The epidemic of thyroid cancer and its evolving management: Is less more?

The epidemic of thyroid cancer and its evolving management: Is less more? Julie Ann Sosa, MD MA FACS Professor of Surgery and Medicine Chief, Section of Endocrine Surgery, and Leader, Endocrine Neoplasia Diseases Group Duke University, Durham, NC, USA Disclosure Member and ATA representative, Medullary Thyroid Cancer Registry Data Monitoring Committee funded by GlaxoSmithKline, Novo Nordisk, Astra Zeneca, and Eli Lilly 1

Epidemic of thyroid cancer It s not just looks that can kill. Have your neck checked for thyroid cancer. 2

Thyroid cancer is growing 7 times faster than breast cancer. Ask your doctor to check your neck. It could save your life.. Thyroid cancer is growing 5 times faster than testicular cancer. Ask your doctor to check your neck. It could save your life. Epidemiology of thyroid cancer Thyroid cancer is the most common endocrine malignancy. Fastest increasing cancer The 8 th (2005) 5 th (2013) most incident cancer among women Anticipated to be 3 rd (2019) American Cancer Society 2013; 2005 SEER Stat Fact Sheets 2013: Thyroid Cancer 3

Cost of care of thyroid carcinoma, 2013 2030 Millions $4,000 $3,500 $3,000 $2,500 $2,000 $1,500 $1,000 $500 $0 2013 2030 Disease Deaths Surveillance Recurrences Surgical Complications Surgical Deaths Initial Treatment Lubitz, et al., Cancer 2014 4

Thyroid Cancer and Bankruptcy Any cancer doubles the risk of bankruptcy Thyroid cancer carried one of the highest risks 3.5X Most patients file bankruptcy in the first year following the cancer diagnosis 10 9 8 7 6 5 4 3 2 1 0 9.3 9.1 6.8 6.2 5.9 5.7 5.7 3.7 The incidence rates of bankruptcy at one year after diagnosis, per 1,000 person yrs Ramsey S et al. Washington State cancer patients found to be at greater risk for bankruptcy 9 than people without a cancer diagnosis. Health affairs. 2013;32(6):1143 52. N America: increasing in all age groups, genders, extent Pellegriti, et al. J Cancer Epidemiol, 2013 5

Incidence trends by histologic subtype Pellegriti, et al. J Cancer Epidemiol, 2013 Incidence is increasing globally but variably: women, 1973 2002 Increase 81% 18% 6% 37% 107% 74% 87% 252% 85% Kilfoy, et al., Cancer Causes Control 2009 6

South Korea 4 5 fold higher per 100,000 than U.S.! US mortality is NOT decreasing SEER Cancer Statistics Review (CSR), 1975-2010 7

Population graying will increase incidence and aggressiveness Smith, et al., J Clin Oncol, 2009 107% increase in thyroid FNAs, 2006-2011 Thyroid FNAs more than doubled: 16% compounded annual percentage change Thyroid FNAs increased as a percentage of all FNAs, from 49% to 65%. Sosa et al 2013 8

Rate (per 100,000) 7 6 5 4 3 2 1 Surveillance bias: Incidence of thyroid cancer by size SEER, 1988-2009 0.1-1.0 cm 1.1-2.0 cm 2.1-3.0 cm >4.0cm 0 1988 1991 1994 1997 2000 2003 2006 2009 Potential environmental/lifestyle factors contributing to increasing incidence Ionizing radiation Lifestyle related factors Obesity Smoking Diet (iodine, nitrates) Environmental pollutants Polychlorinated biphenyls (PCBs) Dioxins Polybrominated diphenyl ethers (PBDEs) 9

Increasing exposure to radiation in U.S. Early 1980s Effective dose per person: 3.6 msv 2006 Effective dose per person: 6.2 msv Consumer 2% Medical 15% Occupational /industrial 0% Consumer 2% Occupational /industrial 0% Background 83% Medical 48% Background 50% Decline in radiation related somatic mutations 40 50% of sporadic TC <25% of sporadic TC >70% of radiation induced TC Romei et al., J Clin Endocrinol Metab 2012;97:E1758 65. 10

