NCCN Clinical Practice Guidelines in Oncology. Thyroid Carcinoma V Continue.

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1 Clinical in Oncology Thyroid Carcinoma V Continue

2 TOC * Steven I. Sherman, MD/Chair ð The University of Texas M. D. Anderson Cancer Center * R. Michael Tuttle, MD/Co-Chair ð Memorial Sloan-Kettering Cancer Center Douglas W. Ball, MD ð The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins David Byrd, MD Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance Orlo H. Clark, MD UCSF Helen Diller Family Comprehensive Cancer Center Gilbert H. Daniels, MD ð Massachusetts General Hospital Cancer Center Raza A. Dilawari, MD St. Jude Children's Research Hospital/ University of Tennessee Cancer Institute Gerard M. Doherty, MD University of Michigan Comprehensive Cancer Center Hormoz Ehya, MD Fox Chase Cancer Center Guidelines Panel Disclosures Panel Members William B. Farrar, MD Arthur G. James Cancer Hospital and Richard J. Solove Research Institute at The Ohio State University Robert I. Haddad, MD Dana-Farber/Brigham and Women s Cancer Center Fouad Kandeel, MD, PhD City of Hope * Richard T. Kloos, MD ð Arthur G. James Cancer Hospital & Richard J. Solove Research Institute at The Ohio State University Peter Kopp, MD ð Robert H. Lurie Comprehensive Cancer Center of Northwestern University Dominick M. Lamonica, MD Þ Roswell Park Cancer Institute Thom R. Loree, MD Roswell Park Cancer Institute William M. Lydiatt, MD UNMC Eppley Cancer Center at The Nebraska Medical Center Judith McCaffrey, MD H. Lee Moffitt Cancer Center & Research Institute ð Continue * John A. Olson, Jr., MD, PhD Duke Comprehensive Cancer Center Lee Parks, MD ð Vanderbilt-Ingram Cancer Center John A. Ridge, MD, PhD Fox Chase Cancer Center Jatin P. Shah, MD Memorial Sloan-Kettering Cancer Center Cord Sturgeon, MD Robert H. Lurie Comprehensive Cancer Center of Northwestern University Steven G. Waguespack, MD ð The University of Texas M. D. Anderson Cancer Center Thomas N. Wang, MD University of Alabama at Birmingham Comprehensive Cancer Center Lori J. Wirth, MD Massachusetts General Hospital Cancer Center ð Endocrinology Surgery/Surgical oncology Medical Oncology Pathology Þ Internal medicine Nuclear Medicine Otolaryngology * Writing Committee Member Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of.

3 TOC Table of Contents Panel Members Summary of Guidelines Updates Nodule Evaluation (THYR-1) Principles of TSH Suppression (THYR-A) Papillary Carcinoma FNA positive (PAP-1) Incidental finding postlobectomy (PAP-2) Follicular Carcinoma (FOLL-1) Hürthle Cell Carcinoma ( HÜRT-1) Medullary Carcinoma Diagnosed by FNA (MEDU-1) Germline mutation of RET proto-oncogene (MEDU-2) Anaplastic Carcinoma (ANAP-1) Print the Guideline For help using these documents, please click here Staging Discussion References This manuscript is being updated to correspond with the newly updated algorithm. Clinical Trials: The believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. To find clinical trials online at member institutions, click here: nccn.org/clinical_trials/physician.html Categories of Evidence and Consensus: All recommendations are Category 2A unless otherwise specified. See Categories of Evidence and Consensus These guidelines are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network makes no representations nor warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. These guidelines are copyrighted by National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced in any form without the express written permission of Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of.

