2 Thyroid Cancer

Suggested citation:  Endocrine Society. Endocrine Facts and Figures: Cancers and Neoplasias. First Edition. 2017

According to the National Cancer Institute (NCI), thyroid cancer is the most common malignant disease of the endocrine system, and in 2015 it was reported as the eighth most common cancer in the US.1 Thyroid cancer comprises four major histological subtypes, based on whether the cancer arises in follicular (papillary, follicular, and anaplastic) or non-follicular (medullary) cell types.

2.1    PREVALENCE AND INCIDENCE

Based on NCI data from 2000-2012, on January 1 2012, there were 601,789 thyroid cancer cases, comprising 4.37% of all diagnosed cancers (13,776,251 cases) in the US.2 According to the National Institute of Health’s SEER 18 registries database, in 2012, the US incidence of thyroid cancer was 14.25 cases per 100,000.3

Importantly, the most common forms of thyroid cancer, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) (together also referred to as differentiated thyroid cancer), have a better prognosis than the rarer anaplastic thyroid cancer (ATC).4,5 The prevalence of thyroid cancer, by histological subtype, is shown in Table 2.1.

Table 2.1.  Prevalence of thyroid cancer by subtypes from 1992-2012 in the US.
Data source Population Histological type Prevalence (%) References
SEER 13 database, 1992 – 2009

US (n=59,611) PTC 84.6 Aschebrook-Kilfoy et al. 20136
FTC 9.8
MTC 2.1
ATC 0.9
Unspecified 2.6
SEER 18 registries, 2008 – 2012 US, all races, both sexes PTC 88.5 Howlander et al. 20142

 

FTC 5.1
MTC 1.7
ATC 0.8
Unspecified 4

Abbreviations:  SEER, Surveillance, Epidemiology, and End Results; US, United States; PTC, Papillary thyroid cancer; FTC, Follicular thyroid cancer; MTC, Medullary thyroid cancer; ATC Anaplastic thyroid cancer.

A 2013 study by Aschebrook-Kilfoy and colleagues using data from 1992 to 2009 SEER registries (n=59,611), reported an incidence (per 100,000) of 7.3 for PTC, 0.9 for FTC, 0.2 for MTC, and 0.1 for ATC.6 In a follow-up study, PTC was reported to have the highest annual increase among all thyroid cancer subtypes in the US (Table 2.2).7

Table 2.2. Annual percentage change in the 4 subtypes of thyroid cancer in the US.
Data source Population Thyroid cancer subtype Annual percentage change (%)
SEER database, 1992-2009 US (n=59,611) PTC +7.0
FTC +1.0
MTC +2.0
ATC +1.0
Abbreviations: US, United States; SEER, Surveillance, Epidemiology, and End Results; PTC, Papillary thyroid cancer; FTC, Follicular thyroid cancer; MTC, Medullary thyroid cancer; ATC Anaplastic thyroid cancer.

Source: Aschebrook-Kilfoy et al. 20137

In the US, thyroid cancer (mainly PTC) is the fastest increasing cancer, with an estimated 9-fold increase since the 1930s, 3-fold since the 1970s, and almost 2-fold since the start of the millennium (Table 2.3).2,5,8,9 Aschebrook-Kilfoy and colleagues projected that, if current trends continue, by 2019, the incidence rate per 100,000 of the US population would reach 23.8 for PTC, 1.5 for FTC, 0.26 for MTC, and 0.12 for ATC.6 However, it has been suggested that the rapid increase in thyroid cancer observed in the US over the last three decades may be partially due to overdiagnosis as a result of improved imaging technologies.10,11 Furthermore, recent data suggests that rising trends in thyroid cancer may be slowing down.12

Table 2.3. Temporal increase in the incidence of thyroid (papillary) cancer from 1935 to 2012 in the US.
Data source Population Thyroid cancer type Incidence (per 100,000) Fold-increase Reference
1935-1939 1990-1992
Connecticut Tumor Registry US, incident thyroid cancer cases, both sexes (72% females, 28% males), age-adjusted (n=4,315) Thyroid cancer 1.6 8.55 5.3 Zheng et al. 19968
1973 2002
SEER 9 Registries database US, new cases of thyroid cancer, median age 46 years, 2002 (n=2,400) Thyroid cancer 3.6 8.7 2.4 Davies and Welch. 20065
Papillary thyroid cancer 2.7 7.7 2.9
2000 2012
SEER 18 program US, age-adjusted to 2000 US population Thyroid cancer 7.4 14.3 1.9 Howlader et al. 20142
Abbreviations: SEER, Surveillance, Epidemiology, and End Results.

Note: SEER program presents population-based data collected from 9 cancer registries in distinct areas of the United States, covers 10% of the US population in 5 states: Connecticut, Hawaii, Iowa, New Mexico, and Utah; and 4 metropolitan areas: Atlanta, Detroit, San Francisco, and Seattle.

Periods of marked acceleration in thyroid cancer incidence are shown in Table 2.4.2

Table 2.4.  Annual percentage change in invasive thyroid cancer from 1975 to 2012 in the US.
Data source Population Time frame Annual percentage change (%)
SEER 9 Delay-Adjusted Incidence,     1975-2012 US, all races, both sexes 1975-1977 +6.3
1977-1980 -6.6
1980-1997 +2.4
1997-2009 +6.7
2009-2012 +2.3
Note: + denotes an increase and – denotes a decrease. Data are based on rates age-adjusted to the 2000 US standard population, from SEER 9 registries (San Francisco, Connecticut, Detroit, Hawaii, Iowa, New Mexico, Seattle, Utah, and Atlanta).

Source: National Cancer Institute. 20123

The increase in the 1970s is attributed to an increase in head and neck ionizing radiation treatment of benign childhood conditions.8 The increase around the turn of the century is thought to be due to multiple factors, the major one being improved diagnostics (thyroid ultrasound and fine-needle aspiration technology in the 1980s) and improved detection sensitivity of subclinical small-size (£2cm) thyroid tumors (Table 2.5).5,13 In a retrospective cohort study of the SEER program (1988 to 2002), Davies and colleagues reported significant increases, specifically in small tumors: 49% in ≤1cm tumors and 87% in ≤2cm.5 However, Enewold and colleagues reported increases in tumors of all sizes: 50% increase in tumors £1cm, 30% increase in 1.1-2cm, and a 20% increase in >2cm.14 A combination of improved detection sensitivity and a genuine increase in incidence may explain increasing incidence of thyroid cancer.4,14-18,19

From 1999 to 2008, the incidence rates for thyroid tumors have increased in all SEER stages (localized, regional, distant), with the greatest increase in localized tumors (5.2 to 9.6 per 100,000). A significant increase from ~3.5 to ~5 per 100,000 was also seen in the same time frame for regional tumors.13

Table 2.5. Incidence of tumor size in differentiated thyroid cancers (PTC, FTC) in the US.
Data source Population Tumor size (cm) Incidence (%)
SEER registries, 1988-2005 US, patients with differentiated thyroid cancer (n=30,590)

 

<1.0 25
1-2.9 42
3-3.9 9
³4 11
unknown size 12
Abbreviations: SEER, Surveillance, Epidemiology, and End Results; US, United States; cm, centimeters.