Main findings from pooled analysis of 5 prospective studies on thyroid cancer Physical activity High vs. low Medium vs. low 1.18 (1.00 1.39) 1.11 (0.92 1.33) Cigarette smoking Current vs. never Former vs. never 0.68 (0.55 0.85) 0.98 (0.85 1.12) Alcohol intake Per drink per day 0.88 (0.82 0.95) Body mass index Per 5 kg/m 2 1.17 (1.11 1.24) Kitahara, et al., Cancer Epidemiol Biomarkers Prev 2011;20:464 72. Kitahara, et al., Cancer Causes Control 2012;23:1615 24. Kitahara, et al., Cancer Causes Control 2012 [Epub] ATA guidelines for the management of thyroid nodules and differentiated thyroid cancer 2013 2014 2015 11

Aprocess of evolution ATA Thyroid Nodules and Cancer Guidelines Taskforce Erik Alexander* Brigham and Women s Endocrinology Keith Bible* Mayo Clinic Medical Oncology* Jerry Doherty Boston Med Center Endocrine Surgery Susan Mandel Univ Penn Endocrinology Yuri Nikiforov* Pittsburgh Pathology* Furio Pacini Univ Siena Endocrinology Greg Randolph* Mass Eye & Ear H&N Surgery Anna Sawka* Univ Toronto Endo/Methodology* Martin Schlumberger Inst Gustave Roussy Nuclear Medicine Kathryn Schuff* Oregon HS Univ Endocrinology Steve Sherman MD Anderson CC Endocrinology Julie Ann Sosa* Duke Univ Endocrine Surgery Dave Steward Univ Cininnati H&N Surgery Mike Tuttle Memorial Sloan Kettering Endocrinology Len Wartofsky* Washington Hospital Ctr Endocrinology 12

The 4 surgeons: David Steward Jerry Doherty Greg Randolph Julie Ann Sosa Goals of Initial Therapy To improve cancer related survival To minimize the risk of disease recurrence and metastatic spread To permit accurate long term surveillance for disease recurrence To permit accurate staging of disease To minimize treatment related morbidity Risk stratification Adapted from ATA Guidelines, Cooper DS, Thyroid, 2006 Updated 2009 Updating 2015 13

Less is sometimes more, and More is sometimes less! How much surgery is too much, or not enough? Risks of misdiagnosis, long term outcome uncertainty Patient preferences Medico legal considerations Costs to patients and payers Avoid undertreatment of clinically significant cancer Avoid overtreatment of indolent lesions 14

Rate (per 100,000) 7 6 5 4 3 2 1 Surveillance bias: Incidence of thyroid cancer by size SEER, 1988-2009 0.1-1.0 cm 1.1-2.0 cm 2.1-3.0 cm >4.0cm 0 1988 1991 1994 1997 2000 2003 2006 2009 Is the identification and eradication of all PTMCs a worthwhile goal? 15

Challenges To identify those tumors destined to become aggressive before they develop disease progression or at a point in progression at which intervention will still be very effective. Confirmation of appropriateness and safety of observation of PTMCs. Follow up 1235 patients, 1993 2011 (mean, 75 mos) Patients were divided by age (<40, 40 59, 60 yrs) Disease progression defined by: Size enlargement New lateral nodal mets Progression to clinical dz (Tumor 12 mm or lateral mets) 16

Tumor enlargement Nodal metastases Tumor enlargement, by age group Nodal metastases, by age group The proportion of patients with PTMC progression was lowest in the old patients and highest in the young patients. On multivariate analysis, young age was an independent predictor of PTMC progression. 17

Conclusion Older patients with low risk PTMC may be the best candidates for observation. PTMC in young patients is more progressive, but it might not be too late to perform surgery after subclinical PTMC has progressed to clinical disease, regardless of age. Is PTMC an over treated entity? Probably More patients are undergoing total thyroidectomy (73 vs 25% lobectomy) and RAI (31%) despite a lack of evidence this translates into survival benefit. It is important to distinguish patients with risk factors that predispose for high risk for recurrence. 36 Wang et al, WJS 2014 18

Recommendation If surgery is chosen for PTMCs w/o extrathyroidal extension and cn0, initial surgery should be lobectomy unless there are clear indications to remove the contralateral lobe. Lobectomy is sufficient for small, unifocal, intrathyroidal carcinomas in the absence of prior head and neck irradiation, family history, or nodal metastases. 19