4 Summary of the Guidelines updates TOC Summary of changes in the version of the Guidelines from the version include: Thyroid Nodule Evaluation PAP-2 THYR-1 Second column: Chest x-ray, if not recently done changed to Clinical Presentation; Second bullet: Age < 15 or > 45 y changed to Consider chest x-ray... Age < 15 y. Third column: Macroscopic multifocal disease was removed from THYR-2 the middle pathway and placed in the top pathway. Confirmed nodal The procedures for evaluating thyroid nodules have been revised--- metastasis was added to the top pathway. especially those for follicular or Hürthle cell neoplasms or for Last column: Thyroxine therapy to keep TSH low/normal changed to follicular lesions of undetermined significance---which cannot be Suppress TSH with levothyroxine. diagnosed by fine needle aspiration (FNA). The diagnostic categories PAP-3 for FNA results have been revised and reflect recent data from the No gross residual disease in neck pathway: After the TSH + National Cancer Institute state of the science conference, which have thyroglobulin measurement... recommendation, the decision points been carefully evaluated by the panel. for 1 cm and < 1 cm changed to a new Consider radioiodine THYR-A Principles of Thyroid Stimulating Hormone (TSH) Suppression (RAI) therapy pathway. (Also for FOLL-2 and HÜRT-2) Principles of TSH Suppression is a new page that provides specific PAP-4 recommendations for levothyroxine use for TSH suppression Second column:...or Clinical indication for radioiodine therapy throughout the Papillary, Follicular, and Hürthle Cell Guidelines. (category 2B) was added (Also for FOLL-3 and HÜRT-3). Postsurgical therapy: Adjuvant radioiodine ablation ( mci) of Papillary Carcinoma thyroid bed changed from category 2B to category 2A. PAP-1 (Also for FOLL-3 and HÜRT-3) FNA Finding: Footnote a was added stating, There is a potential PAP-5 role for frozen section if FNA is suspicious but not diagnostic for Surveillance and Maintenance: (Also for FOLL-4 and HÜRT-4) papillary carcinoma. Third bullet: Changed to TSH stimulated thyroglobulin in patients Diagnostic Procedures: previously treated with RAI and with negative TSH-suppresssed Third bullet: Consider lateral neck ultrasound changed from thyroglobulin and anti-thyroglobulin antibodies. category 2B to category 2A. (Also for FOLL-1 and HÜRT-1) New bullet added that states, Consider TSH-stimulated radioiodine CT/MRI for fixed or substernal... changed to CT/MRI for fixed, scan in patients T3-4 or M1 at initial staging, or with abnormal bulky, or substernal... (Also for FOLL-1 and HÜRT-1) thyroglobulin levels (either TSH-suppressed or TSH-stimulated), Last column: Suppress TSH with thyroxine changed to Consider abnormal antithyroglobulin antibodies, or abnormal ultrasound levothyroxine therapy to keep TSH low or normal. during surveillance. (Also for PAP-2, FOLL-1, and HÜRT-1) Last bullet regarding 131I scan was revised for clarity. Thyroxine changed to Levothyroxine throughout the algorithm. Footnote i was added stating, In selected patients who may be at (Also for the Follicular Carcinoma and Hürthle Cell Carcinoma higher risk for residual/recurrent disease (eg, N1 patients), obtain a algorithms) stimulated thyroglobulin and consider a concomitant diagnostic RAI scan. With a positive stimulated Tg, the concomitant RAI scan may help determine whether treatment with RAI is indicated (i.e. RAI is often beneficial in iodine-avid disease but not in non-iodine avid disease). (Also for FOLL-4 and HÜRT-4) UPDATES Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. 1 of 2

5 Summary of the Guidelines updates Medullary Carcinoma MEDU-1 Primary Treatment: Consider ipsilateral modified radical neck dissection... changed to...modified neck dissection... Papillary Carcinoma ---continued PAP-6 CNS; Treatment: Image-guided RT: Footnote stating that this recommendation does not include whole brain RT was removed from the page. (Also for FOLL-5 and HÜRT-5) Any extracervical sites changed to Sites other than CNS. Other than CNS; Treatment: Consider surgical resection of selected... changed to Consider surgical resection and/or RT of selected... (Also for FOLL-5 and HÜRT-5)...clinical trials for non-radioiodine avid tumors; sorafenib... changed to clinical trials for non-radioiodine avid tumors; consider small molecule kinase inhibitors, with corresponding new footnote n that states, While not FDA approved for treatment of thyroid cancer, commercially available small molecule kinase inhibitors (such as sorafenib or sunitinib) can be considered if clinical trials are not available or appropriate. (Also for FOLL-5 and HÜRT-5) Follicular Carcinoma (Also see the Papillary Carcinoma Updates) FOLL-1 Pathology Finding: Changed to Follicular neoplasm or Follicular lesion of undetermined significance. Diagnostic Procedures: Chest x-ray changed to Consider chest x-ray. (Also for HÜRT-1) After Primary Treatment, two new branch points were added: Benign and Follicular carcinoma. Hürthle Cell Carcinoma (Also see the Papillary Carcinoma Updates) HÜRT-1 Pathology Finding: Changed to Hürthle cell neoplasm or Lesion of undetermined significance. After Primary Treatment, two new branch points were added: Benign and Hürthle cell carcinoma. TOC Primary Treatment; Third bullet: Changed to Consider adjuvant RT for T4 disease involving major neck structures. (Also for MEDU-3) Footnote about when to evaluate for exon 8 was deleted. MEDU-2 MEN 2A pathway: The recommendation Calcium stimulated calcitonin test if calcitonin undetectable (category 2B for use in timing of surgery) was removed. Footnote b : The second sentence was revised and now states, Prophylatic thyroidectomy may be delayed in patients with these less high risk, later onset RET mutations, provided the annual calcitonin measurement is normal, the annual ultrasound (US) is unremarkable, there is no history of aggressive MTC in the family, and the family is in agreement. (Also for MEDU-3) MEDU-3 After No primary hyperparathyroidism, the recommendation, Evaluate for other causes of hypercalcemia was removed. Primary hyperparathyroidism, Primary Treatment; Fourth bullet: The recommendation regarding multiglandular disease was reworded for clarity. MEDU-4 New footnote f stating, Bone scan, FDG-PET scan, and MRI of axial skeleton should be considered in patients with very elevated calcitonin levels was added. MEDU-5 Last column: Sorafenib changed to Small molecule kinase inhibitors with corresponding footnote g stating, While not FDA approved for treatment of thyroid cancer, commercially available small molecule kinase inhibitors (such as sorafenib or sunitinib) can be considered if clinical trials are not available or appropriate. Anaplastic Carcinoma ANAP-1 Diagnostic Procedures: The following recommendations were added Consider FDG-PET scan and Consider bone scan. Footnote a regarding FNA diagnosis and core biopsy was revised. UPDATES 2 of 2 Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of.