Source: Chen et al. 200916

The first report of thyroid carcinomas as a common feature at autopsy, by VanderLaan in 1947, was followed by other reports of subclinical thyroid carcinomas in the general population.20,21,22 In 1994, Ezzat and colleagues reported identifying more asymptomatic subjects with thyroid nodules by high-resolution ultrasonography (67%) and by palpation alone (21%) (Table 2.6). The concordance rate between the two techniques was 49%.23 However, it has been suggested that Ezzat and colleagues overestimated the incidence of nodules, as 84% of the volunteers in the study were females.24 In 2012, Ahmed and colleagues reported that in CT scans of 2,510 subjects (48.7% females), 61.5% had one or more nodules, and 38.5% had multiple nodules.24  A 2005 study by Frates and colleagues reported that nodules were diagnosed by palpation in 4-8% of adults, by ultrasonography in 10-41% and by autopsy in 50%.25

Table 2.6.  Thyroid nodules identified by palpation or ultrasonography, US.
Data source Population Condition Prevalence (%)
palpation ultrasonography
Asymptomatic healthy volunteers North American, both sexes (84% female), (n=100) no nodules 79 33
multiple nodules 12 45
solitary nodules 9 22
Source: Ezzat et al. 1994 23

 

Table 2.7.  Known risk factors for developing thyroid cancer by subtype.
Thyroid cancer subtype Risk factors Reference
PTC Ionizing radiation exposure, history of benign nodules, goiter Li et al. 201319
FTC Living in iodine-deficient region Scopa. 200426
MTC (sporadic) Goiter or thyroid nodules, late menarche Kalezic et al. 201327
MTC (inherited) germline mutations in RET gene Kloos et al. 200928
ATC Goiter, iodine-deficiency, pre-existing well-differentiated thyroid cancer Are et al. 200629; Nagaiah et al. 201130; Smallridge et al. 201231

Abbreviations: PTC, Papillary thyroid cancer; FTC, Follicular thyroid cancer; MTC, Medullary thyroid cancer; ATC Anaplastic thyroid cancer.

Some of the most common risk factors for thyroid cancer subtypes are outlined in Table 2.7. Germline changes predisposing to thyroid cancer include RET mutations (Multiple Endocrine Neoplasia type 2) in MTC, PTEN mutations (PTEN-hamartomatous tumor syndrome, Cowden disease) in differentiated thyroid cancer, and APC mutations (Familial Adenomatous Polyposis) in the cribriform-morula variant of PTC.  In addition, >100 genetic alterations (mutations, insertions, deletions, rearrangements), in different molecular pathways are found in thyroid cancer, including somatic tumor mutations in the genes for BRAF, RET (RET/PTC1, RET/PTC3), RAS (N-RAS, H-RAS, K-RAS), NTRK1, PTEN, PI3KCA, AKT1, TERT, EIF1AX, PPMID, CHEK2, TRK, CIVER1, MET, VHL, DICER1, and PRKAR1A.32,33-36 Some of these mutations had previously been missed by Sanger sequencing and were recently identified by Next Generation sequencing.

It has yet to be proven whether pre-operative genetic screening of tumor tissue is useful in identifying the risk of cancer recurrence or in guiding the extent of surgery, adjuvant decisions, or follow-up recommendations. The 2015 American Thyroid Association Management Guidelines acknowledge that genotyping may be useful in some situations, but do not recommend the routine use of genotyping to guide treatment.37

Advanced disease stage and earlier recurrence were also identified for BRAFV600E mutations or RET/PTC gene rearrangements and distant metastasis was more common in RET/PTC-positive cases (Table 2.8). The RAS and BRAFK610E mutations and PAX8/PPARg fusions represented 25% of the cases and were associated with indolent disease and disease-free survival of 100% at 5 years.38

Table 2.8. Prevalence of genetic alterations in thyroid cancer and its subtypes, US.
Data source Population Method Thyroid cancer diagnosis Features Prevalence (%)
Department of Surgery, University of Pittsburgh. Thyroid cancer patients who had undergone thyroidectomy US, mean age 49 years, both sexes (77% females), average follow-up 33 months (n=1,510) Pre-operative ultrasound-guided needle biopsy, routine testing for genetic alterations: BRAF, RAS, RET/PTC, PAX8/ PPARg. Total thyroidectomy for abnormal lymph node removal, if necessary. Histological metastasis or recurrent thyroid cancer tracked for 6 months after thyroidectomy Thyroid cancer PTC 97
Poorly differentiated thyroid cancer or ATC 1.1
BRAFV600E-positive 62
RAS-positive 31
BRAFV600E -positive PTC Tall cell variant 58
Extrathyroidal extension 51
Lymph node metastasis 46
RAS-positive PTC Follicular cell variant 87
Infrequent extrathyroidal extension 4.6
Lymph node metastasis 5.6
BRAFV600E or RET/PTC-positive thyroid cancer Stage III/IV 40
Recurrence 10
Distant metastasis 10.8
RAS or PAX/PPARg-positive thyroid cancer Stage III/IV 15
Recurrence 0.7
Abbreviations: PTC, papillary thyroid cancer; RET/PTC, rearranged during transfection/papillary thyroid cancer genetic rearrangements, PAX/PPARg.

Source: Yip et al. 201538

In a 2014 study examining 496 PTC cases, the most common (74.6%) pathogenic somatic mutations were in MAPK-related genes, BRAF, NRAS, HRAS, and KRAS. A BRAF mutation was identified in 61.7% of tumors, the most common of which was BRAFV600E, while RAS was mutated in 12.9% of tumors.33

In a retrospective 2015 US study, the BRAFV600E mutation was identified in 67% of thyroid cancers  (n=508); and in a 2011 study it was reported in 45% of PTC cases, 10-15% of poorly differentiated thyroid carcinomas (PDTC), and in 20-30% of ATC.39,40 The BRAFV600E mutation was also reported in 63% of childhood PTC cases. A recently identified BRAF mutation, BRAFV601E, comprised 5.3% of all BRAF mutations in thyroidectomy samples (2007-2014); 93% of these cases were PTC, and 3.4% FTC.41

TERT mutations have a higher prevalence in aggressive forms of thyroid cancer (ATC, follicular variant of PTC, and tall-cell PTC), and are absent from MTC and benign thyroid cancers (Table 2.9).42,43 The TERTC228 and BRAF mutations in combination occur at a higher prevalence than individually in PTC and ATC samples.42 A number of publications have identified a combination of BRAF and TERT mutations in PTC tumors to be associated with a worse outcome than the single mutations, in terms of tumor aggressiveness, recurrence and mortality. These findings were recently reviewed by Liu and Xing.43

Around 70-75% of MTC cases arise sporadically in one lobe, and 40-50% of these sporadic cases are associated with somatic mutations in RET.28 25-30% of MTC cases are hereditary, and are linked to mutations in the RET oncogene (Table 2.9).28,37,44 The subtypes of inherited MTC, associated with germline mutations, are the multiple endocrine neoplasia type 2 syndromes MEN2A (70-80%; including the subtype familial MTC or FMTC) and MEN2B (Table 2.9).28,45 FMTC results in multifocal MTC without any pheochromocytoma or hyperparathyroidism or other clinical abnormalities, and often occurs at an older age due to the indolent nature of the cancer.45,46

Table 2.9. Prevalence of mutations and genetic alterations in thyroid cancer subtypes, US and worldwide.
Data source Population Thyroid carcinoma subtype Mutation Prevalence (%) References
Review of histopathology, and genetic analysis of PTC tumors US, children and adolescents, age 6-18 years, both sexes (74% females),  (n=27) Pediatric

PTC

fusion oncogenes:

NTRK3/ETV6,

NTRK3/unknown,

NTRK/TPR

26 Prasad et al. 201647
RET protooncogene fusions: RET/PTC1,

RET/PTC3

22

 

