyroidectomy with therapeutic lymph node dissection if resectable (R0/R1) (consider); Locoregional RT + systemic therapy (consider); Palliative intent (consider)

Pretreatment EvaluationClick to collapse

General Nodule Evaluation (All Patients)
Thyroid and neck ultrasound (including central and lateral cervical nodal compartments) if not previously done [PAP-1, FOLL-1, ONC-1]
Essential for all patients with thyroid nodule or suspected thyroid cancer.
Consider neck CT/MRI with contrast when suspicious nodes in the neck detected by ultrasound and/or vocal cord paresis [PAP-1]
Iodinated contrast is required for optimal cervical CT; potential delay in RAI treatment will not cause harm.
Consider assessment of vocal cord mobility (ultrasound, mirror indirect laryngoscopy, or fiberoptic laryngoscopy) [PAP-1]
Especially if abnormal voice, surgical history involving recurrent laryngeal nerve, invasive disease, or bulky central neck disease.
FNA for suspicious lateral neck nodes; Tg washout useful if cytology negative [PAP-1]
FNA of suspicious lymph nodes; consider Tg washout of needle aspirate.
Screen for personal and/or family history suggestive of inherited cancer risk [PAP-1, FOLL-1, ONC-1]
History of radiation, familial syndromes (Cowden, FAP, MEN2, DICER1).
Differentiated Thyroid Carcinoma (Papillary, Follicular, Oncocytic)
TSH, Tg, TgAb measurement (postoperative baseline) [PAP-3, FOLL-2]
Obtain 6-12 weeks after total thyroidectomy. Tg values used for RAI decision-making.
Iodine-123 or iodine-131 total body radioiodine imaging (category 2B) [PAP-3, FOLL-2, ONC-2]
Consider after thyroidectomy if RAI planned; iodine-123 preferred to avoid stunning.
Neck CT or MRI with contrast for gross residual disease in neck [PAP-3, FOLL-2, ONC-2]
Evaluate resectability and extent of residual disease.
Chest CT (non-contrast if suspicion of pulmonary metastases) [PAP-6, FOLL-5]
If suspicion of distant metastases or elevated Tg.
FDG-PET/CT or FDG-PET/MRI as clinically indicated [ONC-2]
For oncocytic carcinoma or when RAI-negative but high Tg.
Molecular analysis to identify actionable somatic alterations (ALK, NTRK1/2/3, BRAF, RET gene fusions) [PAP-10, FOLL-9, ONC-9]
For advanced, progressive, or threatening disease. Also consider dMMR, MSI, TMB in select patients. Testing on tumor preferred; ctDNA only if tumor sample unavailable.
Brain imaging (CT or MRI) with contrast prior to starting systemic therapy [PAP-10, FOLL-9, ONC-9]
Baseline evaluation before TKI therapy due to bleeding risk.
Medullary Thyroid Carcinoma
Basal serum calcitonin level and CEA [MEDU-1]
Essential for diagnosis and surveillance.
Pheochromocytoma screening (plasma or urinary metanephrines) [MEDU-1]
Mandatory before surgery; treat pheochromocytoma first.
Serum calcium to screen for hyperparathyroidism [MEDU-1]
Assess for MEN2A-related hyperparathyroidism.
Screen for germline RET PV (exons 8, 10, 11, 13-16); genetic counseling may be indicated [MEDU-1]
All patients with MTC should have germline RET testing. Do not delay surgery for results.
Consider additional cross-sectional imaging if calcitonin >300 pg/mL (contrast-enhanced CT neck/chest, liver MRI or 3-phase CT) [MEDU-1]
To evaluate for distant metastases.
Consider Ga-68 DOTATATE PET/CT; if not available, consider bone scan and/or whole body MRI [MEDU-1]
For staging and somatostatin receptor status.
Postoperative serum calcitonin and CEA level [MEDU-2, MEDU-5]
Obtain 2-3 months postoperatively to determine residual disease.
Anaplastic Thyroid Carcinoma
Complete blood count with differential, comprehensive chemistry, TSH [ANAP-1]
Routine labs.
Neck ultrasound; CT with contrast of head, neck, chest, abdomen, pelvis [ANAP-1]
Accurate staging and assessment of disease extent.
Laryngoscopy including evaluation of vocal cord mobility; if airway invasion, bronchoscopy [ANAP-1]
Assess airway involvement.
FDG-PET/CT or FDG-PET/MRI [ANAP-1]
Metabolic staging.
Molecular testing for actionable alterations (BRAF, NTRK1/2/3, ALK, RET); BRAF IHC recommended for faster turnaround [ANAP-1]
BRAF IHC is recommended due to speed. Also consider MSI, dMMR, TMB.
Brain MRI with contrast [ANAP-1]
Identify CNS metastases.
Expedient consultation with multidisciplinary management team; discuss prognosis and treatment risks/benefits; discuss palliative care options including airway management and IV steroids [ANAP-1]
Initiate early and often.

SurgeryClick to collapse

Surgery is the primary treatment for most thyroid carcinomas, aiming for complete resection of the primary tumor and involved lymph nodes with preservation of function. For differentiated thyroid cancer, surgery can be lobectomy (for low-risk tumors) or total thyroidectomy (for higher risk). For medullary carcinoma, total thyroidectomy with central neck dissection is standard. For anaplastic carcinoma, surgery is considered if resectable, often after neoadjuvant targeted therapy.

Surgical Role

Preoperative vocal cord assessment is imperative in patients with voice changes, invasive disease, or bulky central neck disease [PAP-1].

Routine prophylactic central neck dissection is not indicated in most papillary thyroid cancers [PAP-1].

For clinically apparent or biopsy-proven nodal metastases, therapeutic compartmental neck dissection should be performed (central levels VI, VII; lateral levels II-V as indicated) [PAP-1].

Selective dissection of individual nodal metastases (cherry picking) is not considered adequate surgery for nodal disease in a previously undissected field [MS-25].