6 CLINICAL PRESENTATION Solitary nodule > 1 cm in diametera Nodule Evaluation WORKUP TOC Thyroid nodule with unknown TSH Increased suspicion if any of the following are present: b Age < 15 y Male sex Nodule > 4 cm in diameter History of radiation exposure History of diseases associated with thyroid cancer: Pheochromocytoma MEN2 Gardner s syndrome Familial adenomatous polyposis Carney complex Cowden s syndrome Suspicious criteria by ultrasound Central hypervascularity Irregular border Microcalcification Incidentally identified focal PET positive lesion in the thyroid Highly suspicious: c Rapid nodule growth Very firm nodule Fixation to adjacent structures Family history of thyroid cancer Vocal cord paralysis Enlarged regional lymph nodes Symptoms of invasion into neck structures Clinically euthyroid: TSH measurement Ultrasound of thyroid and neck including central and lateral neck compartments (category 2B) FNA of nodule FNA of clinically suspicious lymph nodes See FNA Results (THYR-2) Thyroid nodule with low TSH Nodules < 1 cm in diameter without suspicious findings and without suspicious lymph nodes by ultrasound, or simple cyst Follow-up as clinically indicated Consider lateral neck ultrasound If findings consistent with criteria of increased suspicion - see above pathway See Primary Treatment (THYR-2) Papillary carcinoma, finding postlobectomy for benign disease See Primary Treatment (PAP-2) ain selected cases, it may be reasonable to follow with serial ultrasounds. bpatients with elevated TSH levels, may have an increased risk of malignancy. cconsider surgery after FNA. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. THYR-1

7 Nodule Evaluation TOC FNA RESULTS Carcinoma Papillary or suspicious for papillary Medullary or suspicious for medullary TREATMENT See Primary Treatment (PAP-1) See Primary Treatment (MEDU-1) Diagnostic categories for FNA results reflect NCI state of the science conference, available from Cytology reports should be interpreted in light of terminology used by local cytopathologists. Follicular or Hürthle cell neoplasm d Anaplastic or suspicious for anaplastic TSH high or normal TSH low See Primary Treatment (ANAP-1) Surgery g Thyroid scan Cold Hot Surgery g Evaluate and treat for thyrotoxicosis as indicated (malignancy is rare) See Primary Treatment for Follicular (FOLL-1) or Hürthle (HURT-1) Follicular lesion of undetermined significance e Thyroid lymphoma Insufficient biopsy, nondiagnostic Benign f TSH high or normal TSH low Cystic Solid Thyroid scan See Non-Hodgkin s Lymphoma Guideline Repeat FNA, consider ultrasound guidance and immediate cytologic review or consider surgery Observe If nodule growth, repeat FNA or consider surgery dalternative term: Suspicious for follicular or Hürthle cell neoplasm. Estimated risk of malignancy is 20%-30%. e Alternative terms include: Atypia of undetermined significance, rule out neoplasm, atypical follicular lesion, and cellular follicular lesion. Estimated risk of malignancy is 5%-10%. fincludes nodular goiter, colloid nodule, hyperplastic/adenomatoid nodule, Hashimoto s thyroiditis. Estimated risk of malignancy is < 1%. g Surgery usually means a diagnostic lobectomy for these follicular lesions. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Cold Hot Repeat FNA, consider surgeryg based on clinical grounds, concerning growth, or suspicious sonographic findings Evaluate and treat for thyrotoxicosis as indicated (malignancy is rare) Correlate with ultrasound, re-aspirate suspicious areas See Primary Treatment for Follicular (FOLL-1) or Hürthle (HURT-1) Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. THYR-2

8 Nodule Evaluation TOC PRINCIPLES OF THYROID STIMULATING HORMONE (TSH) SUPPRESSION Because TSH is a trophic hormone that can stimulate the growth of cells derived from thyroid follicular epithelium, the use of levothyroxine to maintain low TSH levels is considered optimal in treatment of patients with papillary, follicular, or Hürthle cell carcinoma. However, data are lacking to permit precise specification of the appropriate serum levels of TSH. In general, patients with known residual carcinoma or at high risk for recurrence should have TSH levels maintained below 0.1 mu/l, whereas disease-free patients at low risk for recurrence should have TSH levels maintained either slightly below or slightly above the lower limit of the reference range. Patients who remain disease free for several years can probably have their TSH levels maintained within the reference range. Given the potential toxicities associated with TSH-suppressive doses of levothyroxine---including cardiac tachyarrhythmias and bone demineralization as well as frank symptoms of thyrotoxicosis---the risk and benefit of TSH-suppressive therapy must be balanced for each individual patient. Patients whose TSH levels are chronically suppressed should be counseled to ensure adequate daily intake of calcium (1200 mg/day) and vitamin D (800 units/day). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. THYR-A

