Thyroid Carcinoma, Version 2.2014

These NCCN Guidelines Insights focus on some of the major updates to the 2014 NCCN Guidelines for Thyroid Carcinoma. Kinase inhibitor therapy may be used to treat thyroid carcinoma that is symptomatic and/or progressive and not amenable to treatment with radioactive iodine. Sorafenib may be considered for select patients with metastatic differentiated thyroid carcinoma, whereas vandetanib or cabozantinib may be recommended for select patients with metastatic medullary thyroid carcinoma. Other kinase inhibitors may be considered for select patients with either type of thyroid carcinoma. A new section on “Principles of Kinase Inhibitor Therapy in Advanced Thyroid Cancer” was added to the NCCN Guidelines to assist with using these novel targeted agents.

NCCN: Continuing Education

Accreditation Statement

This activity is designated to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer. There is no fee for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians. NCCN designates this journal-based CE activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s Commission on Accreditation.

NCCN designates this educational activity for a maximum of 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. NCCN designates this continuing education activity for 1.0 contact hour(s) (0.1 CEUs) of continuing education credit in states that recognize ACPE accredited providers. This is a knowledge-based activity. UAN: 0836-0000-14-012-H01-P

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/58475; and 4) view/print certificate.

Release date: December 12, 2014; Expiration date: December 12, 2015

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Integrate into professional practice the updates to NCCN Guidelines for Thyroid Carcinoma
  • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Thyroid Carcinoma

F1NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2014

Version 2.2014 © National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0169

NCCN Categories of Evidence and Consensus

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Overview

In 2014, approximately 62,980 new cases of thyroid carcinoma will be diagnosed and approximately 1890 cancer deaths will occur from the disease in the United States.1,2 The main histologic types of thyroid carcinoma include (1) differentiated (including papillary, follicular, and Hürthle cell); (2) medullary (MTC); and (3) anaplastic (aggressive undifferentiated tumor). Of 55,554 patients diagnosed with thyroid carcinoma between 2007 and 2011, 88.0% had papillary carcinoma, 5.5% had follicular carcinoma, 2.3% had Hürthle cell carcinoma, 1.8% had MTC, and 0.9% had anaplastic carcinoma.3 Anaplastic thyroid carcinoma is almost uniformly lethal, but most thyroid carcinoma deaths are from papillary, follicular, or Hürthle cell carcinomas, which account for 95% of all thyroid carcinoma cases. However, most patients can be cured of differentiated thyroid carcinoma when properly treated by experienced physicians and surgeons,4 with a 5-year survival rate of 97.8%.3

F2NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2014

Version 2.2014 © National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0169

Differentiated Thyroid Carcinoma

First-line preferred treatment for differentiated thyroid carcinoma is surgery, whenever possible, followed by radioactive iodine (RAI) in selected patients, and levothyroxine therapy in all patients (see THYR-A, page 1673).5 However, some patients have metastatic or recurrent disease that cannot be treated with surgery and/or is resistant to RAI. For patients with metastatic disease, the NCCN Thyroid Carcinoma Panel recommends individualized treatment based on tumor location, such as bone, central nervous system, or soft tissue (see PAP-9, page 1675). Although not curative, systemic and/or locoregional therapy may be recommended for patients with symptomatic and/or progressive disease that is not amenable to treatment with RAI.57

Systemic therapy includes kinase inhibitors, cytotoxic chemotherapy, and novel agents available on clinical trials. Treatment of locoregional disease depends on the site and includes external-beam radiation therapy (EBRT), resection, stereotactic radiotherapy, and other therapies (see PAP-9, page 1675).5,813 Systemic therapy can be considered for tumors that are not surgically resectable, are not responsive to RAI, are not amenable to EBRT, and have shown clinically significant structural disease progression during the past 6 to 12 months.7,14

Traditional cytotoxic systemic chemotherapy, such as doxorubicin, has minimal efficacy in patients with metastatic differentiated thyroid disease.15,16 Among 49 patients treated with 5 chemotherapy protocols, only 2 patients (3%) had objective responses.17 In a review of published series, 38% of patients had a response (defined as a decrease in tumor mass) to doxorubicin.18 Combination chemotherapy is not clearly superior to doxorubicin therapy alone.19 A recent study showed that targeted therapy of the MAP kinase pathway with selumetinib (an MEK inhibitor) significantly increased the effectiveness of RAI therapy in patients who were previously RAI-refractory.20