Extent of surgery: controversy Total thyroidectomy: Eradication of possible bilateral disease Ability to use of radioactive iodine Easier detection of recurrence Lobectomy: Indolent disease with excellent prognosis Higher risks for complications with more extensive surgery No survival benefit DeGroot L, et al. JCEM (1990) Shaha A, et al. Arch Otolaryngol Head Neck Surg (2010) Thyroid nodule related surgery increased 31%, 2006 11 Combined thyroid nodule related operations Thyroidectomy 140,000 120,000 Lobectomy 120,945 127,602 130,216 100,000 99,613 106,319 114,697 80,000 60,000 40,000 54,055 53,837 45,558 52,482 62,295 58,650 68,742 72,344 58,083 56,614 58,860 57,872 20,000 0 2006 2007 2008 2009 2010 2011 40 Sosa et al, Surgery 2013. 20

Total thyroidectomy is associated with more complications even in the hands of high volume surgeons. Hauch et al SSO 2014 Total thyroidectomy Bilimoria et al. 2007: 52,173 PTC patients from National Cancer Database (1985 1998) Overall survival benefit with total thyroidectomy for tumors 1 cm American Thyroid Association (ATA) guidelines: Lobectomy: tumors <1 cm Total thyroidectomy: tumors >1 cm Bilimoria KY, et al. Ann Surg 2007 Cooper DS, et al. Thyroid 2009 21

Total thyroidectomy was associated with improved survival for tumors 1 cm. Bilimoria KY, et al. Ann Surg 2007 Evidence for lobectomy Concerns regarding Bilimoria et al; exclusion of possible confounders: Patient comorbidities Multifocality Extrathyroidal extension Adequacy of resection Mendelsohn et al 2010 22,724 patients with PTC No difference in survival between lobectomy and total thyroidectomy *Shah JP. Ann Surg 2008 Mendelsohn AH, et al. Arch Otolaryngol Head Neck Surg 2010 22

To examine the association between extent of surgery and overall survival among patients with papillary thyroid carcinoma 1 4 cm. Study variables National Cancer Data Base >1500 hospitals 85% of all incident thyroid cancer cases in the U.S. Independent variables Demographics: Age, gender, race, income Patient comorbidities: Charlson Deyo scores Pathology: Tumor size, multifocality, extrathyroidal extension, nodal/ distant metastases Extent of surgery: Lobectomy, total thyroidectomy Dependent variable/outcome Overall survival 23

Patient characteristics (N=61775) Lobectomy Total Thyroidectomy P value (N=6849) (N=54926) Female 81% 79% <0.01 Age <0.01 <45 51% 53% 45 64 37% 37% 65 12% 10% Race <0.01 White 88% 88% Black 7% 6% Asian 4% 4% Other 1% 2% Comorbidity NS 0 88% 89% 1 10% 9% 2 2% 1% Tumor/treatment characteristics Lobectomy (N=6849) Total Thyroidectomy (N=54926) P value Tumor size NS 1.0 2.0 cm 60% 59% 2.1 4.0 cm 40% 41% Multifocality 29% 44% <0.001 Extrathyroidal extension 5% 16% <0.001 Nodal metastases 7% 27% <0.001 Distant metastases 0.4% 1.0% <0.001 Positive surgical margin 7% 27% <0.001 RAI administration 33% 65% <0.001 24

Adjusted survival analysis Tumor size Total thyroidectomy vs. lobectomy Adjusted hazard ratio* (95% CI) P value 1.0 4.0 cm 0.95 (0.83 1.04) 0.40 *Adjusted for: age, gender, race, annual income, insurance status, hospital volume, patient comorbidities, tumor multifocality, extrathyroidal extension, lymph node involvement, distant metastases, surgical margins, and radioactive iodine (RAI) treatment. Total thyroidectomy (2009) For thyroid cancer >1 cm, initial surgery should be total thyroidectomy unless there are contraindications. Lobectomy may be sufficient for <1 cm, low risk, unifocal, intrathyroidal PTCs w/o prior head/neck irradiation or nodal metastases. (Recommendation rating: A) ATA Guidelines 2009 25

Total thyroidectomy or lobectomy (2015) For patients with thyroid cancer >1 cm and <4 cm w/o extrathyroidal extension, and cn0, the initial surgery can be either total thyroidectomy (high risk tumors with nodal mets, requiring RAI), or thyroid lobectomy (low and medium risk tumors). ATA Guidelines 2014 26