Completion thyroidectomy has a complication rate similar to that of total thyroidectomy [MS-14].

Lobectomy alone is adequate for papillary microcarcinoma (≤1 cm) without risk factors [MS-13].

Total thyroidectomy is recommended for patients with any of: known distant metastases, extrathyroidal extension, lateral cervical lymph node metastases or gross central node metastases, poorly differentiated or high-grade histology, prior radiation exposure (category 2B), bilateral nodularity or tumors >4 cm [PAP-1].

For follicular and oncocytic neoplasms, diagnostic lobectomy is the initial surgery. Completion thyroidectomy is required if invasive cancer (widely invasive or angioinvasive with ≥4 vessels) is found [FOLL-1, ONC-1].

For medullary carcinoma, total thyroidectomy with central neck dissection is standard. Lobectomy can be considered in select cases without RET PV if no contralateral nodules [MEDU-1].

For anaplastic carcinoma, total thyroidectomy with therapeutic lymph node dissection is considered for potentially curable disease. Tracheostomy only if strongly indicated (avoid prophylactic) [ANAP-2].

Risk of hypoparathyroidism and recurrent laryngeal nerve injury is higher after total thyroidectomy; complication rates are lower when performed by high-volume surgeons (>100 per year) [MS-14].

Procedures

Lobectomy + isthmusectomy

Low-risk papillary carcinoma (tumor 1-4 cm, no ETE, no LN metastases, no prior radiation), follicular or oncocytic neoplasm for diagnosis, minimally invasive follicular/oncocytic carcinoma, NIFTP, small papillary microcarcinoma (≤1 cm) with low-risk features.

Total thyroidectomy

Papillary carcinoma with high-risk features (ETE, LN metastases, >4 cm, aggressive histology, known distant metastases, prior radiation), bilateral nodularity, medullary carcinoma, anaplastic carcinoma (if resectable), completion thyroidectomy for invasive follicular/oncocytic carcinoma.

Central neck dissection (level VI)

Therapeutic for clinically apparent/biopsy-proven central nodal metastases. Prophylactic not recommended for most papillary cancers. Routine for medullary carcinoma.

Modified radical neck dissection (levels II-V)

Therapeutic for lateral neck nodal metastases from any thyroid carcinoma. Prophylactic ipsilateral dissection may be considered for medullary carcinoma with high-volume central disease.

Prophylactic thyroidectomy (for germline RET carriers)

MEN2B: first year of life for M918T mutation; before age 5 for A883F. MEN2A: surgery before age 5 for highest-risk/high-risk mutations; may be delayed for moderate/low-risk mutations with normal calcitonin and US.

Radiation TherapyClick to collapse

Radiation therapy for thyroid carcinoma includes radioactive iodine (RAI) for differentiated thyroid cancer and external beam radiation therapy (EBRT) for selected cases of differentiated, medullary, and anaplastic carcinoma. RAI is used for remnant ablation, adjuvant therapy, and treatment of known disease. EBRT is used for unresectable gross residual disease, threatening vital structures, palliation of metastases, and as adjuvant therapy for anaplastic carcinoma.

Principles

  • RAI preparation can be via thyroid hormone withdrawal (4-8 weeks for TSH >30 mU/L) or thyrotropin alfa stimulation. Both are acceptable for distant metastases [THYR-C 1 of 5].
  • An iodine-restricted diet is recommended for 7-14 days prior to RAI. Iodinated contrast should be avoided for 2 months prior. 24-hour urine iodine may confirm adequate restriction (target <50 mcg) [THYR-C 1 of 5].
  • Negative pregnancy test is required before RAI in reproductive-age patients. Breastfeeding should be ceased 2-6 months prior and permanently after RAI [THYR-C 2 of 5].
  • Post-treatment whole body iodine-131 scan should be performed in all cases. Pre-treatment diagnostic scan may be considered but can cause stunning (prevent with iodine-123 or low-dose iodine-131) [THYR-C 1 of 5].
  • Cumulative lifetime activity >1000 mCi requires monitoring for myelosuppression and long-term toxicities [THYR-C 1 of 5].
  • For EBRT, conformal techniques (IMRT, SIB) are strongly encouraged to reduce toxicity. Pre-treatment imaging (CT, MRI, iodine scan, PET) guides volumes [THYR-C 3 of 5].
  • For anaplastic carcinoma, RT should start as quickly as possible after diagnosis or within 2-3 weeks postoperatively for adjuvant therapy [THYR-C 3 of 5].
  • Treatment volumes for differentiated/medullary cancer: GTV includes gross residual disease; CTV includes thyroid bed and involved lymph node levels II-VI; PTV margin 0.3-0.5 cm. For anaplastic: GTV includes primary and involved nodes; high-risk CTV includes involved regions and postoperative bed [THYR-C 3 of 5].