9 FNA FINDING Papillary carcinoma FNA positive a a b c d e DIAGNOSTIC PROCEDURES Consider chest x-ray Thyroid ultrasound, if not previously done Consider lateral neck ultrasound CT/MRI for fixed, bulky, or substernal lesions (avoid iodinated contrast, unless essential) Evaluate vocal cord mobility (category 2B) Papillary Carcinoma PREOPERATIVE OR INTRAOPERATIVE DECISION-MAKING CRITERIA Indications for total thyroidectomy: (any present) Age < 15 y or > 45 yb Radiation history Known distant metastases Bilateral nodularity Extrathyroidal extension Tumor > 4 cm in diameter Cervical lymph node metastases Aggressive variantc Indications for total thyroidectomy or lobectomy: (all present) Age 15 y - 45 yb No prior radiation No distant metastases No cervical lymph node metastases No extrathyroidal extension Tumor < 4 cm in diameter No aggressive variantc PRIMARY TREATMENT Total thyroidectomy If lymph node(s) palpable or biopsy positive: Central neck dissection (level VI) Lateral neck dissection (levels II-IV, consider level V, sparing spinal accessory nerve, internal jugular vein, and sternocleidomastoid muscle) Consider preservation of the cervical sensory nerves If node(s) negative, consider prophylactic central neck dissection (level VI) (category 2B) d Total thyroidectomy (most common) (category 2B) Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. or Lobectomy + isthmusectomy (category 2B) There is a potential role for frozen section if FNA is suspicious but not diagnostic for papillary carcinoma. Age is an approximation and not an absolute determination. Tall cell, columnar cell, insular, oxyphilic, or poorly differentiated features. Possible benefit to reduce recurrence must be balanced with risk of hypoparathyroidism. See Principles of TSH Suppression (THYR-A). Aggressive variantc Macroscopic multifocal disease Positive isthmus margins Cervical lymph node metastases Extrathyroidal extension Negative margins No contralateral lesion TOC See Postsurgical Evaluation (PAP-3) Completion of thyroidectomy Consider thyroglobulin measurement Consider levothyroxine therapy to keep TSH low or normal e See Surveillance and Maintenance (PAP-5) Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. PAP-1

10 Papillary Carcinoma TOC CLINICAL PRESENTATION PRIMARY TREATMENT Papillary carcinoma found postlobectomy for benign disease Thyroid and neck ultrasound, if not previously done Consider chest x-ray, if not recently done > 4 cm Positive margins Extra-thyroidal invasion (T3 or T4) Macroscopic multifocal disease Confirmed nodal metastasis Clinically suspicious lymph node, contralateral lesion, or perithyroidal node Aggressive variantc 1 cm in diameter Negative margins No contralateral lesion < 1 cm in diameter No suspicious lymph node Completion of thyroidectomy Completion of thyroidectomy (category 2B) or Thyroglobulin measurement + antithyroglobulin antibodies Consider thyroglobulin measurement + antithyroglobulin antibodies Suppress TSH with levothyroxine e Consider levothyroxine therapy to keep TSH low or normal e See Postsurgical Evaluation (PAP-3) See Surveillance and Maintenance (PAP-5) c Tall cell, columnar cell, insular, oxyphilic, or poorly differentiated features. e See Principles of TSH Suppression (THYR-A). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. PAP-2

11 Papillary Carcinoma TOC POSTSURGICAL EVALUATION AFTER THYROIDECTOMY No gross residual disease in neck Resectable Resect, if possible No gross residual disease TSH + thyroglobulin measurement + antithyroglobulin antibodies (1-12 wk postoperatively) Consider radioiodine (RAI) therapy Yes (based on clinical indication for RAI) f No clinical indication for RAI f See Postsurgical Therapy (PAP-4) Gross residual disease in neck Unresectable Gross residual disease TSH + thyroglobulin measurement + antithyroglobulin antibodies (1-12 wk postoperatively) Total body radioiodine scan (category 2B) Inadequate uptake Adequate uptake No scan performed RT Radioiodine treatment Posttreatment 131I scan RT Suppress TSH with levothyroxine e See Surveillance and Maintenance (PAP-5) esee Principles of TSH Suppression (THYR-A). f Suspicion based on pathology, postoperative thyroglobulin, and intraoperative findings. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. PAP-3

12 Papillary Carcinoma TOC POSTSURGICAL THERAPY 1-12 wk postthyroidectomy: No gross residual disease in neck Total body radioiodine scan (category 2B) with adequate TSH stimulation (thyroid withdrawal or recombinant rhtsh stimulation) or Clinical indication for radioiodine therapyf (category 2B) Thyroglobulin < 1 ng/ml with negative thyroglobulin antibodies and radioiodine scan negative Suspected f or proven thyroid bed uptake Suspectedf or proven radioiodine avid residual tumorg No radioiodine treatment Adjuvant radioiodine ablation ( mci) of thyroid bed and post-treatment scan Radioiodine treatment ( mci) and post-treatment scan or consider dosimetry for distant metastasis T4 (surgically evident extrathyroidal invasion) and age > 45 y All others Consider RT Suppress TSH with levothyroxine e See Surveillance and Maintenance (PAP-5) esee Principles of TSH Suppression (THYR-A). fsuspicion based on pathology, postoperative thyroglobulin, and intraoperative findings. gall patients should be examined, and palpable neck disease should be surgically resected before radioiodine treatment. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. PAP-4