BRAFV600E 48
Memorial Sloan-Kettering Cancer Center; 52 primary tumors; 55 recurrent and nodal and/or distant metastatic samples from patients with radioactive iodine-refractory (RAIR) differentiated thyroid cancers positive on 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET), 1983-2007 US,

DNA sequencing and mass spectrometry genotyping in patients

(n=42)

Primary PDTC (n=34) RAS

(NRAS; KRAS; HRAS)

44

(26; 9; 9)

Ricarte-Filho. 200932
BRAF 9
BRAF/PIK3CA 3
PIK3CA 3
RET/PTC 18
Unknown 23
Radioactive iodine refractory FDG-PET-positive metastatic PDTC (n=23) BRAF 26
BRAF/AKT1 13
AKT1 4
RAS

(NRAS; HRAS)

13

(9; 4)

RET/PTC 9
Unknown 35
Primary

ATC (n=18)

BRAF 38
BRAF/PIK3CA 6
RAS

(NRAS; HRAS)

23

(17; 6)

Unknown 33
Published studies meta-analysis International studies (n=2,470) PTC BRAFV600E 45;

higher association of mutation with PTC recurrence, lymph node metastasis, and advanced stage III/IV

Tufano et al. 201248; Xing et al. 201349
PTC-derived ATC BRAFV600E 24
Sequencing of genomic DNA isolated from thyroid tumors US, 85 benign tumors, 257 PTC, 79 FTC, 54 ATC, 16 MTC, and 8 poorly differentiated thyroid cancer (PDTC) PDTC TERT C228T with

TERT C250T

43.2 Liu et al. 201342; Liu et al. 201643
ATC 40.1
FTC 17.1
PTC 11.3
Sequencing of genomic DNA isolated from thyroid tumors US, 85 benign tumors, 257 PTC, 79 FTC, 54 ATC, 16 MTC, 8 poorly differentiated thyroid cancer PDTC TERT C228T

 

37.5 Liu et al. 201643

 

ATC 42.6
FTC 11.4
PTC 11.7
papillary- follicular variant 3.6
Tall cell variant 30.8
Sanger or next-generation sequencing US, 266 thyroid tumors and hyperplastic nodules; 647 thyroid fine needle aspiration (FNA) samples with indeterminate cytology analyzed ATC EIF1AX mutation occurs in thyroid cancers and benign tumors; confers ~20% risk of cancer in FNA samples. 25 Karunamurthy et al. 201650
PTC 2.3
follicular adenomas, 7.4
hyperplastic nodules, 1.4
MTC 0
Genomic sequencing and in informative cases also SNP arrays, exomes, RNA-seq, miRNA-seq, DNA methylation The Cancer Genome Atlas (TCGA) project, (n=496), tumor samples and matched germline DNA from blood or normal thyroid. Informative tumors (n=390) were those analyzed on all major platforms (SNP arrays, exomes, RNA-seq, miRNA-seq, DNA methylation) PTC MAPK-related genes, BRAF, NRAS, HRAS, KRAS 74.6 Agrawal et al. 201433
BRAF 61.7
RAS 12.9
MLL 1.7
ARID1B 1.0
MLL3 1.0
PI3K and PPARg pathway genes: PTEN, AKT1/2, PAX8/PPARG 4.5
WNT pathway related genes 1.5
Tumor suppressor genes: TP53, RB1, NF1/2,

MEN1, PTEN

3.7
ZFHX3 1.7
BDP1 1.2
thyroglobulin 2.7
TSHR 0.5
RET fusions 6.8
BRAF fusions 2.7
PAX8/PPARG 0.8
ETC6/NTRK3, RBPMS/NTRK3 fusions 1.2
THADA fusions 1.2
ALK-associated fusions 0.8
Informative tumors (n=384) subsection from all PTCs (n=496) TERT 9.4

Abbreviations: FNA, final-needle aspiration; PTC, Papillary thyroid cancer; FTC, Follicular thyroid cancer; MTC, Medullary thyroid cancer; ATC, Anaplastic thyroid cancer; PDTC, poorly differentiated thyroid cancer; FDG-PET, positive on 18F- fluorodeoxyglucose-positron emission tomography; NTRK, neurotrophic tyrosine kinase receptor.

Thyroid cancer is associated with upregulation of microRNA-146, -181, -121/222, -224 in PTC, upregulation of microRNA-181 and -200, downregulation of miR-199 in FTC, upregulation of microRNA-17, and -221/222 and downregulation of let-7, -microRNA-30 and -29 families in ATC.51 In an association study (US, Finland, Poland; n=608 PTC patients, n=901 controls), microRNA-146a-3p increased the risk of developing PTC (Odds Ratio OR, 1.62) in the heterozygous form (G/C) over the homozygous forms GG  (OR, 0.69) or CC (OR, 0.42). Furthermore, 4.7% of tumors had undergone mutation from the homozygous to the heterozygous state.52

1.2    COST BURDEN OF DISEASE

For thyroid cancer patients diagnosed after 1985, the estimated overall societal cost of care in 2013 was $1.6 billion (Table 2.10).53 At the current rate of increase, there are expected to be 90,000 new cases of thyroid cancer in 2019, with an estimated cost-of-care between $3.1 billion and $3.5 billion (based on the National Cancer Institute’s SEER 13 database, 1992-2009 and SEER 18 registries, 1985-2013 respectively).6,53

Table 2.10. Breakdown of health care costs of well-differentiated* thyroid cancer in 2013, US.
Breakdown of costs Percentage of $1.6 billion (100%)
Diagnosis, surgery, adjuvant therapy (newly diagnosed patients) 656,000,000 (41%)
Surveillance of survivors 592,000,000 (37%)
Non-operative death costs attributable to thyroid cancer care 352,000,000 (22%)
Note: *, Well-differentiated thyroid cancer includes papillary, follicular (including Hürthle cell) thyroid carcinomas.

Source: Lubitz et al. 201453

Treatment of thyroid cancer shows an increasing trend away from privately-insured Outpatient procedures towards more cost-effective Medicare-insured Outpatient procedures (Tables 2.11, 2.12).54,55 From 1996 to 2006, the population-adjusted annual rate increased by 8.7 per 100,000 for Inpatient thyroidectomies and 45.9 per 100,000 for outpatient thyroidectomies.54

Table 2.11. Insurance and cost for inpatient and outpatient thyroidectomies in 1996 vs. 2006, US.
Population Description Patient category 1996 2006
National Survey of Ambulatory Surgery (NSAS); Nationwide Inpatient Sample (NIS) databases, 1996 and 2006 All thyroidectomies (per year) Outpatient 19,099 30,731
Inpatient 52,062 62,200
Total thyroidectomies All 71,161 92,931
Private insurance (%) Outpatient 76.8 39.9
Inpatient 63.8 60.1
Medicare (%) Outpatient 17.2 45.7
Inpatient 22.8 25.8
Per-capita charge ($) Outpatient not stated 7,222
Inpatient 9,934 22,537
Total charges ($) Outpatient not stated 1.16 billion
Inpatient 464 million 1.37 billion
Note: Dollars were inflation adjusted from 1996 to 2006. Medicare defines outpatient as hospital stay <24 hours.