Dose Frameworks

NameTotal DoseDose Per FractionFractionsScheduleIndication
RAI remnant ablation (low-risk)30-50 mCi (1110-1850 MBq)N/A (single administration)1Single doseLow-risk DTC (T1b/T2, N0, no adverse features). Category 1 for 30-50 mCi. Also category 2B for T1b/T2 with small-volume N1a (<5 LN mets <2 mm) and primary <4 cm, M0 with minor ETE [THYR-C 2 of 5].
RAI adjuvant therapy75-150 mCi (2775-5550 MBq)N/A1Single doseHigher likelihood of residual disease based on operative pathology or pretherapy radioiodine scan [THYR-C 2 of 5].
RAI treatment of known disease100-200 mCi (3700-7400 MBq)N/A1Single dose; dosimetry can be used to determine maximal safe doseProven unresectable or metastatic disease. Higher doses for large-volume disease. For diffuse lung metastases, 48-h whole-body dose should not exceed ~80 mCi to avoid pulmonary fibrosis; bone marrow retention max ~120 mCi at 48 h [THYR-C 2 of 5].
EBRT for differentiated/medullary adjuvant (after R1 resection)60-66 Gy1.8-2 Gy30-33Daily fractionsHigh-risk disease after incomplete resection (microscopic residual). Elective nodal regions: 50-56 Gy [THYR-C 4 of 5].
EBRT for differentiated/medullary salvage (R2 or inoperable)66-70 Gy (gross disease), 60-66 Gy (microscopic), 50-56 Gy (elective nodes)1.8-2 Gy33-35 (gross), 30-33 (microscopic), 25-28 (elective)Daily fractionsGross residual disease or inoperable patients [THYR-C 4 of 5].
EBRT for anaplastic adjuvant (R0/R1 resection)60-66 Gy (microscopic); 45-54 Gy (elective nodes via SIB)1.2 Gy BID or 1.8-2 Gy daily for microscopic; 0.8-1.0 Gy BID or 1.6-1.8 Gy daily for elective nodesVaries (BID: 50-55 fractions; daily: 30-33 fractions)Twice-daily or once-daily fractions. Chemoradiation may be considered on individual basis [THYR-C 4 of 5].
EBRT for anaplastic salvage (R2 or inoperable)66-70 Gy (gross); 60-66 Gy (microscopic); 45-54 Gy (elective nodes)1.2 Gy BID or 1.8-2 Gy daily for gross; 1.2 Gy BID or 1.8-2 Gy daily for microscopic; 0.8-1.0 Gy BID or 1.6-1.8 Gy daily for electiveVariesTwice-daily or once-daily. Chemoradiation may be considered [THYR-C 4 of 5].
Palliative RT for bone/soft tissue metastases (all histologies)8 Gy (single fraction); 20 Gy/5 fractions; 30 Gy/10 fractions8 Gy x1, 4 Gy x5, 3 Gy x101, 5, or 10Daily or single fractionPalliation for painful metastases. For oligometastases and good PS, consider 45-60 Gy in 1.8-2 Gy fractions or SBRT [THYR-C 4 of 5].
Palliative neck RT for anaplastic20 Gy/5 fx, 30 Gy/10 fx, 45 Gy/15 fx4 Gy, 3 Gy, or 3 Gy5, 10, or 15Daily fractionsPalliation for local symptoms [THYR-C 4 of 5].

Approaches

NameDose FractionationConcurrent ChemotherapyIndicationKey TrialToxicities
Postoperative RAI for differentiated thyroid cancerSingle administration of 30-200 mCi based on risk categoryNoneRemnant ablation, adjuvant therapy, or treatment of known disease after total thyroidectomy, based on clinicopathologic risk factors [PAP-4, FOLL-3, ONC-3].SELECT trial (lenvatinib vs placebo) showed PFS 18.3 vs 3.6 months (HR 0.21) [MS-26]. DECISION trial (sorafenib vs placebo) showed PFS 10.8 vs 5.8 months (HR 0.59) [MS-27]. COSMIC-311 (cabozantinib vs placebo) showed PFS improvement in RAI-refractory DTC after prior VEGFR TKI [MS-27]. Ablation trials: Mallick 2012 and Schlumberger 2012 established 30 mCi for low-risk ablation [MS-16].Salivary gland dysfunction, lacrimal gland dysfunction, transient gonadal dysfunction, secondary primary malignancies (especially if cumulative >1000 mCi), myelosuppression [MS-17].
Adjuvant/definitive EBRT for differentiated/medullary thyroid cancer60-70 Gy to gross disease, 50-66 Gy to microscopic disease, 50-56 Gy to elective nodes, all at 1.8-2 Gy/fractionNone typically; may consider concurrent doxorubicin based on prospective data (phase II study showed 79.7% LRPFS and 77.3% OS with IMRT ± doxorubicin) [MS-20].High-risk disease after surgery (R1/R2), unresectable locoregional recurrence, gross residual disease not amenable to further resection, threatening vital structures [PAP-3, MEDU-1, ONC-2].Romesser et al 2021: phase 2 trial of IMRT ± doxorubicin showed locoregional PFS 79.7% and OS 77.3% at 2 years [MS-20]. Choi et al 2025: long-term results of EBRT ± chemotherapy in DTC [THYR-C 5 of 5].Acute: mucositis, dysphagia, dermatitis. Late: xerostomia, esophageal stricture, laryngeal edema, hypothyroidism (if thyroid remaining), spinal cord myelopathy (rare with modern techniques).
EBRT for anaplastic thyroid carcinomaAdjuvant: 60-66 Gy (microscopic) ± SIB to elective nodes 45-54 Gy. Salvage: 66-70 Gy to gross disease. Palliative: 20-45 Gy in 5-15 fractions. Often twice-daily fractionation (1.2 Gy BID) [THYR-C 4 of 5].Chemotherapy with radiosensitizing agents (carboplatin/paclitaxel, docetaxel, or doxorubicin) is often used concurrently. Adjuvant chemoradiation is associated with improved survival [MS-39].Adjuvant after R0/R1 resection; definitive for unresectable locoregional disease; palliation for metastatic disease.Pezzi et al 2017: higher RT dose associated with improved OS for unresected ATC (NCDB) [MS-39]. Heron et al 2002: hyperfractionation chemoradiotherapy improved local response to ~80%, median survival 1 year [MS-41].Significant acute toxicity: severe mucositis, dermatitis, dysphagia often requiring enteral nutrition. Late: fibrosis, esophageal stenosis. Consider obtaining dental, speech/swallow, and nutrition evaluation pre-treatment [THYR-C 3 of 5].

