NCCN: Continuing Education
Target Audience: This activity is designed to meet the educational needs of physicians, nurses, and pharmacists involved in the management of patients with cancer.
Accreditation Statement NCCN
Physicians: National Comprehensive Cancer Network is accredited by the Accreditation Council for Continuing Medical Education (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™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.
Nurses: National Comprehensive Cancer Network 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.
Pharmacists: National Comprehensive Cancer Network is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: 0836-0000-18-012-H01-P
All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the educational content; 2) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/84621; and 3) view/print certificate.
Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please e-mail email@example.com.
Release date: December 10, 2018; Expiration date: December 10, 2019
Upon completion of this activity, participants will be able to:
Integrate into professional practice the updates to the NCCN Guidelines for Thyroid Carcinoma
Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Thyroid Carcinoma
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 patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
Thyroid nodules, often palpated during routine physical examination, are relatively common and increase in frequency throughout life, reaching a prevalence of approximately 5% of US individuals aged ≥50 years having palpable thyroid nodules.1–3 Nodules are even more prevalent when the thyroid gland is examined at autopsy or surgery, or when using ultrasonography; 50% of the thyroids studied have nodules, which are almost always benign.2,4 By contrast, thyroid carcinoma is uncommon. For the US population, the lifetime risk of being diagnosed with thyroid carcinoma is 1.2%,5 with an estimated 53,990 new cases of thyroid carcinoma being diagnosed in 2018.6 As with thyroid nodules, thyroid carcinoma occurs 2 to 3 times more often in women than in men and is currently the fifth most common malignancy diagnosed in women.6 The main histologic types of thyroid carcinoma are (1) differentiated thyroid carcinoma (DTC; including papillary, follicular, and Hürthle cell); (2) medullary thyroid carcinoma (MTC); and (3) anaplastic thyroid carcinoma (ATC). Of 63,324
Mortality rates for thyroid carcinoma are, in general, very low. DTC usually has an excellent prognosis, with 10-year survival rates exceeding 90% to 95%.7 In contrast, ATC, an aggressive undifferentiated tumor, is almost uniformly lethal. However, because DTCs represent >95% of all cases, most thyroid carcinoma deaths are from papillary, follicular, and Hürthle cell carcinomas. In 2018, it is estimated that approximately 2,060 cancer deaths will occur among persons with thyroid carcinoma in the United States.6 The stable age- and sex-adjusted mortality rate for thyroid carcinoma contrasts distinctly with the declining rates for other solid tumors in adults, and highlights the need for new treatment options for advanced thyroid cancers.5,8,9
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Thyroid Carcinoma provide recommendations for management of the different types of thyroid carcinoma, including papillary, follicular, Hürthle cell, MTC, and ATC. These NCCN Guidelines Insights summarize the panel discussion behind recent updates to the guidelines, including the expanding role of molecular testing for DTC, implications of the new pathologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), and the addition of a new targeted therapy option for BRAF V600E–mutated ATC.
Molecular Testing for DTC
Molecular testing for DTC may be conducted for diagnostic, prognostic, and/or predictive purposes. Because many thyroid cancers have an excellent prognosis and benign nodules are common, diagnostic or prognostic markers can be useful for evaluating suspicious thyroid nodules so that appropriate treatment options can be determined.1,10,11 Predictive markers,
Fine-needle aspiration (FNA) with ultrasound guidance is the preferred procedure for evaluating suspicious thyroid nodules.3,11,12 FNA of clinically significant or suspicious cervical lymph nodes should also be considered if identified in the ultrasonographic evaluation of the thyroid and neck. Cytologic examination of an FNA specimen is typically categorized as:
Category I: nondiagnostic or unsatisfactory biopsy;
Category II: benign (ie, nodular goiter, colloid goiter, hyperplastic/adenomatoid nodule, Hashimoto's thyroiditis);
Category III: atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS);
Category IV: follicular neoplasm or suspicious for follicular neoplasm (includes Hürthle cell neoplasm);
Category V: suspicious for malignancy; or
Category VI: malignancy (includes papillary, MTC, ATC or lymphoma).