Source: Sun et al. 201354

Table 2.12. Change in inpatient and outpatient thyroidectomies from 1996 to 2006 in the US.
Data source Population Procedure Number of patients Change in patient number (%),   1996 to 2006
1996 2006
National Survey of Ambulatory Surgery and Nationwide Inpatient Sample databases, cross-sectional analysis US, total thyroidectomy patients: n=71,161 in 1999 and 92,931 in 2006 All thyroidectomies
Inpatient 52,062 62,200 +20
Outpatient a 19,099 30,731 +61
Total thyroidectomies
Inpatient 12,314 27,602 +124
Outpatient a 1840 2403 +31
Subtotal thyroidectomies
Inpatient 37,908 32,196 -15
Outpatient a 16,194 26,726 +65
Note: a, Medicare defines outpatient as hospital stay less than 24 hours. Percentage change is rounded up.

Source: Sun et al. 201354

In a 2007 US-based study of 16,878 Health Care Utilization Project National Inpatient patients who had undergone thyroid procedures (2003-2004), the mean total cost of thyroidectomy treatment (including surgery, mean length of hospital stay) was significantly higher for Blacks ($6,587) and Hispanics ($6,294) than for Whites ($5,447).56 Population differences are discussed further in section 2.3.

1.3    DEMOGRAPHIC DIFFERENCES

The prevalence of thyroid nodules detected by ultrasound in randomly selected individuals is 2-fold higher in females than males.23,57 In 2012, Ahmed and colleagues reported that females had a higher prevalence of unsuspected single and multiple thyroid nodules (Table 2.13).24 Patients with nodules were significantly older than those without nodules (age 64 vs. 58 years), and age correlated with the number of nodules (age 62 years for single nodule; age 66 years for multiple nodules). No association was seen between race and presence of nodules.24

Table 2.13. Prevalence of unsuspected thyroid nodules in an outpatient population (not diagnosed as having thyroid cancer) US.
Data source Population Characteristics Prevalence of nodules (% of patients)
Females Males
Outpatient Center, unsuspected thyroid nodules in patients not diagnosed as having thyroid disease. Detection by contrast enhanced 16- and 64-modified discrete cosine transform (MDCT) of the chest (to detect distant metastasis) US, adults, age 18-94 years (n=2,510) presence of nodules 30.5 19.9
multiple nodules 13.7 5.8
single nodule 16.9 14.1

Source: Ahmed et al. 201224

Data from several SEER registries indicates that the overall incidence of thyroid cancer in the US is 2-4-fold higher in females than males (Table 2.14).

Table 2.14. Incidence and Incidence Rate Ratio (IRR) for thyroid cancer in the US.
Data source Population Diagnosis Incidence rate per 100,000 person years Female to Male Incidence Rate Ratio (IRR) References
Females Males
SEER 9 Registries Database

1976-2005

US, age 0->80 years; age-adjusted rates standardized for 2000 US population, both sexes (n=44,705) Thyroid cancer 9.2 3.6 2.55 Kilfoy et al. 20094
SEER 13 Registries Database 1992-2009 US (n=59,611) Thyroid cancer 12.7 4.5 2.8 Aschebrook-Kilfoy et al. 20136
SEER 9 Registries Database 1975-2009 US, adults, age >18 years, ~10% of US population Thyroid cancer 14.9 3.8 3.9 Davies and Welch. 201458

 

The female-to-male IRR is highest for differentiated thyroid cancer (PTC and FTC subtypes) (Table 2.15).4

Table 2.15. Incidence of subtypes in diagnosed cases of thyroid cancer from 1976 to 2005, US.
Data source Population Thyroid cancer subtypes Incidence per 100,000 person years Female to Male Incidence rate ratio (IRR)
SEER 9 Registries Database

1976-2005

US, adults, age 0->80 years, both sexes (n=44,705) PTC 5.1 2.85
FTC 0.8 2.15
MTC 0.2 1.33
ATC 0.1 1.22
Other/unknown 0.2 0.71
Abbreviations: SEER, Surveillance, Epidemiology, and End Results; PTC, Papillary thyroid cancer; FTC, Follicular thyroid cancer; MTC, Medullary thyroid cancer; ATC Anaplastic thyroid cancer; IRR, incidence rate ratio.
Note: SEER 9 registry includes 10% of the US population and includes following areas: Atlanta, Connecticut, Detroit, Hawaii, Iowa, New Mexico, San Francisco-Oakland, Seattle-Puget Sound, and Utah.

Source: Kilfoy et al. 2009 4

Newly-diagnosed cases of PTC follow a normal distribution, with a peak (median 24.1% of cases) at age 50 years, whereas rates of FTC, MTC, and ATC continue to increase with age.1,15. The highest incidence of PTC in females is at reproductive age (11.3-12.8 per 100,000, age 30-59 years), possibly due to greater detection during annual examinations, and routine thyroid testing in prenatal care practices in some areas, whereas the highest incidence in males, at age 50-79 years  (4.9-5.5 per 100,000), may reflect an increase in doctor’s visits later in life.4,59 As a result, the female-to-male incidence rate ratio (IRR) for PTC declines with age (5.0-5.4 at age 10-29 years, 3.4-3.9 at age 30-49 years, 2.44 at age 50-59 years and <2.0 above 60 years).4 The highest incidence of FTC (SEER 9 database, 1980-2009) is in older individuals, peaking at age 70-79 years with 2.46 per 100,000 in females and 1.77 per 100,000 in males. The female-to-male IRR for FTC is highest at a younger age (4.5-5.67 at age 10-29 years, 2.9-3.76 at age 30-49, and <2.0 at age ³50 years).7

The most notable increase in the incidence of thyroid cancer was in females at age 55-64 years, from 1999 to 2008 (~15 to ~33 per 100,000).13 The American Cancer Society projected that in 2016, there would be 64,300 new cases of thyroid cancer (77% in females).10 With a continued trend of 7% APC (1992-2009), new PTC cases in females are set to increase from 12.1 per 100,000 in 2009 to 37 per 100,000 in 2019, making thyroid cancer the third most common cancer in females in the US.6

Analyses of race or ethnicity information from databases from 1992 to 2008, shows the lowest incidence of thyroid cancer in American Indian/Alaskan Natives (AI/AN) and Blacks, while the Female-to Male IRR are highest in Hispanics Table 2.16.

Table 2.16. Trends in thyroid cancer by race/ethnicity and gender, US.
Data source Population Race/Ethnicity Incidence rate per 100,000 person years Female-to-Male Incidence rate ratio (IRR) References
Females Males
North American Association of Central Cancer Registries (NAACCR), covering 48 States, 2004-2008 US, age 15->65 years, covering 48 States and 96% of the US population, cross-sectional rates, standardized to 2000 US population All 21.0 7.0 3.0 Simard et al. 201213
White 21.6 7.4 2.9
Asian/Pacific Islander 21.5 6.3 3.4
Hispanic (any race) 20.4 5.4 3.8
Black 12.6 3.8 3.3
American Indian/Alaskan Native 10.0 3.1 3.2
SEER 13 registry database, 1992-2006 US, age-adjusted incidence rates standardized to 2000 US population: (n=43,644 *) All 11.3 4.1 2.8 Aschebrook-Kilfoy et al. 201115
White 12.1 4.6 2.6
Asian 12.5 3.9 3.2
Hispanic 11.4 3.3 3.5
Black 6.4 2.4 2.7
American Indian/Alaskan Native 9.7 3.5 2.8
Abbreviations: SEER, Surveillance, Epidemiology, and End Results.

Note: *, Numbers rounded up to one decimal place.