Systemic TherapyClick to collapse

Systemic therapy is indicated for progressive or symptomatic disease that is not amenable to surgery or RAI. For differentiated thyroid cancer (DTC) that is RAI-refractory, lenvatinib (category 1) is the preferred first-line option; sorafenib (category 1) is an alternative. Cabozantinib is category 1 for progression after lenvatinib and/or sorafenib for papillary carcinoma. For NTRK fusions, entrectinib, larotrectinib, or repotrectinib are options. For RET fusions, selpercatinib or pralsetinib. For BRAF V600E, dabrafenib/trametinib. Other options include lenvatinib + pembrolizumab, pembrolizumab (for TMB-H or MSI-H/dMMR), and agents like axitinib, everolimus, pazopanib, sunitinib, vandetanib (useful in certain circumstances). For medullary thyroid carcinoma (MTC), selpercatinib (category 1 for RET PV-positive) is preferred. Cabozantinib and vandetanib are category 1 options. Pralsetinib (category 2B for RET PV-positive) and lutenium dotatate (for SSTR+ disease) are useful in certain circumstances. For anaplastic thyroid carcinoma (ATC), neoadjuvant dabrafenib/trametinib is category 2B for BRAF V600E-mutated borderline resectable disease. For metastatic ATC, preferred options include dabrafenib/trametinib (BRAF V600E), binimetinib/encorafenib (BRAF V600E), pralsetinib/selpercatinib (RET fusion). Ipilimumab + nivolumab is an option for non-RAS tumors. Other recommended regimens include lenvatinib + pembrolizumab. Useful in certain circumstances: carboplatin/pemetrexed, cisplatin/doxorubicin, doxorubicin, nivolumab, NTRK inhibitors, paclitaxel, pembrolizumab, carboplatin/paclitaxel (category 2B), docetaxel/doxorubicin (category 2B). Kinase inhibitor therapy should not be used for stable indolent disease; the pace of progression and quality of life must be considered.

RAI-refractory DTC (locoregionally invasive, recurrent, or metastatic) – first-line or progressive disease
Phase 3 SELECT trial: median PFS 18.3 vs 3.6 months (HR 0.21) [MS-26]. Tumor response rate 65% vs 12% for sorafenib (not directly compared) [MS-26].
Preferred: Lenvatinib (category 1)
RAI-refractory DTC – progression after lenvatinib and/or sorafenib
Phase 3 COSMIC-311: median PFS 11.0 vs 1.9 months (HR 0.22) [MS-27]. ORR 11% vs 0%.
Preferred: Cabozantinib (category 1 for papillary; category 2A for follicular/oncocytic)
Medullary thyroid carcinoma – recurrent or persistent locoregional or distant metastatic, symptomatic or progressive
LIBRETTO-531: median PFS not reached vs 16.8 months for cabozantinib/vandetanib (HR 0.28) [MS-35-M36]. ORR 69.4% vs 38.8%. LIBRETTO-001: ORR 69% (prior TKI) and 73% (TKI-naive) [MS-35].
Preferred: Selpercatinib (category 1) for RET PV-positive disease
Anaplastic thyroid carcinoma – neoadjuvant for borderline resectable stage IVA/IVB
Subbiah et al 2018: ORR 69%, 12-month OS 43.2% [MS-39-M40]. Wang et al 2019: complete surgical resection achieved in 6/6 initially unresectable patients after neoadjuvant dabrafenib/trametinib, 1-year OS 83% [MS-41].
Preferred: Dabrafenib/Trametinib (for BRAF V600E-mutated) (category 2B)
Anaplastic thyroid carcinoma – metastatic (stage IVC) – first-line
ROAR trial: dabrafenib/trametinib ORR 56%, median OS 14.5 months [MS-40]. Subbiah et al 2021 (ARROW): pralsetinib ORR 60-74% in RET-mutated MTC; also effective in RET fusion-positive ATC [MS-36]. Binimetinib/encorafenib: phase 2 study in metastatic BRAF-mutated thyroid cancer in Japan [THYR-B 5 of 5].
Preferred: Dabrafenib/Trametinib for BRAF V600E; Binimetinib/Encorafenib for BRAF V600E; Pralsetinib/Selpercatinib for RET fusion

Key Regimens

Lenvatinib
Lenvatinib 24 mg orally once daily oral Continuous
Sorafenib
Sorafenib 400 mg orally twice daily oral Continuous
Cabozantinib
Cabozantinib 60 mg orally once daily oral Continuous
Vandetanib
Vandetanib 300 mg orally once daily oral Continuous
Selpercatinib
Selpercatinib 160 mg orally twice daily (adults); pediatric dose weight-based (≥2 years) oral Continuous
Pralsetinib
Pralsetinib 400 mg orally once daily oral Continuous
Larotrectinib
Larotrectinib 100 mg orally twice daily (adults); pediatric dose 100 mg/m² body surface area (max 100 mg) twice daily oral Continuous
Entrectinib
Entrectinib 600 mg orally once daily (adults); pediatric dose based on BSA oral Continuous
Repotrectinib
Repotrectinib 160 mg orally once daily (adults) oral Continuous
Dabrafenib + Trametinib
Dabrafenib 150 mg orally twice daily oral Continuous + Trametinib 2 mg orally once daily oral Continuous
Binimetinib + Encorafenib
Encorafenib 450 mg orally once daily oral Continuous + Binimetinib 45 mg orally twice daily oral Continuous
Lenvatinib + Pembrolizumab
Lenvatinib 20 mg orally once daily (or 24 mg based on tolerability) oral Continuous + Pembrolizumab 200 mg IV every 3 weeks or 400 mg IV every 6 weeks IV Day 1 of each cycle
Pembrolizumab
Pembrolizumab 200 mg IV every 3 weeks or 400 mg IV every 6 weeks IV Day 1
Ipilimumab + Nivolumab
Ipilimumab 3 mg/kg IV every 3 weeks (for 4 doses) IV Day 1 + Nivolumab 1 mg/kg IV every 3 weeks (for 4 doses) then 240 mg IV every 2 weeks or 480 mg IV every 4 weeks IV Day 1
Carboplatin + Paclitaxel
Carboplatin AUC 5-6 IV day 1 IV Day 1 + Paclitaxel 175 mg/m² IV day 1 (or 60-90 mg/m² IV weekly for radiosensitizing) IV Day 1 (or weekly)
Lutenium Dotatate (177Lu-DOTATATE)
Lutenium Dotatate 7.4 GBq (200 mCi) IV every 8 weeks IV Day 1

Treatment Response AssessmentClick to collapse

Title

Response Assessment and Disease Monitoring

Timing

For patients treated with total thyroidectomy (with or without RAI), initial disease monitoring begins at 6-12 weeks postoperatively with TSH, Tg, and TgAb measurement. Neck ultrasound is performed at 6-12 months. For patients who received RAI, post-therapy whole body iodine-131 scan is performed several days after treatment. Subsequent surveillance intervals depend on risk category and response.