These diagnostic categories for FNA results reflect the 2017 Bethesda System for Reporting Thyroid Cytopathology.13
Molecular diagnostic testing to detect individual mutations (eg, BRAF V600E, RET/PTC, RAS, PAX8/PPARγ) or pattern recognition approaches using molecular classifiers may be useful in evaluating FNA samples that are indeterminate to assist in management decisions.14–22 The BRAF V600E mutation occurs in approximately 45% of papillary carcinomas
Rather than proceeding to immediate surgical resection to obtain a definitive diagnosis for these indeterminate FNA cytology groups (follicular neoplasm or AUS/FLUS), patients can be followed with active surveillance if the application of a specific molecular diagnostic test (in conjunction with clinical and ultrasound features) results in a predicted risk of malignancy that is comparable to the rate seen in cytologically benign thyroid FNAs (approximately ≤5%). It is important to note that the predictive value of molecular diagnostics may be significantly influenced by the pretest probability of disease associated with the various FNA cytology groups. Furthermore, in the cytologically indeterminate groups, risk of malignancy from FNA can vary widely between institutions.13,31 Therefore, proper implementation of molecular diagnostics into clinical care requires an understanding of both the performance characteristics of the specific molecular test and its clinical meaning across a range of pretest disease probabilities.32,33
The NCCN panel discussed the use of molecular diagnostic testing for evaluating FNA results of follicular neoplasm/suspicious for follicular neoplasm or AUS/FLUS. Although most of the panel members agreed that they are using molecular diagnostics for this purpose, they expressed uncertainty regarding whether the testing was helpful in guiding treatment. Some panel members voiced concern that the structure of THYR-4 placed too much emphasis on the role of molecular diagnostics. Therefore, the algorithm on THYR-4 was restructured to deemphasize molecular diagnostic testing and to allow an option for active surveillance when molecular diagnostics are not performed for AUS/FLUS (page 1431). In addition, the panel softened the recommendation for molecular diagnostic testing by adding the word “consider” to emphasize that implementation of molecular diagnostics is not mandatory in these cases. With these changes, a re-vote on molecular diagnostics changed the recommendation from category 2B to category 2A, reflecting the increasing number of institutions that consider molecular diagnostic testing to be an appropriate intervention, albeit not standard of care.
Historically, studies have shown that molecular diagnostics do not perform well for Hürthle cell neoplasms.34–36 A 2015 publication of 134 patients looked at the performance of the Afirma GEC (Veracyte, Inc.) in guiding management of FNA diagnoses of suspicious for Hürthle cell neoplasm or AUS concerning for Hürthle cell neoplasm. This study found that 86% of patients with suspicious findings on Afirma GEC had unnecessary surgery.36 However, results presented at the 2017 American Thyroid Association Annual Meeting described improved results using the Afirma Genomic Sequencing Classifier (Veracyte, Inc.) with 2 dedicated classifiers to (1) differentiate Hürthle cell–containing specimens from non-Hürthle specimens, and (2) differentiate neoplastic Hürthle specimens from nonneoplastic. By applying this process to 186 specimens, this study reported an 88.9% sensitivity for detection of Hürthle cell malignancies and a 58.8% specificity for identification of benign Hürthle lesions, representing a marked improvement over previous results.37 Another molecular test, the ThyroSeq v3 Genomic Classifier (CBLPath, Inc.), has also shown promise for the diagnosis of Hürthle cell–containing specimens. This test analyzes 112 genes for a variety of genetic alterations and was validated in 238 tissue samples and 174 FNA samples with known surgical follow-up. A 2018 publication on the ThyroSeq v3 Genomic Classifier reported a sensitivity of 92.9% (95% CI, 80.52%–98.50%) and a specificity of 69.3% (95% CI, 48.21%–85.67%) for detecting Hürthle cell cancers.38
The NCCN panel discussed the limitations of molecular testing for Hürthle cell lesions at the panel meetings for both the 2017 and 2018 updates. Panel members' experiences agreed with the published literature on this subject—several commented that they did not use molecular testing for Hürthle cell lesions because the false-positive rates for malignancy were unacceptably high. In response, the panel added a footnote in the 2017 version to clarify that molecular diagnostic testing was not recommended for Hürthle cell neoplasms. For the 2018 update, the panel discussed recent data showing that the Afirma Genomic Sequencing Classifier and the ThyroSeq v3 Genomic Classifier may perform better with Hürthle cell neoplasms. The panel agreed that although the data were encouraging, they were not yet mature enough to make a recommendation for molecular testing in Hürthle cell lesions; however, they did soften the language of the footnote to read “molecular diagnostics may not perform well for Hürthle cell neoplasms” to account for these emerging data (see THYR-4, page 1431).
In addition to their utility in diagnostics, molecular markers may drive decisions related to targeted therapy for advanced disease. Systemic therapy can be considered for locally recurrent, advanced, and/or metastatic DTCs that are not surgically resectable, are not amenable to radioactive iodine (RAI), and are progressing and/or symptomatic. Overall, traditional cytotoxic systemic chemotherapy, such as doxorubicin, has minimal efficacy in patients with metastatic DTC.39 Therefore, novel treatments for patients with metastatic DTC have been evaluated. Agents with documented efficacy in this setting include lenvatinib,40,41 sorafenib,42 sunitinib,43,44 axitinib,45–47 everolimus,48 vandetanib,49 cabozantinib,50,51 and pazopanib among others.52 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.40–42,53 Dose modifications of kinase inhibitors may be required.