A 2016 study (newly-identified cases 2009-2011), reported highest thyroid cancer incidences in non-Hispanic Whites (22.4 vs. 8.1 per 100,000 in females vs. males; n=1,327,727) and Asians (21.5 vs. 6.8 per 100,000 in females vs. males; n=90,709). The highest incidence in the Asian group was in Filipinos (28.5 vs. 9.7 per 100,000 in females vs. males).60 Age-adjusted rates for PTC (California Cancer Registry, 1988-2004) in Filipina and Vietnamese females were double those in Japanese females (13.7, 12.7, and 6.2 per 100,000 respectively). The place of birth was also a risk factor; Chinese and Filipina females born in the US had a higher incidence (IRR 0.48 and 0.74 respectively) than those who were foreign-born; but the opposite was seen in Japanese females (IRR 1.55).61

Unlike PTC, MTC and ATC, FTC shows no differences in race/ethnicity (Table 2.17). The highest Female-to-Male IRRs were: 3.55 in Hispanics, 2.53 in Asians, and ~2.0 in Whites and Blacks (Table 2.18).15

Table 2.17. Incidence of papillary (PTC) and follicular (FTC) thyroid cancers by race/ethnicity, US.
Data source Population Thyroid cancer subtype Race/ethnicity Incidence (per 100,000)
SEER 9 registries, 1980-2009 US, ages 0-³80 years; age-adjusted to the 2000 US standard population (n=45,942 PTC; n=6,410 FTC) PTC White 6.41
Black 3.28
Other* 7.32
FTC White 0.87
Black 0.85
Other* 0.92
Abbreviations: SEER, Surveillance, Epidemiology, and End Results; US, United States; PTC, Papillary thyroid cancer; FTC, Follicular thyroid cancer; MTC, Medullary thyroid cancer; ATC, Anaplastic thyroid cancer.
Note: *, Other includes American Indians, Alaskan Natives, Asians, Pacific Islanders.

Source: Aschebrook-Kilfoy et al. 20137

MTC incidence rates among Whites and Hispanics are higher than among Asians and Blacks. The female-to-male IRR was 1.47 in Asians, 1.28 in Whites, and almost equal in Hispanics (1.19) and Blacks (1.09).15 In Whites, the Female-to-Male IRR decreased with age, most steeply for FTC, and least for MTC.15 ATC incidence is the highest among Hispanic females and lowest among Hispanic males (female-to-male IRR 2.92).15

 Table 2.18. Incidence of thyroid cancer subtypes in females and males.

Data source Population Thyroid cancer subtype Race/ethnicity Incidence Rate per 100,000 in females Incidence Rate per 100,000 in males Female-to-Male Incidence rate ratio (IRR)
SEER 13 registry database, 1992-2006 US, age-adjusted to US standard population; (n=18,523 PTC, n=2,137 FTC, n=400 MTC, n=225 ATC) PTC White 10.39 3.58 2.90
Hispanic 9.72 2.57 3.78
Asian 10.96 3.20 3.43
Black 4.9 1.56 3.14
AI/AN 8.12 2.68 3.03
FTC White 1.16 0.58 1.99
Hispanic 1.04 0.29 3.55
Asian 1.07 0.42 2.53
Black 1.03 0.53 1.92
AI/AN 1.02 nc/na nc/na
MTC White 0.22 0.17 1.28
Hispanic 0.21 0.18 1.19
Asian 0.14 0.10 1.47
Black 0.11 0.10 1.09
AI/AN nc/na nc/na nc/na
ATC White 0.10 0.10 0.99
Hispanic 0.17 0.06 2.92
Asian 0.14 0.11 1.32
Black 0.13 0.08 1.65
AI/AN nc/na nc/na nc/na
Abbreviations: AI/AN, American Indian/Alaskan Native; nc/na, not calculated or not applicable; SEER, Surveillance, Epidemiology, and End Results; US, United States; PTC, Papillary thyroid cancer; FTC, Follicular thyroid cancer; MTC, Medullary thyroid cancer; ATC Anaplastic thyroid cancer.

Source: Aschebrook-Kilfoy et al. 201115

From 1999 to 2008, the incidence of thyroid cancer increased significantly in all races/ethnicities in both genders (average annual percent change, AAPC, 3.1-7.3%), except in American Indian or Alaskan Native (AI/AN) males (AAPC 0.6%).13

The most common SEER stages (according to American Joint Committee on Cancer, AJCC) for differentiated thyroid cancer (PTC and FTC) are localized and regional tumors (Table 2.19).62

Table 2.19. SEER stages of differentiated thyroid cancers, US.
Data source Population Tumor SEER stage Incidence per 100,000
PTC FTC
SEER 9 registry, 1980-2009 US (n=45,942 PTC, n=6,410 FTC) Localized 3.86 0.46
Regional 2.00 0.33
Distant 0.22 0.06
Other/Unknown 0.12 0.03
Abbreviations: SEER, Surveillance, Epidemiology, and End Results; US, United States.

Source: Aschebrook-Kilfoy et al. 20137

A 2010 study identified significant differences in the incidence of PTC and localized, staged, thyroid cancer by race/ethnicity groups over a 13-year period (Table 2.20).

Table 2.20.  Annual percent change in local staged papillary thyroid cancer (PTC) by race/ethnicity from 1992-1996 to 2000-2004, US.
Data source Population Race/Ethnicity Annual percent change in PTC (%) Increase in proportion of local staged PTC (%)
SEER 13, 1992-1996 and 2000-2004 13.8% of the US population with PTC diagnosis White 5.6 14.3
Black 4.3 24
White Hispanic 2.8 14.4
Asian 1.5 4
American Indian/Alaska Native 1.1 N/A
Abbreviations: N/A, not available; SEER, Surveillance, Epidemiology, and End Results; US, United States; PTC, Papillary thyroid cancer; FTC, Follicular thyroid cancer; MTC, Medullary thyroid cancer; ATC Anaplastic thyroid cancer.

Source: Yu et al. 201018

Studies of pediatric thyroid cancer (1973-2007, SEER 9 registries, n=1,360, 11% of total population) reported an incidence rate of 0.4-0.7 per 100,000 at age 0-19 years, with a higher incidence amongst girls (0.72-1.3 per 100,000) age 15-19 years (1.0-2.3 per 100,000) and Whites (0.4-0.8 per 100,000).63 These findings in children and adolescents were confirmed in a 2014 report of cases between 2001 and 2009. While the rate of all cancers among children and adolescents (age 0-19 years) remained relatively stable (+0.3%), thyroid carcinomas increased at 4.9% annual percentage change (APC), with increases specifically among adolescents age 15-19 years (APC +5.7%).64 Rates for age 0-19 years increased in all US geographic regions except the Midwest (APC: Northeast +5.8%, South +4.3%, West +6.6%). The forces driving the thyroid cancer rate increase in children and adolescents (of all race/ethnicities) (Table 2.21) have not been confirmed, but possibilities include radiation from dental radiographs, CT scans, reproductive or hormonal factors, obesity, and enhanced detection.64

Table 2.21. Incidence of thyroid carcinomas in children and adolescents by sex and race/ethnicity, US.
Data source Population Sex or race/ethnicity Incidence rate per 1,000,000 Annual percent change (APC)
CDC’s NPCR and NCI’s SEER programs, 47 population-based state cancer registries, covering 94.2% of the US populations, 2001-2009, age-adjusted to 2000 US population US, childhood and adolescent, age 0-19 years

(n=120,137)

All 6.83 +4.9
Males 2.59 +4.7
Females 11.31 +4.9
White 7.81 +4.0
Black 2.36 +6.8
Hispanic 6.53 +9.1
Abbreviations: CDC, Centers for Disease Control and Prevention; NPCR, National Program of Cancer Registries; NCI, National Cancer Institute; SEER, Surveillance, Epidemiology, and End Results; US, United States.