Response Logic

  • Biochemical response: Serum Tg is the main marker. In athyrotic patients, undetectable Tg (<1 ng/mL unstimulated or <2 ng/mL stimulated) with negative TgAb indicates remission. Rising Tg or new appearance of TgAb suggests recurrence [MS-17-M18].

  • Structural response: Assessed by neck ultrasound, cross-sectional imaging (CT/MRI), FDG-PET, or RAI imaging. Structural disease that is stable and non-progressive may not require immediate intervention.

  • Dynamic risk stratification: Initial risk estimates are modified over time based on response to therapy (excellent, indeterminate, biochemical incomplete, structural incomplete) [MS-12-M13].

  • For patients after lobectomy: Trending Tg is not recommended due to limited utility. A one-time Tg and TgAb measurement may be considered. If very elevated and without other causes (bilateral nodules, renal insufficiency), further imaging is warranted [PAP-7].

  • For patients after lobectomy with contralateral nodule meeting FNA criteria or abnormal lymph node: biopsy (with Tg washout if lymph node) [PAP-7].

  • For patients after total thyroidectomy without RAI: Abnormal imaging and/or rising Tg prompts biopsy and consideration of additional imaging (neck CT/MRI, chest/abdomen CT, FDG-PET, or RAI imaging). Rising Tg or new TgAb requires similar workup [PAP-7, FOLL-6, ONC-6].

  • For patients after total thyroidectomy with RAI: NED (no evidence of disease) is defined by clinical, imaging, and biochemical criteria (undetectable Tg, no Tg antibodies). Neck ultrasound every 1-3 years for 5-8 years then discontinue for low-risk patients. After 10-15 years of no recurrence in low-risk patients, no further monitoring is indicated [PAP-8, FOLL-7, ONC-7].

Imaging Recommendations

  • Neck ultrasound is the principal imaging modality for surveillance, including central and lateral compartments [MS-24].

  • For patients with rising Tg or new TgAb after total thyroidectomy with RAI, consider additional imaging: neck CT/MRI with contrast, chest/abdomen CT, FDG-PET, or RAI imaging (diagnostic iodine-131 or iodine-123) [PAP-8, FOLL-7, ONC-7].

  • For anaplastic carcinoma, imaging (CT or MRI with contrast) of brain, neck, chest, abdomen, pelvis at frequent intervals. Consider FDG-PET/CT 3-6 months after initial therapy [ANAP-3].

  • For medullary carcinoma, calcitonin and CEA are the primary surveillance markers. Imaging (neck ultrasound, CT/MRI neck/chest/liver) indicated if calcitonin ≥150 pg/mL or elevated CEA. Ga-68 DOTATATE PET/CT can be used [MEDU-5].

  • Iodine-131 whole body scan is used for differentiated thyroid cancer to detect RAI-avid disease. Iodine-123 or low-dose iodine-131 (1-3 mCi) is used for diagnostic scans to minimize stunning [THYR-C 1 of 5].

  • FDG-PET is indicated for patients with negative whole body scan and elevated Tg suggesting structural disease not seen on other imaging [MS-17].

  • In selected patients at higher risk for residual/recurrent disease (e.g., N1), obtain a stimulated Tg measurement and consider concomitant diagnostic RAI imaging [PAP-8, FOLL-7, ONC-7].

Biopsy Or Salvage Logic

  • Lesions suspicious for locoregional recurrence should undergo FNA biopsy before salvage therapy. Tg washout is a useful adjunct to FNA, especially if cytology is negative [PAP-9, MS-25].

  • For biopsy-proven locoregional recurrence: surgery is preferred if resectable. Preoperative vocal cord assessment is recommended for central neck recurrence [PAP-9].

  • If surgery is not feasible (unresectable): RAI therapy if updated whole body scan shows RAI-avid disease; EBRT for non-avid disease; systemic therapy for progressive disease; local ablative therapies (ethanol ablation, RFA) for limited burden nodal disease [PAP-9].

  • For iodine-avid locoregional recurrence after prior RAI: repeat RAI therapy may be considered if there is evidence of response [PAP-9].

  • For distant metastatic disease: RAI therapy if iodine-avid; local therapies (surgery, radiation, ablation) for symptomatic or weight-bearing bone metastases; systemic therapy for progressive/symptomatic non-avid disease [PAP-10, FOLL-9, ONC-9].

  • Active surveillance is appropriate for low-volume disease that is stable and distant from critical structures. Routine intervention for biochemically only (Tg positive, imaging negative) disease is not recommended [PAP-9].

  • For medullary carcinoma: increasing biomarkers (calcitonin/CEA) alone are not an indication for systemic therapy; structural progression by RECIST criteria is required [MEDU-6].

  • For anaplastic carcinoma: if NED is achieved after initial therapy, continued disease monitoring with imaging (CT/MRI) at frequent intervals; second-line systemic therapy or clinical trial for progression [ANAP-3].