13 SURVEILLANCE AND MAINTENANCE Papillary Carcinoma RECURRENT DISEASE TOC Physical examination, TSH and thyroglobulin measurement + antithyroglobulin antibodies at 6 and 12 mo, then annually if disease-free Periodic neck ultrasound h TSH stimulated thyroglobulin in patients previously treated with RAI and with negative TSH-suppressed thyroglobulin and anti-thyroglobulin antibodiesi Consider TSH-stimulated radioiodine scan in patients with T3-4 or M1 at initial staging, or with abnormal thyroglobulin levels (either TSHsuppressed or TSH-stimulated), abnormal antithyroglobulin antibodies, or abnormal ultrasound during surveillance If detectable thyroglobulin or distant metastases or soft tissue invasion on initial staging, radioiodine scan every 12 mo until no response is seen to RAI treatment in iodine avid tumors (either withdrawal of thyroid hormone or rhtsh) j If 131I scans negative and stimulated Tg > 2-5 ng/ml, consider additional nonradioiodine imaging (eg, FDG PET ± CT if Tg 10 ng/ml) Stimulated Tg 1-10 ng/ml Non-resectable tumors Non-radioiodine avid Locoregional recurrence Stimulated Tg > 10 ng / ml Scans (including PET) negative Metastatic disease Suppress TSH with levothyroxine e Surgery (preferred) if resectablek and/or Radioiodine treatment, if radioiodine scan positive and/or RT, if radioiodine scan negative Consider radioiodine therapy with mci, post-treatment 131I scan (category 3) See Treatment of Metastases (PAP-6) esee Principles of TSH Suppression (THYR-A). ha subgroup of low risk patients may only require an ultrasound if there is a reasonable suspicion for recurrence. iin selected patients who may be at higher risk for residual/recurrent disease (eg, N1 patients), obtain a stimulated thyroglobulin and consider a concomitant diagnostic RAI scan. With a positive stimulated Tg, the concomitant RAI scan may help determine whether treatment with RAI is indicated (ie, RAI is often beneficial in iodineavid disease but not in non-iodine avid disease). jif there is a high likelihood of therapy, thyroid hormone withdrawal suggested; if not, suggest using rhtsh. kconsider preoperative vocal cord assessment, if central neck recurrence. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. PAP-5

14 CNS Papillary Carcinoma TREATMENT OF METASTASES TOC Consider neurosurgical resectionl and/or Radioiodine treatment with rhtsh and steroid prophylaxis, if radioiodine scan positive with consideration of dosimetry to maximize dosing and/or Image-guided RTl Metastatic disease Continue to suppress TSH with levothyroxinee e l m Bone Sites other than CNS Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Surgical palliation, if symptomatic or asymptomatic in weight-bearing extremities and/or Radioiodine treatment, if radioiodine scan positive with consideration of dosimetry to maximize dosing and/or RT Consider bisphosphonate therapy Consider embolization of metastases Consider surgical resection and/or RT of selected, enlarging, or symptomatic metastases and/or Radioiodine if positive uptake, with consideration of dosimetry to maximize dosing and/or For clinically progressive or symptomatic disease: clinical trials for non-radioiodine avid tumors; m consider small molecule kinase inhibitorsn or systemic therapy (if trial not available) or Best Supportive Care See Principles of TSH Suppression (THYR-A). For solitary lesions, either neurosurgical resection or stereotactic radiosurgery preferred. Cytotoxic chemotherapy has shown to have minimal efficacy. Clinical trials investigating novel targeted therapies are ongoing. See Clinical trials available at the member institutions. nwhile not FDA approved for treatment of thyroid cancer, commercially available small molecule kinase inhibitors (such as sorafenib or sunitinib) can be considered if clinical trials are not available or appropriate. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. PAP-6

15 Follicular Carcinoma TOC PATHOLOGY FINDING DIAGNOSTIC PROCEDURES PRIMARY TREATMENT Follicular neoplasm or Follicular lesion of undetermined significance ( See THYR-2) Consider chest x-ray Consider lateral neck ultrasound CT/MRI for fixed bulky or substernal lesions (avoid iodinated contrast, unless essential) Evaluate vocal cord mobility (category 2B) Total thyroidectomy if invasive cancer, metastatic cancer, or patient decision If lymph node(s) positive: Central neck dissection (level VI) Lateral neck dissection (levels II-IV, consider for level V, sparing spinal accessory nerve, internal jugular vein, and sternocleidomastoid muscle) Consider preservation of the cervical sensory nerves Benign Follicular carcinoma Invasive cancer (extensive vascular invasion) Completion of thyroidectomy Levothyroxine therapy to keep TSH normal b See Postsurgical Evaluation (FOLL-2) or Lobectomy/isthmusectomy Minimally invasive cancer a Follicular adenoma a Minimally invasive cancer is characterized as a well-defined tumor with microscopic capsular and/or a few foci of vascular invasion and often requires examination of at least 10 histologic sections to demonstrate. b See Principles of TSH Suppression (THYR-A). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Consider completion of thyroidectomy or Observe Observe Consider levothyroxine therapy to keep TSH low or normal b See Surveillance and Maintenance (FOLL-4) Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. FOLL-1

16 Follicular Carcinoma TOC POSTSURGICAL EVALUATION AFTER THYROIDECTOMY No gross residual disease in neck Resectable Resect, if possible No gross residual disease TSH + thyroglobulin measurement + antithyroglobulin antibodies (1-12 wk postoperatively) Consider radioiodine (RAI) therapy Yes (based on clinical indication for RAI) c No clinical indication for RAI c See Postsurgical Therapy (FOLL-3) Gross residual disease in neck Unresectable Gross residual disease TSH + thyroglobulin measurement + antithyroglobulin antibodies (1-12 wk postoperatively) Total body radioiodine scan (category 2B) Inadequate uptake Adequate uptake No scan performed RT Radioiodine treatment Posttreatment 131I scan RT Suppress TSH with levothyroxine b See Surveillance and Maintenance (FOLL-4) bsee Principles of TSH Suppression (THYR-A). c Suspicion based on pathology, postoperative thyroglobulin, and intraoperative findings. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. FOLL-2