Source: Siegel et al. 201464

 

1.4    LIFE EXPECTANCY AND MORTALITY

In January 2012 (SEER 1975-2007), there were an estimated 558,260 thyroid cancer survivors, or 4% of all cancer survivors (13.7 million) in the US, with a majority (78%) being female.2,65 The excellent (90-99%) 5-year thyroid cancer survival rates (time from diagnosis to death from cancer), have increased significantly over time (Table 2.22).1,2,10,65 Survival rates vary by cancer subtype, stage, and age at diagnosis. The 10-year relative survival rates (US, 1985-1995, n=53,856 thyroid carcinoma cases) are 93% PTC, 85% FTC, 76% Hürthle cell, 75% MTC, and 14% anaplastic/undifferentiated carcinomas.66 For all thyroid tumor stages, the 5-year relative cancer survival rates decline with age: 99.5% age £45 years, 82.2% ³75 years (2001-2007).9 The 5-year survival rates (patients age >15 years; 2000-2007) are excellent for localized (99.8%) and regional staged tumors (97%), but poor for distant staged tumors (57.3%).13

Table 2.22. Trends in 5-year relative survival rates by Race and year of diagnosis, US.
Data source Population Race/ethnicity Diagnosis 1975-1977 Diagnosis          2005-2011
SEER 9 registries, 1975-1977 and 2005-2011 US, followed through 2012 All races 92 98
White 92 99
Black 90 97
Abbreviations: SEER, Surveillance, Epidemiology, and End Results; US, United States.

Source: Siegel et al. 201610

Hollenbeak and colleagues suggest that the poor thyroid cancer survival rates in the Black population could be due to later disease presentation and genetic predisposition to the more aggressive forms ATC and FTC (Table 2.23).67 While there were no differences in FTC rates among the racial groups, MTC showed the lowest survival rates in Hispanics. The worst prognosis was for ATC, with Whites having a worse rate than Blacks and Asian/Pacific Islanders (Table 2.21).

Table 2.23. Observed 5-year relative survival rates by thyroid cancer subtype, US.
Data source Population Race/ethnicity PTC FTC MTC ATC
SEER 13 registry database, 1992-2004 US (n=25,653) White 95.3 89.3 80.3 5.6
Hispanic (white) 94.5 88.4 73.5 N/D
Black 91.5 89.7 85.1 8.9
Asian/Pacific Islander 94.4 89.9 88.7 11.4
American Indian Natives 96.2 90.5 N/D N/D
Abbreviations: SEER, Surveillance, Epidemiology, and End Results; US, United States; PTC, Papillary thyroid cancer; FTC, Follicular thyroid cancer; MTC, Medullary thyroid cancer; ATC Anaplastic thyroid cancer; N/D, not determined.

Source: Yu et al. 201018

The mortality rates for thyroid cancer have remained relatively stable (0.4-0.5 per 100,000) since 1973.1,5 A slight increase was identified in males from 2003 to 2012 (0.43 to 0.51 per 100,000).10 The American Cancer Society projected that of the 595,690 deaths from all cancers in 2016, 1,980 (0.33%) would be from thyroid cancer; 910 (46%) in males and 1,070 (54%) in females.10 Based on 2008-2012 US data, the number of deaths in females is higher in Asian/Pacific Islanders, Hispanics, and Blacks (0.8, 0.7, 0.6 per 100,000 respectively) than the average (0.5 per 100,000). In males, deaths in Blacks are lower at 0.4 per 100,000 than other races/ethnicities.1 For all races and both sexes (2008-2012), the number of deaths from thyroid cancer increased with age (28.2% at age 75-84 years).3 Orosco and colleagues in 2015, reported that age (HR, 19.2, age >45 years) and metastatic disease (HR, 13.1) were the strongest predictors of survival in differentiated thyroid cancer (Table 2.24).68

Table 2.24. Mortality rate in thyroid cancer of follicular cell origin (papillary, follicular, follicular variant of papillary, anaplastic thyroid cancer, and Hürthle cell carcinoma), US.
Data source Population Characteristics determining mortality rate in Differentiated Thyroid Cancer Percentage (%)
SEER 17 registries database, 1988-2007 US, differentiated thyroid cancer patients (n=61,523) Overall mortality rate 2.8
Age ≥45 years 94.5
Female mortality rate 60.8
PTC (including follicular variant) 38.1
ATC 31.3
Other subtypes 16.7
FTC 10.1
Hürthle cell 3.8
Tumor size >4cm 49.6
Tumor size >2-4cm 29.2
Tumor size >1-2cm 12.8
Tumor size ≥1cm 7.7
Lymph node metastasis 77.1
Distant metastasis 47
Abbreviations: SEER, Surveillance, Epidemiology, and End Results; US, United States; PTC, Papillary thyroid cancer; FTC, Follicular thyroid cancer; ATC, Anaplastic thyroid cancer.

Source: Nilubol et al. 201569

Differentiated thyroid cancer (PTC and FTC) is often indolent. PTC commonly metastasizes via the lymphatic system, whereas the more aggressive FTC tends to metastasize to distant sites (usually lung and bone) via vasculature. 69 Prognosis for differentiated thyroid cancer is excellent, but poor outcome can result from insensitivity to radioactive iodine treatment and to recurrences. In a 2015 study of 3,664 patients (1985-2010) who underwent surgery and adjuvant treatment, the 10-year survival rate was 96%. Mortality increased with age, with a 37-fold increase in HR from the age <45 years to age >70 years.70 Poorly differentiated thyroid cancer, ATC, and radioactive iodine-refractory differentiated thyroid cancer have a high mortality.32

The BRAFV600E mutation is associated with higher recurrence rate (risk ratio 1.93), the risk ratios are 1.32 for lymph node metastasis, 1.71 for extra-thyroidal extension, and 1.7 for advanced stage III/IV.48 Relative to PTC in adults, childhood cancer has higher lymph node involvement, 10-fold higher incidence of distant metastasis, and often require extensive and repeated treatment, despite an excellent 30-year survival (90-99%).71

MTC is slow growing, but metastasizes locally and regionally to lymph nodes and distally to lungs, liver, and bone. For MTC, 10-year survival rates are 95% without metastasis, 40% with distant metastasis, and can vary according to the SEER stage: 100% for I, 93% for II, 71% for III, and 21% for IV. Survival rates are worse with increasing age (HR, 5.69 for age >65 years), larger tumors (HR 2.9 for >4cm), distant metastases (HR 5.7), and the number of positive regional lymph nodes (HR 3.4 for ³16).72 Approximately half of MTC patients have lymph node metastasis with 28% survival rate at stage IV, and 11% have distant metastasis with survival rate of 22%.72

ATC, a rare and extremely aggressive cancer, can metastasize to lymph nodes and distant sites early on in progression. At the time of diagnosis, the cancer is considered Stage IV (American Joint Committee on Cancer), and sub stages IVA-IVC show increasing metastasis and worsening prognosis.30,73 ATC accounts for only 1-3% of all thyroid cancer, but 14-50% of all deaths from thyroid cancer, with median survival of 5-6 months and survival rates of 10-20% for 1-year and <5% for 5-year.30,31