SurveillanceClick to collapse

Clinical Follow Up Schedule

  • Differentiated (lobectomy): physical exam, TSH, neck ultrasound at 6-12 months; consider one-time Tg/TgAb. Then annually if NED for 5 years, then every 1-3 years for 5-8 years, then discontinue. After 10-15 years no recurrence, no further monitoring [PAP-7, FOLL-6, ONC-6].
  • Differentiated (total thyroidectomy without RAI): physical exam, TSH, Tg/TgAb at 6-12 weeks; neck ultrasound at 6-12 months. Then annually if stable, neck ultrasound as clinically indicated [PAP-7, FOLL-6].
  • Differentiated (total thyroidectomy with RAI): physical exam, neck ultrasound at 6-12 months, TSH, Tg/TgAb. Then annually if NED; neck ultrasound every 1-3 years for 5-8 years, then discontinue [PAP-8, FOLL-7, ONC-7].
  • Medullary: if undetectable postoperative calcitonin, annual serum calcitonin, CEA; consider neck ultrasound [MEDU-5]. If detectable calcitonin, CT/MRI as indicated; then calcitonin/CEA every 6-12 months, imaging based on doubling times [MEDU-5].
  • Anaplastic: imaging (CT or MRI) of brain, neck, chest, abdomen, pelvis at frequent intervals as clinically indicated; consider FDG-PET/CT 3-6 months after initial therapy [ANAP-3].

Imaging Strategy

  • Neck ultrasound is principal imaging modality for surveillance of differentiated thyroid cancer [369].
  • Cross-sectional imaging (CT/MRI with contrast) when suspicious nodes detected on ultrasound or for vocal cord paresis [PAP-1].
  • FDG-PET/CT for suspected recurrence with negative iodine imaging and elevated Tg [263].
  • For medullary: CT/MRI of neck, chest, abdomen with liver protocol if calcitonin ≥150 pg/mL; consider Ga-68 DOTATATE PET/CT [MEDU-5].
  • For anaplastic: CT with contrast of head, neck, chest, abdomen, pelvis; FDG-PET/CT or PET/MRI; brain MRI [ANAP-1].

Laboratory Monitoring

  • Tg and TgAb: functional sensitivity ≤0.1 ng/mL for Tg, ≤0.9 ng/mL for TgAb recommended [269,270]. Tg should be measured using same laboratory and assay due to inter-laboratory variability [3].
  • TSH: to guide levothyroxine dose for suppression or normalization [THYR-A].
  • Medullary: serum calcitonin and CEA are cornerstone [MEDU-5].
  • Anaplastic: CBC with differential, comprehensive chemistry, TSH [ANAP-1].

Supportive Follow Up

  • See NCCN Guidelines for Survivorship for general survivorship care [PAP-7, FOLL-6, ONC-6].
  • Counsel patients with chronically suppressed TSH on adequate calcium and vitamin D intake [THYR-A].
  • In MEN2 families, genetic counseling and testing for family members [MEDU-3, THYR-E].
  • For patients with distant metastases, best supportive care per NCCN Guidelines for Palliative Care.

ComplicationsClick to collapse

Disease-Related

ComplicationManagement
Airway obstruction and suffocation (especially in ATC)Tracheostomy only if strongly indicated; prophylactic tracheostomy avoided [525,531]. Airway management and IV steroids discussed early [ANAP-1].
Hoarseness due to vocal cord paralysis (from invasion)Vocal cord assessment recommended; management per multidisciplinary team.
Diarrhea and flushing (from calcitonin secretion in MTC)Somatostatin analogs (e.g., octreotide, lanreotide) may be useful [439].
Cushing syndrome (from ACTH production by MTC)Treat underlying tumor; consider somatostatin analogs.
Hyperparathyroidism (MEN2A associated)Parathyroid exploration during thyroidectomy; autotransplant or cryopreservation [MEDU-4].
Pheochromocytoma (MEN2A/2B associated)Screen preoperatively; resect before thyroid surgery [MEDU-1].

Supportive CareClick to collapse

Supportive care is essential in thyroid cancer management, especially for advanced/metastatic disease and anaplastic carcinoma. Early initiation of palliative care and discussions about end-of-life care are critical, particularly for ATC where airway management is paramount [520,525]. The NCCN Guidelines for Palliative Care should be referenced.

Nutritional Support

Consider dental, speech and swallowing, and nutrition evaluation prior to RT; gastrostomy placement may be appropriate [THYR-C 3 of 5]. Enteral nutrition may be useful for patients with difficulty swallowing (see NCCN Guidelines for Head and Neck Cancer). In ATC, if enteral feeding considered, careful conversation with patient about wishes [THYR-C 3 of 5].

Anti Emetic Protocol

Not specifically detailed in the thyroid carcinoma guideline. General antiemetic protocols per NCCN Guidelines for Antiemesis should be followed when using chemotherapy.

Gcsf Guidance

Not specifically detailed in the thyroid carcinoma guideline. G-CSF use per NCCN Guidelines for Myeloid Growth Factors when indicated for chemotherapy-induced neutropenia.

Vte Prophylaxis

Not specifically detailed in the thyroid carcinoma guideline. VTE prophylaxis per NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease.

Pain Management

Bone metastases: Consider surgical palliation, RT, embolization, bisphosphonates/denosumab [PAP-11, FOLL-10, ONC-10, MEDU-7]. Pain management per NCCN Guidelines for Adult Cancer Pain.

Psychosocial Support

Refer to the NCCN Distress Thermometer and Problem List, which includes social determinants of health. See NCCN Guidelines for Distress Management [THYR-1A, footnote g].

Dental Care

Consider dental evaluation prior to RT to determine if pre-treatment optimization of dental and oral health is appropriate [THYR-C 3 of 5].