17 Follicular Carcinoma TOC POSTSURGICAL THERAPY Thyroglobulin < 1 ng/ml with negative thyroglobulin antibodies and radioiodine scan negative No radioiodine treatment 1-12 wk post-thyroidectomy: No gross residual disease in neck with adequate TSH stimulation (thyroid withdrawal or recombinant rhtsh stimulation) Total body radioiodine scan (category 2B) with adequate TSH stimulation (thyroid withdrawal or recombinant rhtsh stimulation) or Clinical indication for RAI therapy c (category 2B) Suspected c or proven thyroid bed uptake Adjuvant radioiodine ablation ( mci) of thyroid bed and post-treatment scan Suppress TSH with levothyroxine b See Surveillance and Maintenance (FOLL-4) Suspectedc or proven radioiodine avid residual tumord Radioiodine treatment ( mci) and post-treatment scan or consider dosimetry for distant metastasis bsee Principles of TSH Suppression (THYR-A). csuspicion based on pathology, postoperative thyroglobulin, and intraoperative findings. dall patients should be examined, and palpable neck disease should be surgically resected before radioiodine treatment. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. FOLL-3

18 SURVEILLANCE AND MAINTENANCE Follicular Carcinoma RECURRENT DISEASE TOC Physical examination, TSH and thyroglobulin measurement + antithyroglobulin antibodies at 6 and 12 mo, then annually if disease-free Periodic neck ultrasounde TSH stimulated thyroglobulin in patients previously treated with RAI and with negative TSH-suppressed thyroglobulin and anti-thyroglobulin antibodies f Consider TSH-stimulated radioiodine scan in patients with T3-4 or M1 at initial staging, or with abnormal thyroglobulin levels (either TSHsuppressed or TSH-stimulated), abnormal antithyroglobulin antibodies, or abnormal ultrasound during surveillance. If detectable thyroglobulin or distant metastases or soft tissue invasion on initial staging, radioiodine scan every 12 mo until no response is seen to RAI treatment in iodine avid tumors (either withdrawal of thyroid hormone or rhtsh) g If 131I scans negative and stimulated Tg > 2-5 ng/ml, consider additional nonradioiodine imaging (eg, FDG PET ± CT if Tg 10 ng/ml) Stimulated Tg 1-10 ng/ml Non-resectable tumors Non-radioiodine avid Locoregional recurrence Stimulated Tg > 10 ng / ml Scans (including PET) negative Metastatic disease Suppress TSH with levothyroxine b Surgery (preferred) if resectableh and/or radioiodine treatment, if radioiodine scan positive and/or RT, if radioiodine scan negative Consider radioiodine therapy with mci, posttreatment 131I scan (category 3) See Treatment of Metastases (FOLL-5) bsee Principles of TSH Suppression (THYR-A). ea subgroup of low risk patients may only require an ultrasound if there is a reasonable suspicion for recurrence. fin selected patients who may be at higher risk for residual/recurrent disease (eg, N1 patients), obtain a stimulated thyroglobulin and consider a concomitant diagnostic RAI scan. With a positive stimulated Tg, the concomitant RAI scan may help determine whether treatment with RAI is indicated (ie, RAI is often beneficial in iodineavid disease but not in non-iodine avid disease). gif there is a high likelihood of therapy, thyroid hormone withdrawal suggested; if not, suggest using rhtsh. hconsider preoperative vocal cord assessment, if central neck recurrence. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. FOLL-4

19 CNS Follicular Carcinoma TREATMENT OF METASTASES TOC Consider neurosurgical resectioni and/or Radioiodine treatment with rhtsh and steroid prophylaxis, if radioiodine scan positive with consideration of dosimetry to maximize dosing and/or Image-guided RTi Metastatic disease Continue to suppress TSH with levothyroxine b Bone Surgical palliation, if symptomatic or asymptomatic in weightbearing extremities and/or Radioiodine treatment, if radioiodine scan positive with consideration of dosimetry to maximize dosing and/or RT Consider bisphosphonate therapy Consider embolization of metastases b i j Sites other than CNS Consider surgical resection and/or RT of selected, enlarging, or symptomatic metastases and/or Radioiodine if positive uptake, with consideration of dosimetry to maximize dosing and/or For clinically progressive or symptomatic disease: clinical trials for non-radioiodine avid tumors; j consider small molecule kinase inhibitork or systemic therapy (if trial not available) or Best Supportive Care See Principles of TSH Suppression (THYR-A). For solitary lesions, either neurosurgical resection or stereotactic radiosurgery preferred. Cytotoxic chemotherapy has shown to have minimal efficacy. Clinical trials investigating novel targeted therapies are ongoing. See Clinical trials available at the member institutions. kwhile not FDA approved for treatment of thyroid cancer, commercially available small molecule kinase inhibitors (such as sorafenib or sunitinib) can be considered if clinical trials are not available or appropriate. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. FOLL-5