1.5    KEY TRENDS AND HEALTH OUTCOMES

Table 2.25. Treatment trends for papillary thyroid cancer, 1940 – 2000, US.
Data source Population Treatment or Outcome Percent of cases by time frame (%)
1940-1954 1955-1969 1970-1984 1985-2000
Mayo Clinic, Minnesota US (n=2,512) Unilateral lobectomy 52 5 <5 <10
Bilateral thyroidectomy 43 94 97 91
Radioactive iodine ablation 1 3 32 46
15 years cause-specific mortality 7.4 4.9 4.0 2.7
15-year recurrence 18.4 7.6 11.0 11.7

Source: Hay et al. 200274

Thyroidectomy is the main treatment for both benign and malignant thyroid cancers, although the surgeon’s experience in performing thyroidectomies (i.e. patient volume) influences patient outcome (Table 2.26).75

Table 2.26. Clinical outcomes from thyroidectomy influenced by experience of surgeon, US. 
Data source Population Surgeon experience (thyroidectomy cases/year) Mean length of hospital stay (days) Complication rate
Non-federal acute care hospitals in Maryland, benign or malignant thyroidectomies, cross-sectional analysis of hospital discharge data, 1991-1996 US, Maryland, age >18 years (n=5,860) 1-9 1.9 8.6
10-29 1.7 6.1
30-100 1.7 6.1
>100 1.4 5.1

Source: Sosa et al. 1998 75

 

Surgeon volume may also partially explain racial disparities in clinical and economic outcomes of thyroidectomies (Table 2.27). Highest-volume surgeons (>100 cases per year) performed merely 5% of the thyroidectomies, but 90% of their patients were White.56

Table 2.27. Racial disparities in clinical outcomes from thyroidectomy, US. 
Data source Population Race/ Ethnicity Patients (%) Mean length of hospital stay (days) In-hospital mortality Complication rate Surgery by lowest volume surgeons  (1-9 cases/ year)
Health Care Utilization Project National Inpatient samples, selected samples undergone thyroid procedures, 2003-2004 US (n=16,878) White 71 1.8 0.1 3.8 44
Black 14 0.5* 0.4* 4.9 52
Hispanic 9 2.2 0.1 3.6 55
Note: *, denotes statistically significant data relative to the white population.

Source: Sosa et al. 2007 56

For PTC (that can metastasize to cervical lymph nodes), the most common initial therapies are surgery (total thyroidectomy) with or without 131I radioactive iodine treatment. For more uncommon aggressive cases, treatment may also include external beam therapy and cytotoxic chemotherapy, traditionally including doxorubicin (as monotherpy or with cisplatin).7,76 Due to toxic side-effects, partial response rate (25-37%), and rarely complete remission, doxorubicin and/or cisplatin are used for patients with rapidly progressive metastatic disease or if patient conditions are not suitable for surgery, radioiodine, external beam therapy, or where tyrosine kinase inhibitors cannot be used or have failed.77 However, as the cancer metastasizes to distant sites, a drop in survival rate can be expected, as surgery and radioactive iodine are no longer effective. The 10-year survival rate in differentiated thyroid cancer after distant metastasis drops to between 25% and 42%.78,79

In the last two decades, somatic and germline genetic mutations have been discovered in distinct biological pathways associated with development and progression of thyroid cancer. Therapies targeting some of these pathways have already proved to be effective in clinical trials, including for the tyroisine kinase inhibitors axitinib, lenvatinib, motesanib, pazopanib, sorafenib, sunitinib, and vandetinib. In addition to the approval of sorafenib and lenvatinib by the FDA, the National Comprehensive Cancer Network (NCCN) Guidelines allow for the use of other tyroisine kinase inhibitors for thyroid cancer (see below).80

Mutations in BRAF are found in ~45% of sporadic PTCs with the BRAFV600E mutation making up >90% of these cases.81 In a 2015 retrospective study (2,099 patients, 16 international medical centers), the mutation BRAF V600E (prevalence 48%) was associated with increased risk of PTC recurrence (recurrence rates 47.7 for mutation-positive versus 26.0 for mutation-negative per 100,000), with HR of 1.82.82,83

Raf kinase inhibitors, can inhibit growth of poorly differentiated thyroid cancer cell lines with RET or Raf mutations, and include the multikinase inhibitor sorafenib (targeting VEGFR-1, VEGFR-2, VEGFR-3, RET, and FLT3, c-KIT, wildtype and mutant BRAF). Sorafenib, approved by the FDA in 2013, improved progression-free survival in clinical trials for locally recurrent, or metastatic, radioiodine-refractory PTC (BRAFV600E) progressive differentiated thyroid cancer (Table 2.28).76,81,84

MTCs are more invasive and metastatic than PTC and FTC; at diagnosis, 50% of patients have neck lymph node metastases and 20% have distant metastases.85 Radioactive-iodine cannot effectively treat metastases in MTC as the cancer originates in non-follicular C cells, which do not absorb iodine; therefore, repeated surgery (total thyroidectomy) is performed on recurrent tumors.86 Moreover, 25% of MTCs are positive for inheritable RET mutations.28,85 RET encodes a tyrosine kinase receptor, and therefore, tyrosine kinase inhibitors are being explored to manage advanced metastases; vandetanib and carbozantinib are already FDA-approved. Some of the current thyroid cancer treatments and their outcomes are summarized in Table 2.28. Vandetanib is a multi-kinase selective inhibitor that targets VEGFR-2, VEGFR-3, EGFR, and RET kinases, and was FDA approved in 2011 for the treatment of MTC in unresectable, locally advanced, or metastatic MTC (Table 2.28).76,81 Lenvatinib is a multi-kinase inhibitor of VEGFR 1,2,3 FGFR 1-4, PDGFRa, RET, KIT; approved by the FDA in February 2015 to treat locally recurrent or metastatic or progressive RAI-refractory differentiated thyroid cancer (PTC, PDTC, FTC, Hürthle cell) (Table 2.27).76,87-89 Cabozantinib (XL184) is a tyrosine kinase inhibitor, that targets multiple pathways, via VEGFR-2, RET, and mesenchymal-epithelial transition factor c-MET.90,91 It was approved by the FDA in November 2012 for the treatment of progressive metastatic MTC (Table 2.28).76

Gene rearrangements involving the PPAR nuclear receptor, such as the PAX8/PPARg translocation, have been reported in ~35% of FTC, and PPAR-g agonist may be effective treatment in these cases (Table 2.28).92

Table 2.28. Treatments and outcomes by thyroid cancer subtypes after surgery, radiotherapy, chemotherapy, and/or targeted therapies, US and worldwide.
Data source Population Characteristics Treatment Outcome References
Differentiated thyroid cancer (DTC) (Papillary and Follicular)
Prospective multi-institutional registry, 1987-2012 US, n=4,941 differentiated thyroid cancer; 3,268 thyroid hormone suppression therapy; 6-year median follow-up 88% PTC,

8% FTC,

4% Hürthle cell cancer

Total or near-total thyroidectomy, radioactive iodine, thyroid hormone suppression therapy

 

 