The operation should be selected in the setting of the larger overall treatment strategy formulated by the care team. Patient preference is critical when evaluating relative risks and benefits. What is the significance of cervical lymph node metastases? and Is prophylactic central lymph node dissection warranted? 27

Zaydfudim et al. 2008: 1. 15,497 PTC patients from SEER 2. Lymph node metastases: 45 yrs: associated with survival (HR 1.46, p<0.01) <45 yrs: NOT associated with survival (HR 1.11, p=0.54) Zaydfudim V, et al. Surgery 2008 Tran Cao et al. 2012: 1. 49,240 pts with DTC in SEER 2. For pts <45 yrs: Lymph node metastases were associated with compromised survival (HR 2.09, p<0.01) 3. Potential limitations: Extent of surgery Radioactive iodine therapy Tran Cao, et al. Surgery 2012 28

Hypotheses 1. Presence of lymph node metastases and number of metastatic lymph nodes are associated with compromised survival for patients <45 yrs with Stage I PTC. 2. It is possible to stratify patients risk of death based on the number of metastatic lymph nodes. 29

Methods Data sets National Cancer Data Base (NCDB) Validation: Surveillance Epidemiology End Results (SEER) Inclusion criteria PTC: ICD O 3 codes: 8050; 8260; 8340; 8341; 8342; 8343 Age 18 yrs with Stage 1 PTC who underwent surgery Study period: 1998 2006 Exclusion criteria Aggressive variants (tall, diffuse sclerosing, insular) Multiple cancer diagnoses Unknown extent of surgery, removal of less than a lobe Study variables Independent variables Demographics: Age, gender, race, income Pathologic: Tumor size, multifocality, extrathyroidal extension, number of metastatic lymph nodes, distant metastases Treatment: Extent of surgery, RAI Dependent variable/outcome Overall survival 30

Study design 1. Unadjusted analysis: Statistical analysis Chi square; Wilcoxon 2. Adjusted survival analysis: Adjusted Kaplan Meier Cox proportional hazards 3. Number of lymph nodes on survival Restrictive Cubic Splines 31

Restrictive Cubic Splines 1. Piecewise polynomial functions 2. Relax the linearity assumption in multivariable regression analyses 3. Examine a relationship between a continuous predictor and an outcome in the setting of a nonlinear relationship Stone C, Koo C: Additive Splines in Statistics, American Statistical Association 1986 Adjusted survival analysis: NCDB Lymph node metastases are associated with compromised survival (p<0.05) 32

Adjusted survival analysis: SEER Lymph node metastases are associated with compromised survival (p<0.05) Metastatic lymph nodes are associated with survival. 33

Adjusted association of the number of metastatic lymph nodes and survival Effect HR (95% CI) p Number of metastatic LNs 6 1.12 (1.01 1.25) 0.03 >6 0.99 (0.92 1.05) 0.75 Implications 1. Cervical lymph node metastases are associated with compromised survival among patients <45 yrs. 2. In the current AJCC staging, young patients with nodal metastases may be under staged. 3. Rigorous preoperative screening for lymph node metastases is warranted for patients <45 yrs. 34

Which thyroid nodule should be biopsied? Which thyroid nodule does not need a biopsy? jugular carotid 35

Microcalcifications, microcalcifications, hypoechoic nodule hyperechoic cystic irregular margins taller than wide nodule irregular margins, extrathyroidal extension nodule with irregular margins, suspicious left lateral lymph node 70-90% 10-20% hypoechoic solid regular margin hyperechoic solid regular margin spongiform hypoechoic solid regular margin isoechoic solid regular margin partially cystic no suspicious features partially cystic with eccentric solid area partially cystic no suspicious features partially cystic with eccentric solid areas < 3% 5-10% Risk of malignancy jugular carotid < 1% cyst FNA Recommendations Recommendations for diagnostic FNA based on sonographic features: A) Nodules with sonographic features of high suspicion and >1cm (Strong recommendation, Moderate quality evidence) B) Nodules with sonographic features of intermediate suspicion and >1 cm (Strong recommendation, Low quality evidence) C) Nodules with sonographic features of low suspicion and >1.5cm (Weak recommendation, Low quality evidence) D) Nodules with sonographic features of very low suspicion (e.g. spongiform) and > 2cm (Strong recommendation, Moderate quality evidence) E) FNA is not required for thyroid nodules that do not meet the above criteria, including all nodules < 1 cm (Strong recommendation, Moderate quality evidence) F) FNA is not required for purely cystic nodules (Weak recommendation, Low quality evidence) Ito Y, Thyroid 13:381 7, 2003 Ito Y, World J Surg 34:28 35, 2010 36