Although the clinical use of predictive markers is currently limited for advanced thyroid cancers, recent data have shown that the BRAF inhibitors vemurafenib and dabrafenib can be effective treatment options for DTC harboring the BRAF V600E mutation.54–56 Because this mutation is common in papillary thyroid cancers, these therapies may be especially promising for this tumor type. An open-label nonrandomized phase II trial of 51 patients with BRAF V600E mutation–positive recurrent or metastatic papillary thyroid cancer that was refractory to RAI investigated the safety and efficacy of vemurafenib.56 Of these 51 patients, 26 had never received a VEGFR-targeted therapy (cohort 1) and 25 had previously received this class of therapy (cohort 2). The primary end point, best overall response rate for cohort 1, was 38.5% (95% CI, 20.2–59.4). Grade ≥3 adverse events were reported in 65% of patients in cohort 1 and 68% in cohort 2.56 In a subset of 14 patients with BRAF V600E–mutant thyroid carcinoma from a phase I study of dabrafenib, 29% showed partial responses and 64% showed at least a 10% decrease.54 In addition, another study of 10 patients with BRAF V600E–mutant, RAI-refractory papillary thyroid cancer showed that dabrafenib stimulated radioiodine uptake in 60% of patients, suggesting that dabrafenib may sensitize these tumors to RAI therapy.55 Both of these studies reported that dabrafenib was well tolerated.54,55 Additionally, emerging data suggest that anaplastic lymphoma kinase (ALK) inhibitors may be effective in patients with papillary carcinoma who have ALK gene fusion.57–60
In response to these emerging data, the panel added a recommendation for genomic testing to identify actionable mutations for patients with advanced, progressive, or threatening DTC (see PAP-9, page 1433). Panel members commented that molecular testing is particularly important to inform eligibility for clinical trial participation. The panel also voted to add vemurafenib and dabrafenib as treatment options for patients with BRAF mutation–positive DTCs that are locally recurrent, advanced, and/or metastatic, are not surgically resectable, are not amenable to RAI, and are progressing and/or symptomatic (see PAP-9, page 1433). The decision was made to not specify BRAF V600E mutation, because data show that these inhibitors can work for BRAF-activating mutations other than V600E.61 The panel discussed whether to add the dabrafenib/trametinib combination (discussed for ATC in the following section) as an option for BRAF-mutated DTC, but decided to not add this regimen due to preliminary results from a phase II clinical trial for DTC presented at the 2017 ASCO Annual Meeting that did not show clear improvements compared with dabrafenib alone.62
NIFTP Pathologic Diagnosis
NIFTP, formerly known as noninvasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC), is characterized by its follicular growth pattern, encapsulation or clear demarcation of the tumor from adjacent tissue with no invasion, and nuclear features of papillary carcinoma.63,64 NIFTP has a low risk for adverse outcomes and, therefore, requires less aggressive treatment.64–67 NIFTP was reclassified in 2016 to prevent overtreatment of this indolent tumor type and the psychological consequences of a cancer diagnosis on patients.63,64 The College of American Pathologists updated its protocols with NIFTP in the June 2017 version. Per their protocol, reporting is optional because NIFTP is not overtly malignant and only size, laterality, and margin status are reported.68
Although molecular diagnostic testing may be useful for diagnosing NIFTP in the future, currently available tests were not validated using NIFTP samples. Studies have shown that NIFTP specimens frequently carry characteristic mutations/alterations, including RAS, PAX8/PPARγ, and/or BRAF (with the exception of the aggressive BRAF V600 mutations), differentiating it from papillary subtypes that more frequently show BRAF V600E and RET/PTC alterations.18,69,70 However, multiple studies investigating the performance of molecular diagnostics for this subtype have reported that most thyroid nodules histologically diagnosed as NIFTP are classified as “suspicious” by GEC, possibly leading to more aggressive surgical treatment than is necessary.71,72 Therefore, the validation of molecular diagnostics with NIFTP samples will be necessary to ensure that the tests are accurately classifying these.
The panel members agreed that although NIFTP is still considered a subset of papillary carcinoma, these tumors have low malignant potential and therefore do not require completion thyroidectomy after lobectomy. Based on this, the panel consensus was to conduct no further treatment after lobectomy and histologic diagnosis of NIFTP, and rather to proceed to active surveillance with consideration of thyroglobulin measurement and anti-Tg antibodies 6 to 12 weeks after lobectomy. Levothyroxine therapy may be considered to keep thyroid-stimulating hormone levels low to normal (see PAP-1, page 1432). At the time of the panel meeting, some panel members mentioned that the NIFTP terminology was still in the process of being accepted within practice patterns and that some institutions may still be classifying these tumors as EFVPTC. To address this, they decided to add a footnote clarifying that noninvasive EFVPTC had been reclassified as NIFTP.