Overall survival improved in stage III by radioactive iodine (risk ratio 0.66), and in stage IV by total/near-total thyroidectomy (0.66) followed by radioactive iodine (risk ratio 0.7). Only total/near-total thyroidectomy improved both overall survival (risk ratio 0.13, 0.09,0.13, 0.33 in stages I-IV) and disease-free survival (risk ratio 0.52, 0.4, 0.18 in stages I-III). Radioactive iodine was not beneficial in low-risk patients. Carhill et al. 201593
Phase III trial, randomized, double-blind, multicenter study, Aug 2011- Oct 2012 Worldwide; Lenvtinib n=261, placebo n=13; 124mg/day oral dose, in 28 cycles DTC refractory to 131I iodine: PTC, PDTC, FTC, Hürthle cell Targeted therapy: Lenvatinib, Progression-free survival: lenvatinib 18 months (HR, 0.21), placebo 3.6 months (HR 0.14); Response rate: lenvatinib 64.8% (4 complete and 165 partial responses), 1.5% placebo. Discontinuation due to adverse events 14.2% lenvatinib, 2.3% placebo; drug-related mortality: 30% Schlumberger et al. 201587
Phase II clinical trial, 2004-2007 US, n=41 PTC, BRAF mutation in 77% of 22 PTCs analyzed. Metastatic PTC Targeted therapy: Sorafenib Progression-free survival 15 months (median). Partial response 15% (median duration 7.5 months), stable disease (> 6 months) 56%. Kloos et al. 200994
Systemic literature review (Dec 2012) in 7 phase II or open label trials

 

Worldwide, n=219 (in total 7 trials),

n=159 DTC, n=52 MTC,

n=8 ATC

First-line treatment for radioiodine-resistant metastatic differentiated thyroid cancer (DTC) Targeted therapy: Sorafenib Progression-free survival disease stabilization but no complete remission. Overall: 21% partial response (21% DTC, 22% MTC, 13% ATC), 60% stable disease, 20% progressive disease (93% MTC and 79% DTC for overall clinical benefit i.e. partial response and stable disease response). Drug discontinued in 16%, and dose reduction in 56%. Mortality not related to progressive disease in 4%. Thomas et al. 201495
Papillary thyroid cancer
Thyroid carcinomas of follicular cell origin who had undergone thyroidectomy for PTC and received follow-up care,

1974-2009

Washington University, School of Medicine, age 5.8-84.6 years

(n=508)

 

Average tumor size 2cm, 54.8% disease limited to thyroid, 42.2% disease in neck nodes and thyroid, 2.8% distant metastases to lung, 0.2% disease in thyroid and bone metastasis.

Mean follow-up 9.8 years.

BRAFV600E mutation (n=508) in ~70%

Surgery: Total thyroidectomy 97%, lobectomy or partial resection 3%, thyroid biopsy only 0.6%.

Surgery for metastatic lymph nodes 57%, neck lymph node removal 43%. Postoperative 131I 94%.

Overall survival rate: 95.4% for 10 years, 84.5%. Disease-specific survival: 97.4% at 10 years, 96.8% 20 years. Recurrence-free survival 88.8% at 10 years, 80.3% 20 years.

Mortality: 10%, mortality from thyroid cancer 2.6%.  No association of mutation with recurrence-free survival or disease-specific survival

 

Henke et al. 201539
Medullary thyroid cancer
National Cancer database, 1985-2005 US, both sexes (n=2,968) 38.4% regional lymph node positive and 65.8% resected, 11.1% distant metastases Surgery: 83.0% total thyroidectomy, 10.2% lobectomy, 6.8% no surgery No effect of surgery on survival in tumors <2cm/no distant metastases. Tumors >2cm/no distant metastases. Mortality: 61.1% no surgery, 30.4% lobectomy, 21.8% total thyroidectomy.

For any tumor size + distant metastases: lower mortality (70.1%) with total thyroidectomy + regional lymph nodes resected than total thyroidectomy (89.7), or no surgery (85.1)

Esfandiari et al. 201472
Phase III randomized, double-blinded trial: Dec 2006-Nov 2007, with median follow up of 24 months Multicenter, adults, mean age 52 years, 90% sporadic, 95% metastatic (n=331: 231 vandetanib, 100 plascebo) Presenting with unresectable locally advanced or metastatic, hereditary or sporadic medullary thyroid carcinoma (MTC). Tumor sample submission or RET germline mutation. Serum calcitonin ³500pg/ml Targeted therapy: vandetanib starting oral dose 300mg/day or placebo. At 24 months follow-up: disease progressed in 37%; mortality 15%;

Overall response rate 44%. Progression-free survival (PFS) vandetanib 30 months, placebo 19 months. Adverse events more common with vandetanib than placebo.

Long-term use required as non-curative

Wells et al. 201296
Phase II/II clinical trials Children age 5-12 years and adolescents age 13-18 years (n=16) Locally advanced or metastatic medullary thyroid carcinoma (MTC) Targeted therapy: Vandetanib in MTC and germline RET mutations, oral dose 100mg/m2, daily Partial response in 47% Fox et al. 201397
Phase III multicenter trial Patients with radiological progression before enrollment

(n=330)

Metastatic medullary thyroid carcinoma (MTC) Targeted therapy: Cabozantinib 140mg/day orally. Overall response rate for cabozantinib 28%. Patients alive and progression-free at 1 year: 47.3% cabozantinib and 7.2% placebo. Progression-free survival cabozantinib 11.2 months, placebo 4 months. Adverse events noted in most cases.

Long-term use required as not curative

Elisei et al. 201390
Anaplastic thyroid cancer
National Cancer Center Database, diagnosis Jan 1998 to Dec 2012 US, 68.4% ³65 years, 75% White, 44.7% positive nodes, 41.6% metastatic disease, 8.9% primary tumor confined to thyroid (n=3,552) 50.5% no surgery, 23.2% total thyroidectomy, 26.3% other surgery, 58.7% external-beam. Radiotherapy, 41.6% chemotherapy, 33.1% radiotherapy and chemotherapy.

Median follow-up 46.7 months for those alive or 3.5 months.

Thyroidectomy, radiotherapy, chemotherapy Survived 2 years:  total thyroidectomy 18.6%, other surgery 11.9%, no surgery 5.0%; radiotherapy ³59.4 Gy 21.6%, 36.1-59.3 Gy 10.9%, £36 Gy 3.2%, none 7.1%; chemotherapy 13.1%, no chemotherapy 7.3%. Glaser et al. 201673
National Cancer Database, 2003-2006 US (n=345) Anaplastic thyroid carcinoma (ATC) thyroid resection Median survival rates were 9.7, 4.2, and 3.4 months for stages IV-A, IV-B and IV-C, respectively Goffredo et al. 201598
Multicenter phase 1 trial US, adults age 43-82 years (n=15) Advanced Anaplastic thyroid carcinoma (ATC), most partial tumor resection, 53% radiotherapy, 26% chemotherapy 20% coexisting PTC. Combinatorial therapy: PPAR-g agonist efatutazone with paclitaxel 1/15 patients showed durable RECIST response, 2/15 showed ~42% improved time to progression and survival, 8/15 showed periods of disease stabilization; adverse events included edemas: fluid retention. Promising results-further trials necessary. Smallridge et al. 201399

Abbreviations: CEA, carcinoembryonic antigen; c-MET, mesenchymal-epithelial transition factor; DTC, differentiated thyroid cancer; EGFR, Epidermal Growth Factor Receptor; FDA, United States Food and Drug Administration; FGFR 1-4, Fibroblast growth factor receptor; FMTC, familial medullary thyroid carcinoma; Gy, Gray unit; HR, hazard ratio for progression or death; KIT, transmembrane receptor tyrosine kinase; MEN2A, MEN2B, multiple endocrine neoplasias; PDGFR, platelet-derived growth factor receptor; PPAR-g, peroxisome proliferator-activated receptor-gamma; RECIST, Response Evaluation Criteria in Solid Tumors; RET, Rearranged during transfection; VEGFR, vascular endothelial growth factor.

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