20 Hürthle Cell Carcinoma TOC PATHOLOGY FINDING DIAGNOSTIC PROCEDURES PRIMARY TREATMENT Hürthle cell neoplasm or Lesion of undetermined significance ( See THYR-2) Consider chest x-ray Consider lateral neck ultrasound CT/MRI for fixed, bulky, or substernal lesions (avoid iodinated contrast unless essential) Evaluate vocal cord mobility (category 2B) Total thyroidectomy, if invasive cancer or patient decision If lymph node(s) positive: Central neck dissection (level VI) Lateral neck dissection (Level II-IV, consider for level V, sparing spinal accessory nerve, internal jugular vein, and sternocleidomastoid muscle) Consider preservation of the cervical sensory nerves If node(s) negative, consider prophylactic central neck dissection (category 2B) a or Lobectomy/isthmusectomy Benign Hürthle cell carcinoma Invasive cancer (extensive vascular invasion) Minimally invasive cancer b Completion of thyroidectomy Strongly consider completion of thyroidectomy Levothyroxine therapy to keep TSH normal c See Postsurgical Evaluation (HÜRT-2) Hürthle adenoma or Observe Observe Consider levothyroxine therapy to keep TSH low or normal c apossible benefit to reduce recurrence must be balanced with risk of hypoparathyroidism. bminimally invasive cancer is characterized as a well-defined tumor with microscopic capsular and/or a few foci of vascular invasion and often requires examination of at least 10 histologic sections to demonstrate. c See Principles of TSH Suppression (THYR-A). Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. See Surveillance and Maintenance (HÜRT-4) HÜRT-1

21 Hürthle Cell Carcinoma TOC POSTSURGICAL EVALUATION AFTER THYROIDECTOMY No gross residual disease in neck Resectable Resect, if possible No gross residual disease TSH + thyroglobulin measurement + antithyroglobulin antibodies (1-12 wk postoperatively) Consider radioiodine (RAI) therapy Yes (based on clinical indication) d No clinical indication for RAI d See Postsurgical Therapy (HÜRT-3) See Surveillance and Maintenance (HÜRT-4) Gross residual disease in neck Unresectable Gross residual disease TSH + thyroglobulin measurement + antithyroglobulin antibodies (1-12 wk postoperatively) Total body radioiodine scan (category 2B) Inadequate uptake Adequate uptake No scan performed RT Radioiodine treatment Posttreatment 131I scan RT Suppress TSH with levothyroxine c See Surveillance and Maintenance (HÜRT-4) csee Principles of TSH Suppression (THYR-A). d Suspicion based on pathology, postoperative thyroglobulin, and intraoperative findings. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. HÜRT-2

22 Hürthle Cell Carcinoma TOC POSTSURGICAL THERAPY 1-12 wk postthyroidectomy: No gross residual disease in neck with adequate TSH stimulation (thyroid withdrawal or recombinant rhtsh stimulation) Total body radioiodine scan (category 2B) with adequate TSH stimulation (thyroid withdrawal or recombinant rhtsh stimulation) or Clinical indication for RAI therapyd (category 2B) Thyroglobulin < 1 ng/ml with negative thyroglobulin antibodies and radioiodine scan negative Suspectedd or proven thyroid bed uptake Suspectedd or proven radioiodine avid residual tumore No radioiodine treatment Adjuvant radioiodine ablation ( mci) of thyroid bed and posttreatment scan Radioiodine treatment ( mci) and post-treatment scan or consider dosimetry for distant metastasis T4 (surgically evident extrathyroidal invasion) and age > 45 y All others Consider RT Suppress TSH with levothyroxine c See Surveillance and Maintenance (HÜRT-4) csee Principles of TSH Suppression (THYR-A). dsuspicion based on pathology, postoperative thyroglobulin, and intraoperative findings. eall patients should be examined and palpable neck disease should be surgically resected before radioiodine treatment. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. HÜRT-3

23 SURVEILLANCE AND MAINTENANCE Physical examination, TSH and thyroglobulin measurement + antithyroglobulin antibodies at 6 and 12 mo, then annually if disease-free Hürthle Cell Carcinoma RECURRENT DISEASE TOC Periodic neck ultrasoundf TSH stimulated thyroglobulin in patients previously treated with RAI and with negative TSH-suppressed thyroglobulin and anti-thyroglobulin antibodiesg Consider TSH-stimulated radioiodine scan in patients with T3-4 or M1 at initial staging, or with abnormal thyroglobulin levels (either TSHsuppressed or TSH-stimulated), abnormal antithyroglobulin antibodies, or abnormal ultrasound during surveillance. If detectable thyroglobulin or distant metastases or soft tissue invasion on initial staging, radioiodine scan every 12 mo until no response is seen to RAI treatment in iodine avid tumors (either withdrawal of thyroid hormone or rhtsh) h If 131I scans negative and stimulated Tg > 2-5 ng/ml, consider additional nonradioiodine imaging (eg, FDG PET ± CT if Tg 10 ng/ml) Stimulated Tg 1-10 ng/ml Non-resectable tumors Non-radioiodine avid Locoregional recurrence Stimulated Tg > 10 ng / ml Scans (including PET) negative Metastatic disease Suppress TSH with levothyroxine c Surgery (preferred) if resectablei and/or Radioiodine treatment, if radioiodine scan positive and/or RT, if radioiodine scan negative Consider radioiodine therapy with mci, posttreatment 131I scan (category 2B) See Treatment of Metastases (HÜRT-5) csee Principles of TSH Suppression (THYR-A). fa subgroup of low risk patients may only require an ultrasound if there is a reasonable suspicion for recurrence. gin selected patients who may be at higher risk for residual/recurrent disease (eg, N1 patients), obtain a stimulated thyroglobulin and consider a concomitant diagnostic RAI scan. With a positive stimulated Tg, the concomitant RAI scan may help determine whether treatment with RAI is indicated (ie, RAI is often beneficial in iodine-avid disease but not in non-iodine avid disease). hif there is a high likelihood of therapy, thyroid hormone withdrawal suggested; if not, suggest using rhtsh. iconsider preoperative vocal cord assessment, if central neck recurrence. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. HÜRT-4