F3NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2014

Version 2.2014 © National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0169

Kinase Inhibitors

Novel systemic therapies for patients with metastatic differentiated thyroid carcinoma have been evaluated.7,14,2124 Multitargeted kinase inhibitors that are currently recommended in the NCCN Guidelines for Thyroid Carcinoma (to view the complete version, visit NCCN.org) for select patients with differentiated thyroid carcinoma include sorafenib,2532 sunitinib,29,33 vandetanib,34 pazopanib, and axitinib35,36 (see PAP-9, above).37 For the 2014 update of the NCCN Guidelines, a new section on “Principles of Kinase Inhibitor Therapy in Advanced Thyroid Cancer” was added to assist with using these novel targeted agents (see THYR-B, page 1674). This new section also pertains to patients with MTC. Other revisions to the recommended multikinase inhibitors are discussed in the following paragraphs. Novel agents under investigation include other multitargeted kinase inhibitors, such as lenvatinib, and BRAF (V600E) mutation inhibitors, such as vemurafenib.13,14,3842

Clinical trials suggest that kinase inhibitors have a clinical benefit (partial response rates plus stable disease) in 50% to 60% of patients, usually for approximately 12 to 24 months.14,29,37,4345 Patients with rapidly progressive disease may benefit from kinase inhibitor therapy even if they experience side effects.7 Kinase inhibitor therapy may cause severe side effects, and therefore may not be appropriate for patients with stable or slowly progressive indolent disease.6,7,32,46 Watchful waiting may be appropriate for asymptomatic patients with indolent disease.47 Severe or fatal side effects from kinase inhibitors include bleeding, hypertension, stroke, and liver toxicity; however, most side effects can be managed and are reversible with discontinuation of the drug.32,4852 Dose modification and dose holds of the kinase inhibitors may enable patients to continue therapy (see the prescribing information). The dose of levothyroxine often needs to be increased in patients taking kinase inhibitors.46,47 Because some kinase inhibitors

F4NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2014

Version 2.2014 © National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0169

are metabolized by cytochrome P450 isoenzymes, patients are at risk for drug-drug interactions.53 Patients should be cautioned not to drink grapefruit juice if they are taking kinase inhibitors such as sunitinib, pazopanib, or axitinib.

Kinase inhibitor therapy may be used to treat thyroid carcinoma that is symptomatic and/or progressive and not amenable to treatment with RAI. For the 2014 update, recommendations were revised for the use of kinase inhibitors. Sorafenib may be considered for select patients with differentiated thyroid carcinoma; other kinase inhibitors are also an option (see PAP-9, page 1675). Sorafenib may be considered for progressive and/or symptomatic differentiated thyroid carcinoma based on a recent phase III randomized trial and a recent FDA approval.25,32,54 For the 2014 update, sorafenib was from a footnote and into the algorithm based on this information (see PAP-9, page 1675).25 If patients need to discontinue sorafenib because they have severe side effects, do not experience response to sorafenib, or experience progression on sorafenib, then other commercially available small molecule kinase inhibitors may also be considered, including pazopanib, sunitinib, vandetanib, or axitinib, although none have been approved by the FDA for differentiated thyroid cancer (see PAP-9, page 1675).5557 For the 2014 update, vandetanib and axitinib were added to the footnote as additional recommended kinase inhibitors that may also be considered based on results from recent phase II trials.3436 In addition, pazopanib was changed from a category 2B recommendation to a category 2A recommendation based on results of a phase II trial and on panel experience.37

Medullary Thyroid Carcinoma

Surgery is the main treatment for MTC, because no curative systemic therapy for MTC is available, although kinase inhibitors may be recommended for

F5NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2014

Version 2.2014 © National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 12, 12; 10.6004/jnccn.2014.0169

locally advanced and metastatic MTC that is structurally progressive (see MEDU-6 and MEDU-7, page 1676 and above, respectively).5861 MTC cells do not concentrate RAI, and MTC does not respond well to conventional cytotoxic chemotherapy. Therefore, iodine-131 imaging cannot be used, and RAI treatment is not effective in these patients. Postoperative levothyroxine is indicated for all patients; however, thyroid stimulating hormone (TSH) suppression is not appropriate because C cells lack TSH receptors. Thus, TSH should be kept in the normal range by adjusting the levothyroxine dose.62