Use of RAI in the United States Haymart MR, J Clin Endo Metab, 2013 System for Estimating Risk of Recurrence ATA Guidelines 2009 Low Risk Classic PTC No local or distant mets Complete resection No ETE No vascular invasion If given, no RAI uptake outside TB Cooper et al, Thyroid 2009 Intermediate Risk Microscopic ETE Cervical LN mets Aggressive Histology Vascular invasion High Risk Macroscopic gross ETE Incomplete tumor resection Distant Mets Tg elevation 37

Risk of Structural Disease Recurrence ATA risk category Risk stratification within categories High Risk Intermediate Risk Low Risk FTC, extensive vascular invasion (30 55%) pt4a gross ETE (23 40%) pn1, any LN > 3 cm (27%) Clinical N1 ( 22%) BRAF mutated, not intrathyroidal (11 40%) PTC, vascular invasion (16 30%) pn1, > 5 LN involved ( 19%) BRAF mutated, intrathyroidal, < 4 cm ( 8%) pt3 minor ETE (3 8%) pn1, all LN < 0.2 cm ( 5%) pn1, < 5 LN involved ( 4%) Intrathyroidal 2 4 cm PTC (5 6%) Multifocal PMC (4 6%) Minimally invasive FTC (0 7%) BRAF wild type, intrathyroidal, < 4 cm ( 1%) BRAF mutated, intrathyroidal unifocal PMC (<1%) Intrathyroidal, encapsulated, FV PTC ( 1%) Unifocal PMC (1 2%) Impact of RRA on OS and DFS in 1,298 Low Risk (pt1 or 2, N0 or Nx) DTC Patients, 1975 2005 OS RAI (911) 95% CI 93 96 No RAI (387) 96% CI 93 98 10 year DFS 89% CI 86 91 93% CI 90 95 Recurrences 19 Deaths 105 No sig differences (based on propensity score) Schvartz C, J Clin Endo Metab 97:1526, 2012 38

Radioiodine (I 131) Adverse effects Sialadenitis/xerostomia Dental caries Epiphoria Gonadal dysfunction Marrow suppression Secondary malignancy To Reduce Adverse Effects 1) Don t use radioiodine 2) Use rhtsh for preparation 3) Use lower administered doses of radioiodine Schlumberger M, NEJM, 2012 Mallick U, NEJM, 2012 Radioiodine Remnant Ablation/Adjuvant Therapy Preview of the 2015 ATA guidelines ATA recurrence risk TNM Staging ATA Low Risk T1a/N0,NX/M0,MX ATA Low Risk T1b, T2/N0,NX/M0,MX ATA Low to intermediate risk T3/N0,NX/M0,MX ATA Low to intermediate risk T1 3/N1a/M0,MX ATA Low to intermediate risk AnyT1 3/N1b/M0,MX ATA High risk T4/any N/any M ATA High risk M1 (any T, any N) Description T <1cm (unifocal or multifocal) T 1 4 cm T > 4cm or microscopic invasion Central compartment LN metastases Lateral compartment LN metastases Gross extrathyroidal extension Distant metastases No Post surgical RAI indicated? Not routine Consider Consider (size and number) Consider (size, number,age) Yes Yes 39

Unadjusted survival difference for all intermediate PTC risk patients (n=21,870) by RAI use 40

Multivariate Cox Proportional Hazards model of overall survival (n=17,062) How do we prepare patients for RAI? Withdrawal or rhtsh (Thyrogen) ATA low and intermediate risk DTC: rhtsh stimulation is a reasonable alternative to withdrawal and is associated with superior short term quality of life. (Strong recommendation, moderate quality evidence) ATA high risk DTC (eg. T4 and/or distant metastatic disease) (No recommendation, Insufficient evidence) 41

New ATA Guidelines are anticipated this fall 42