PrognosisClick to collapse

Differentiated thyroid carcinomas (papillary, follicular, oncocytic) generally have an excellent prognosis with 10-year survival rates exceeding 90% to 95% [10,11]. In contrast, anaplastic thyroid carcinoma (ATC) is almost uniformly lethal. Mortality rates for thyroid carcinoma are, in general, very low. Differentiated thyroid carcinomas represent more than 95% of all cases, so most thyroid carcinoma deaths are from papillary, follicular, and oncocytic carcinomas. In 2024, it is estimated that approximately 2170 cancer deaths will occur among persons with thyroid carcinoma in the United States [8]. The stable age- and gender-adjusted mortality rate for thyroid carcinoma contrasts distinctly with the declining rates for other solid tumors in adults [32,33].

Overall Prognosis

By Stage

StageFive Yr SurvivalContext
Differentiated (papillary, follicular, oncocytic) – overallNot explicitly stated as 5-year; 10-year survival >90-95%10-year survival rates exceeding 90% to 95% [10,11]
Medullary – Stage I-III~93%5-year relative survival for stages I to III is about 93% [193,437]
Medullary – Stage IV (distant metastases)~28%5-year survival for stage IV is about 28% [193,437]
Anaplastic – overall~20% 1-year survival1-year survival rate is about 20% [519,524]; median survival from diagnosis is about 5 months [515,524]
Anaplastic – confined to neckNoneMean survival of 8 months if disease confined to neck compared with 3 months if extends beyond neck [526]

Prognostic Factors

  • Age at diagnosis is the most important prognostic variable for thyroid cancer mortality [112].
  • Tumor histology, primary tumor size, local invasion, necrosis, vascular invasion, BRAF V600E mutation status, and metastases are important [133-135].
  • Lymph node metastases are generally associated with worse prognosis, especially in older patients [176-178].
  • Distant metastases are the principal cause of death from papillary and follicular carcinomas [182,183].
  • In medullary carcinoma, somatic RET oncogene mutation confers adverse prognosis [140]; calcitonin and CEA doubling times are predictive [440].
  • In anaplastic carcinoma, older age, distant metastases, WBC ≥10,000 mm3, and dyspnea predict worse prognosis [527-529].
  • The presence of anti-Tg antibodies and postoperative Tg levels are important for recurrence risk.
  • Tumor size >4 cm, gross extrathyroidal extension, and aggressive histologic subtypes are adverse factors.

Follow UpClick to collapse

Post Curative Treatment

Follow-up after curative treatment for differentiated thyroid cancer depends on initial therapy (lobectomy, total thyroidectomy with or without RAI). For lobectomy: physical exam, TSH, neck ultrasound at 6-12 months, consider one-time Tg and TgAb measurement. For total thyroidectomy without RAI: physical exam, TSH, Tg and TgAb at 6-12 weeks, neck ultrasound at 6-12 months. For total thyroidectomy with RAI: physical exam, neck ultrasound at 6-12 months, TSH, Tg and TgAb measurement. In selected patients at higher risk, obtain Tg measurement and consider concomitant diagnostic RAI imaging [PAP-7, PAP-8, FOLL-6, FOLL-7, ONC-6, ONC-7]. For medullary carcinoma: postoperative calcitonin and CEA at 2-3 months; detectable calcitonin leads to further imaging; if undetectable, annual serum calcitonin and CEA [MEDU-5]. For anaplastic carcinoma: imaging at frequent intervals as clinically indicated [ANAP-3].

Surveillance Rationale

Most recurrences occur in first 5 years, with remaining within 8 years [105]. However, small-volume lymph node recurrences detected by sensitive assays may show little progression over years and not increase mortality [109,110]. Dynamic risk assessment allows modification of initial risk estimates over time [206]. After 10-15 years of no recurrence for patients at low risk, no further monitoring for thyroid cancer is indicated [PAP-7, FOLL-6, ONC-6].

Late Effects Screening

  • RAI: salivary gland dysfunction, lacrimal gland dysfunction, secondary malignancies (leukemia, salivary gland malignancies) – monitor as clinically indicated [246,256].
  • TSH suppression: cardiac tachyarrhythmias (especially elderly), bone demineralization (post-menopausal women), symptoms of thyrotoxicosis – counsel on adequate calcium/vitamin D intake [THYR-A].
  • Kinase inhibitors: monitor for hypertension, bleeding, liver toxicity, QT prolongation, etc. [363,366,416,424].
  • Post-thyroidectomy hypoparathyroidism: monitor calcium, vitamin D levels.
  • In MEN2: annual screening for pheochromocytoma and hyperparathyroidism [MEDU-5].

Recurrence Patterns

About 75% of recurrences in differentiated thyroid cancer occur during first 5 years, remaining within 8 years [105]. Recurrences typically located in cervical lymph nodes or thyroid bed [105]. Distant metastases occur in ~3-5% and are principal cause of death [182,183]. Sites: lung (49%), bone (25%), both (15%), CNS (10%) [184-187]. In ATC, most have extensive local invasion or distant metastases at presentation; lungs/pleura most common distant site (≤90%) [518,519].

