Low-Dose Vs High-Dose
Differentiated Thyroid Cancer Evolving Treatment and Management Strategies
Jennifer Sipos, MD Associate Professor of Medicine Division of Endocrinology CANM Annual Meeting 13 April 2014 Disclosures
• Genzyme Advisory Board • Research Funding Veracyte Outline
• Epidemiology • Recent developments in the management of thyroid nodules • Surgical approach to DTC • RAI treatment decisions • Follow up protocols • Refractory, progressive disease Epidemiology – thyroid nodules
Autopsy/ Ultrasound
Palpation
Mazzaferri 1993 NEJM 328:553-9 Epidemiology—thyroid cancer
Aschebrook-Kilfoy 2013 Cancer Epidemiol Biomark Prev 22: 1252-9 Prevalence of microcarcinoma of the thyroid
24 autopsy series with 7,156 cases Percent with with Percent cancer thyroid
Study Number
Adapted from: Pazaitou-Panayiotou, et al. 2007 Thyroid 17 (11): 1085-92 Changing mode of diagnosis in PTMC
1945-1979 1980-2004 N=378 N=552 • FNA for thyroid nodules has more than doubled 12% 42% 32% from19% 2006-2011 • Thyroid FNA grew as a percentage of all FNA 69% 13% from 49% to 65% 13% Sosa et al 2013 Surgery epub
Thyroid surgery Thyroid surgery Node biopsy Node biopsy Other Other FNA
Hay et al 2008 Surgery 144: 980-7
Incidence rates of PTC by tumor size Rate per 100,000 population per 100,000 Rate
Year Diagnosed Cramer et al 2010 Surgery 148: 1147-52 Papillary microcarcinoma Likelihood of disease progression with observation
100 Multivariate analysis:
80 .Age <40y RR 4.348 (2.3-8.2) p<0.0001
60 .T≥9mm RR 4.717 (1.9-11.4) p=0.0005 40
disease 20 3.9% 6.8% 0
0 5 10 15 20 Cumulative % progression to clinical Follow-up times (years) Patients 1,235 434 136 27 at risk
Ito et al 2014 Thyroid 24: 27-34 Thyroid Nodules Thyroid Imaging Reporting and Data System--TIRADS
PPV: 0.25% PPV: 0%
Russ et al 2013 Eur J Endocrinol 168: 649-55 Thyroid imaging reporting and data system--TI-RADS
PPV: 6%
PPV: 100% PPV: 69%
Russ et al 2013 Eur J Endocrinol 168: 649-55 Indications for FNA
Nodule Features Size Threshold for FNA Solid Nodules With suspicious US features ≥1.0cm Without suspicious US features ≥1.5cm Mixed cystic-solid nodule With suspicious US features ≥1.5-2.0cm Without suspicious US features ≥2.0 cm Spongiform nodule ≥2.0cm Simple cyst Not indicated Suspicious cervical LN FNA node ± FNA associated thyroid nodule
In patients with high-risk clinical features (radiation in childhood, 1º relative with thyroid cancer or MEN2, PET positivity, personal hx thyroid Ca, personal hx of thyroid cancer-associated conditions), evaluation of nodules smaller than listed may be appropriate. NCCN 2013 Clinical Practice Guidelines in Oncology, Thyroid Carcinoma. v.2.2013: 1-91 Postoperative malignancy rates for each cytology subtype
NCI Frequency % % Classification of Malignant Malignant diagnosis (ideally) (actually) Benign 32-76% <1% 2-18% Follicular lesion of undetermined 3-15% 5-10% 0-48% significance Atypia of undetermined significance Follicular neoplasm 5-20% 20-30% 14-49% Hurthle cell neoplasm
Suspicious for malignancy 1-8% 50-75% 53-87% Malignant 4-18% 98-100% 96-100% Non-diagnostic 4-13% 0-50%