Kinase Inhibitors

Kinase inhibitors may be recommended for select patients with MTC who have recurrent or persistent disease that is unresectable and structurally progressive (see MEDU-6 and MEDU-7, page 1676 and above, respectively).6365 Multitargeted kinase inhibitors that are currently recommended or may be considered for select patients with MTC include vandetanib, cabozantinib, sorafenib, and sunitinib (see MEDU-6 and MEDU-7, page 1676 and above respectively). Vandetanib and cabozantinib are oral kinase inhibitors that increase progression-free survival (PFS) in patients with metastatic MTC.58,61,6668 The NCCN Thyroid Carcinoma Panel recommends vandetanib or cabozantinib (both are category 1) for select patients with MTC based on recent phase III trials and FDA approval.5861 Severe or fatal side effects from kinase inhibitors include bleeding, hypertension, and liver toxicity; however, many side effects can be managed.46,49,55,69 Because some patients may have indolent and asymptomatic disease, these agents may not be appropriate (see THYR-B, page 1674).63 Locoregional therapies, such as resection, ablation, and EBRT, are also recommended for the treatment of MTC (see MEDU-6 and MEDU-7, page 1676 and above, respectively).62,65

Vandetanib is a multitargeted kinase inhibitor that inhibits RET, vascular endothelial growth factor receptor (VEGFR), and endothelial growth factor receptor.58 In the phase III randomized ZETA trial for unresectable, locally advanced, or metastatic MTC (N=331), vandetanib increased PFS compared with placebo (hazard ratio [HR], 0.46; 95% CI, 0.31–0.69; P<.001); overall survival data are not yet available.58 Vandetanib was FDA-approved for use in patients with locally advanced or metastatic MTC who are not eligible for surgery and whose disease is causing symptoms or growing.58,59 However, access to vandetanib is restricted through a Risk Evaluation and Mitigation Strategy (REMS) program because of potential cardiac toxicity69; other adverse events may also occur.69,70

Cabozantinib is a multitargeted kinase inhibitor that inhibits RET, VEGFR-2, and MET. In a recent phase III randomized trial (EXAM) for patients with locally advanced or metastatic MTC (N=330), cabozantinib increased median PFS compared with placebo (11.2 vs 4.0 months; HR, 0.28; 95% CI, 0.19–0.40; P<.001); overall survival data are not yet available.61 The FDA recently approved the use of cabozantinib for patients with progressive metastatic MTC.60,61,71,72 Rare adverse events with cabozantinib include severe bleeding and gastrointestinal perforations or fistulas; severe hemorrhage is a contraindication for use of this agent.63 If disease progresses on vandetanib or cabozantinib, systemic chemotherapy can be administered using dacarbazine or combinations that include dacarbazine.62,73,74 EBRT can be used for focal symptoms. Bisphosphonate therapy or denosumab can be considered for bone metastases.7577 Best supportive care is also recommended.

Sorafenib or sunitinib can be considered, although not FDA-approved for MTC, if vandetanib, cabozantinib, or clinical trials are not available or appropriate (see MEDU-6 and MEDU-7, pages 1676 and 1677, respectively).33,7886 In patients with metastatic MTC, sorafenib reduces symptoms caused by hypercalcitonemia and metastases.78,80 Sunitinib was associated with clinical response in several case reports.81,85,86 Clinical trials are assessing the effectiveness of novel multitargeted therapies, such as pazopanib.87

Summary

These NCCN Guidelines Insights focus on some of the major updates to the 2014 NCCN Guidelines for Thyroid Carcinoma. Kinase inhibitor therapy may be used to treat thyroid carcinoma that is symptomatic and/or progressive and not amenable to treatment with RAI. Sorafenib may be considered for select patients with metastatic differentiated thyroid carcinoma, whereas vandetanib or cabozantinib may be recommended for select patients with metastatic MTC. Other kinase inhibitors may be considered for select patients with either type of thyroid carcinoma. A new section on kinase inhibitors was added to the NCCN Guidelines to assist with using these novel targeted agents.

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    NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2014

    Version 2.2014 © National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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    NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2014

    Version 2.2014 © National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery
    NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2014

    Version 2.2014 © National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery
    NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2014

    Version 2.2014 © National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

  • View in gallery
    NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2014

    Version 2.2014 © National Comprehensive Cancer Network, Inc. 2014, All rights reserved. The NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN®.

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