Key TrialsClick to collapse

AcronymFull NameYearNInterventionComparatorPopulationPrimary EndpointKey ResultSecondary OutcomesPractice ChangeJournal
SELECTPhase 3 trial of lenvatinib versus placebo in radioiodine-refractory differentiated thyroid cancer2015392Lenvatinib 24 mg/dayPlaceboPatients with radioiodine-refractory differentiated thyroid cancerProgression-free survivalMedian PFS: 18.3 months (lenvatinib) vs. 3.6 months (placebo); HR 0.21, 99% CI 0.14-0.31, p<0.001Overall response rate 65% vs. 12%; six treatment-related deaths in lenvatinib armLenvatinib became preferred first-line systemic therapy for RAI-refractory differentiated thyroid cancer (category 1)New England Journal of Medicine
DECISIONPhase 3 trial of sorafenib versus placebo in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer2014417Sorafenib 400 mg twice dailyPlaceboPatients with RAI-refractory differentiated thyroid cancerProgression-free survivalMedian PFS: 10.8 months (sorafenib) vs. 5.8 months (placebo); HR 0.59, 95% CI 0.45-0.76, p<0.0001One treatment-related death; hand-foot syndrome commonSorafenib established as a category 1 option for RAI-refractory differentiated thyroid cancerLancet
COSMIC-311A randomised, double-blind, placebo-controlled, phase 3 trial of cabozantinib for radioiodine-refractory differentiated thyroid cancer2021187 (interim analysis), 330 (total)Cabozantinib 60 mg dailyPlaceboPatients with RAI-refractory differentiated thyroid cancer who progressed during or after VEGFR TKI (lenvatinib and/or sorafenib)Progression-free survivalMedian PFS: not reached vs. 1.9 months; HR 0.22, 99% CI 0.13-0.36, p<0.0001. At extended follow-up: median PFS 11.0 vs. 1.9 months; HR 0.22, 95% CI 0.15-0.32, p<0.0001ORR 11.0% vs. 0% (p=0.0003); no treatment-related deathsCabozantinib became a category 1 option for disease progression after lenvatinib and/or sorafenibLancet Oncology
ZETAPhase 3 trial of vandetanib in patients with locally advanced or metastatic medullary thyroid cancer2012331Vandetanib 300 mg dailyPlaceboPatients with unresectable locally advanced or metastatic MTCProgression-free survivalMedian PFS: HR 0.46, 95% CI 0.31-0.69, p<0.001; post-hoc analysis in symptomatic/progressive disease: ORR 37% vs. 2% (p<0.001)OS data not yet available; QTc prolongation risk requiring REMS programVandetanib became a category 1 preferred option for advanced MTC; access restricted through REMS programJournal of Clinical Oncology
EXAMPhase 3 trial of cabozantinib in progressive medullary thyroid cancer2013330Cabozantinib 140 mg dailyPlaceboPatients with radiographically progressive metastatic MTCProgression-free survivalMedian PFS: 11.2 months vs. 4.0 months; HR 0.28, 95% CI 0.19-0.40, p<0.001Median OS: 26.6 vs. 21.1 months (not statistically significant; HR 0.85, 95% CI 0.64-1.12, p=0.24)Cabozantinib became a category 1 preferred option for advanced MTCJournal of Clinical Oncology
LIBRETTO-531Phase 3 trial of selpercatinib versus cabozantinib or vandetanib in advanced RET-mutant medullary thyroid cancer2023291Selpercatinib 160 mg twice dailyCabozantinib or vandetanib (physician's choice)Patients with progressive RET-mutant MTC (first-line treatment)Progression-free survivalMedian PFS: not reached vs. 16.8 months; HR 0.28, 95% CI 0.16-0.48, p<0.001; 12-month PFS 86.8% vs. 65.7%ORR 69.4% vs. 38.8%; treatment failure-free survival significantly improved; safety profile favorableSelpercatinib became a category 1 preferred option for RET-mutant MTC (first-line)New England Journal of Medicine
ROARPhase 2 basket study of dabrafenib plus trametinib in BRAF V600E-mutant anaplastic thyroid cancer2018 (initial), 2023 (update)16 (initial), 36 (updated)Dabrafenib 150 mg twice daily + trametinib 2 mg once dailyNone (single arm)Patients with locally advanced or metastatic BRAF V600E-mutant anaplastic thyroid cancerOverall response rateConfirmed ORR 69% (initial); updated ORR 56% (95% CI 38.1%-72.1%) with 3 complete responses; median PFS 6.7 months, median OS 14.5 months; 12-month OS 43.2%, PFS 51.7%Durable responses; acceptable safety profileDabrafenib/trametinib became a preferred systemic therapy for BRAF V600E-mutated ATC; FDA approved for this indication in 2018Journal of Clinical Oncology (2018), Nature Medicine (2023)

Clinical PearlsClick to collapse

  • Pearl 1: 1. Age is the most important prognostic factor for thyroid cancer mortality; the AJCC 8th edition uses age 55 as cut-off for differentiated thyroid cancer staging, changing from 45 [10,112].
  • Pearl 2: 2. BRAF V600E mutation occurs in ~45% of papillary carcinomas; when combined with TERT promoter mutation, it confers worse prognosis [77-81]. However, BRAF V600E alone is generally not considered a poor prognostic factor [82-84].
  • Pearl 3: 3. Microscopic extrathyroidal extension alone does not warrant RAI [PAP-4A, FOLL-3, ONC-3].
  • Pearl 4: 4. For low-risk papillary microcarcinoma (≤1 cm), active surveillance is an option; patient age is negatively associated with progression [113, THYR-D].
  • Pearl 5: 5. In medullary carcinoma, calcitonin and CEA doubling times are key predictors of disease progression; systemic therapy should not be initiated based on biomarker increase alone without structural progression [MEDU-6, MEDU-7].
  • Pearl 6: 6. For anaplastic thyroid carcinoma, urgent BRAF IHC testing is recommended due to faster turnaround; dabrafenib/trametinib can be life-saving for BRAF V600E-mutated disease [ANAP-1, 541].
  • Pearl 7: 7. After 10-15 years of no recurrence in low-risk patients, no further monitoring for thyroid cancer is indicated [PAP-7, FOLL-6, ONC-6].
  • Pearl 8: 8. Prophylactic central neck dissection is not recommended in most papillary thyroid cancers; three RCTs showed no benefit in outcomes [PAP-1 footnote f, 377-379].

Special SituationsClick to collapse

Active surveillance for low-risk papillary thyroid microcarcinoma (≤1 cm)
Pregnancy and RAI
Breastfeeding and RAI
Pediatric thyroid cancer
Renal impairment and RAI
Radiologically occult recurrence (Tg-positive, imaging-negative)

Guidelines ResourcesClick to collapse

NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma
2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer
ACR Thyroid Imaging, Reporting and Data System (TI-RADS)
AJCC Cancer Staging Manual, 8th Edition
Protocol for the Examination of Specimens From Patients With Carcinomas of the Thyroid Gland
ThyCa.org