24 Hürthle Cell Carcinoma TOC CNS TREATMENT OF METASTASES Consider neurosurgical resection j and/or Image-guided RT j Metastatic disease Continue to suppress TSH with levothyroxine c Bone Sites other than CNS Surgical resection, if symptomatic or asymptomatic in weight-bearing extremities and/or RT Consider bisphosphonate therapy Consider embolization of metastases Consider surgical resection and/or RT of selected, enlarging, or symptomatic metastases and/or Radioiodine if positive uptake, with consideration of dosimetry to maximize dosing and/or For clinically progressive or symptomatic disease: clinical trials for non-radioiodine avid tumors; k consider small molecule kinase inhibitorl or systemic therapy (if trial not available) or Best Supportive Care csee Principles of TSH Suppression (THYR-A). jfor solitary lesions, either neurosurgical resection or stereotactic radiosurgery preferred. kcytotoxic chemotherapy has shown to have minimal efficacy. Clinical trials investigating novel targeted therapies are ongoing. See Clinical trials available at the member institutions. lwhile not FDA approved for treatment of thyroid cancer, commercially available small molecule kinase inhibitors (such as sorafenib or sunitinib) can be considered if clinical trials are not available or appropriate. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. HÜRT-5

25 Medullary Carcinoma TOC CLINICAL PRESENTATION ADDITIONAL WORKUP PRIMARY TREATMENT Medullary thyroid carcinoma on FNA Calcitonin level CEA Pheochromocytoma screening Serum calcium Consider genetic counseling Screen for RET protooncogene mutationsa (exons 10, 11, 13-16) Neck ultrasound Evaluate vocal cord mobility (category 2B) Consider contrast-enhanced CT of chest and mediastinum 1.0 cm in diameter or bilateral thyroid disease < 1.0 cm in diameter and unilateral thyroid disease Total thyroidectomy with bilateral central neck dissection (level VI) Consider ipsilateral modified neck dissection (levels II V). Consider contralateral neck dissection if disease present in ipsilateral neck (levels II, III, IV or V) Consider adjuvant RT for T4 disease involving major neck structures Total thyroidectomy plus bilateral central neck dissection (level VI) See Management 2-3 Months Postoperative (MEDU-4) Germline mutation of RET protooncogene See Additional Workup and Primary Treatment (MEDU-2) a Germline mutation should prompt family testing of first-degree relatives and genetic counseling. ( See Neuroendocrine Tumors Guidelines) Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. MEDU-1

26 Medullary Carcinoma TOC CLINICAL PRESENTATION ADDITIONAL WORKUP PRIMARY TREATMENT Germline mutation of RET protooncogene MEN 2B (codon 918, 883, or 922 RET mutations) Calcitonin level CEA Pheochromocytoma screening c,d Total thyroidectomy during the first year of life or at diagnosis + bilateral central neck dissection (level VI) Consider more extensive node dissection (levels II V) if tumor(s) > 0.5 cm in diameter Consider adjuvant RT for T4 disease involving major neck structures See Management 2-3 Months Postoperative (MEDU-4) MEN 2A or Familial medullary thyroid carcinoma (codon 609, 611, 618, 620, 630, 634, 768, b 790, b 791, b 804b or 891 RET mutations) Basal calcitonin level CEA Pheochromocytoma screeningc,d Serum calcium Neck ultrasound (category 2B) See Primary Treatment (MEDU-3) blethality of medullary thyroid carcinoma associated with codon 768, 790, 791, and 804 RET mutations may be lower than with other RET mutations. Prophylatic thyroidectomy may be delayed in patients with these less high risk, later onset RET mutations, provided the annual calcitonin measurement is normal, the annual ultrasound is unremarkable, there is no history of aggressive MTC in the family, and the family is in agreement. Brandi ML, Gagel RF, Angeli A, et al. Consensus: Guidelines for diagnosis and therapy of MEN type 1 and type 2. J Clin Endocrinol Metab 2001;86(12) cevidence of pheochromocytoma should be evaluated and treated appropriately before proceeding to the next step on the pathway. dscreening for pheochromocytoma (MEN 2A and 2B) and hyperparathyroidism (MEN 2A) should be performed annually. For some RET mutations (codons 768, 790, V804M, or 891) less frequent screening may be appropriate. Note: All recommendations are category 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Version , 03/02/ National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of. MEDU-2