Systemic Therapy for ATC
ATC is an aggressive undifferentiated tumor, with a disease-specific mortality approaching 100%.73 Treatment of ATC should be planned in consultation with a multidisciplinary team and ideally performed at a high-volume center with expertise in treating ATC. Therapy is often multimodal, consisting of surgery, systemic therapy, and/or radiation therapy, because ATC often responds poorly to single-modality therapy.74,75 Given the poor outcome with current standard therapy, all patients—regardless of surgical resection—should be considered for clinical trials.
Panel members commented that few therapies have emerged for treating ATC over the years. Given the limited available treatments and a very poor prognosis, clinicians are grasping for options for these patients. With this in mind, the panel decided to add a recommendation to conduct molecular testing for actionable mutations in all patients with ATC who are considering systemic therapy (see ANAP-2, page 1434). Panel members agreed that molecular testing is part of the global approach to managing patients with ATC and is strongly recommended. Although there is now an FDA-approved therapy for ATC with the BRAF V600E mutation (discussed in the following paragraph), the panel does not intend for the recommendation regarding molecular testing to only apply to BRAF mutations; any targeted therapies that are effective against an identified mutation/alteration may be considered (eg, crizotinib for ALK mutations).
BRAF mutations have been reported in patients with ATC, supporting the utility of BRAF inhibitors for treatment.76–80 An open-label, nonrandomized, multicenter phase II trial evaluated the efficacy and safety of dabrafenib in combination with trametinib for treatment of BRAF V600E–mutated rare cancers (including in a cohort of 16 patients with ATC).80 The primary end point, confirmed overall response rate, was 69% (95% CI, 41%–89%), with 7 responses ongoing. Although duration of response, progression-free survival, and overall survival were not yet reached, the 12-month estimates were 90%, 79%, and 80%, respectively. The combination was found to be well tolerated as evaluated in 100 patients across 7 rare tumor types; common adverse events included fatigue (38%), pyrexia (37%), and nausea (35%).80 Based on these data, the FDA approved dabrafenib/trametinib for patients with ATC and BRAF V600E mutations on May 4, 2018.81
The panel commented that the survival and response rate reported in this trial were very encouraging, especially for a disease with such a poor prognosis. However, they cautioned that the small size of the ATC cohort (N=16) limited their ability to make a strong recommendation for this regimen. Therefore, the panel drafted a footnote suggesting consideration of dabrafenib/trametinib combination therapy in BRAF V600E mutation–positive ATC (see ANAP-2, page 1434). Several panel members mentioned that their institutions have adopted testing for BRAF mutations and are treating patients with dabrafenib/trametinib when BRAF V600E mutations are detected. Anecdotally, they have noted impressive responses in patients with disease that responds to the therapy. The panel also discussed whether the dabrafenib/trametinib recommendation should be limited to only BRAF V600E, because deep sequencing will often yield multiple actionable mutations in this tumor type. The decision was to specify V600E mutation because there are currently no data to guide how to treat ATC with other mutations. The panel looks forward to additional data with larger numbers of patients showing benefit from this regimen in BRAF-mutated ATC, at which time they may consider strengthening their recommendation. In the meantime, the panel stressed that clinical trial participation should still be the preferred treatment option for patients with ATC who qualify.
Recent medical advances have improved treatment for patients with thyroid cancers through better identification of indolent subtypes that require less aggressive treatment and the development of new targeted therapy options for advanced or metastatic disease. Although the data are not yet strong enough to be considered a standard of care, use of molecular diagnostics for indeterminate FNA results may help some patients with indolent nodules avoid surgery. Likewise, the recent reclassification of the NIFTP subtype allows patients with this low-risk tumor to avoid total thyroidectomy and its associated side effects. However, molecular markers can also inform the use of targeted therapies and/or clinical trial eligibility for advanced or metastatic thyroid carcinoma. This approach is especially promising for ATC, a subtype with poor prognosis and few treatment options.
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DuhQYAngellTEBabiarzJ. Development and validation of classifiers to enhance the Afirma genomic sequencing classifier performance among Hürhtle cell specimens. Presented at the 87th Annual Meeting of the American Thryoid Association; October18–222017; Victoria, BC, Canada.
ShahMHDe SouzaJWirthL. Cabozantinib in patients with radioiodine-refractory differentiated thryoid cancer who progressed on prior VEGFR-targeted therapy: results of NCI- and ITOG-sponsored multicenter phase II clinical trial [abstract]. Presented at the 15th International Thyroid Congress; October18–232015; Orlando, Florida. Abstract 73.