Baloch ZW., et al. Diag Cytopath 2008; 36:425-437 Yassa L., et al. Cancer Cytopathology 2007; 111(6):508-16 Yang J., et al. Cancer 2007; 111(5):306-15 Wang et al 2011 Thyroid 21(3): 243-51 Baier et al. AJR 2009; 193: 1175-9 Oppenheimer et al. Cardiovasc Intervent Rad 2010;33:800-5 Interobserver concordance of thyroid FNA Local vs Expert Cytopathologists
Malignant (n=51) 94
SFM (n=38) 37
FN/SFN (n=56) 66
AUS/FLUS (n=83) 35
Indeterminate (n=177) 62
Benign (n=95) 82
Nondiagnostic (n=13) 69
0 20 40 60 80 100 Expert concordance with local cytopathologists (%)
Cibas et al 2013 Ann Int Med 159: 325-332 Reproducibility of FNA results
Intraobserver Variability
100 83 78 80 60 60
40
20 Proportion of identical identical of Proportion
cytopathology (%) diagnoses cytopathology 0 Cytologist 1 Cytologist 2 Cytologist 3 (n=96) (n=82) (n=75)
Cibas et al 2013 Ann Int Med 159: 325-332 Indeterminate FNA Mutations tested: BRAF, NRAS, KRAS, HRAS RET/PTC1, RET/PTC3 PAX8/PPARƔ
Histology Malignant Histology Benign (n=93) (n=368) Mutation Positive 3 RAS FTC 8 (RAS+ Follicular (n=63) 42 RAS-PTC adenomas) 7 BRAF-PTC 3 PAX8/PPARγ –PTC Mutation Negative 38 (32 PTC, 6 FTC) 360 (n=395)
Sensitivity 59% Specificity 97.8% PPV 87.3% NPV 90.4% Rate of malignancy=25.2%
Nikiforov et al 2011 JCEM 96: 3390-97 Targeted next-generation sequencing panel
Genes included in ThyroSeq panel Chromosomes Genes 70% chr 1 NRAS chr 3 CTNNB1 PIK3CA 83% chr 7 BRAF chr 10 RET PTEN chr 11 HRAS 78% chr 12 KRAS chr 14 TSHR 39% chr 17 TP53 chr 20 GNAS
Nikiforova et al 2013 JCEM 98: E1852-60 ThyroSeq Testing of Follicular Neoplasms
• Prospective analysis of 62 consecutive nodules with follicular neoplasm by cytology
Histologically Histologically benign malignant ThyroSeq malignant 1 BRAF (PTC) 1 NRAS (FA) 6 KRAS (PTC) 1 PTEN (FA) 4 NRAS (PTC) ThyroSeq benign 2 FVPTC 47 hyperplastic nodules
NPV 95.7% Prevalence of malignancy 21.3%
Nikiforova et al 2013 American Thyroid Association annual meeting. Oral Abstract 13. San Juan, Puerto Rico Gene Expression Classifier (GEC) to Identify Benign Nodules among those with Indeterminate Cytology
Identify genes and measure their Multidimensional algorithm expression using microarray technology
142 genes 22,000 genes 3000 genes
1. Chudova D, et al. J Clin Endocrinol Metab. 2010;95:5296-5304. 2. Haugen BR, et al. 14th International Thyroid Congress, Paris, FR. Presented September 15, 2010. Afirma GEC Identifies Cytologically Indeterminate Thyroid Nodules with a Low Risk of Malignancy
Pretest probability of malignancy Posttest probability of malignancy
70 62
NPV) NPV) 60 – 50 40 30 24 25 15 20 6 5 6 10
Risk of Malignancy (1 Malignancy of Risk 0 Benign (47) AUS/FLUS FN/HCN (81) SFM (55) (129)
Cytopathology Diagnosis (N)
Alexander EK, et al. N Engl J Med 2012. Minimizing unnecessary surgery for thyroid nodules
>1cm thyroid nodule Radionuclide scan Low TSH
US-guided FNA Cold nodule Hot nodule
Ablate, Benign AUS/FLUS Follicular SFM Malignant resect, or neoplasm medically treat Monitor Genetic Testing Surgery
Benign Suspicious
Monitor/ Surgery hemithyroidectomy Modified from: Jameson JL. N Engl J Med 2012. NCCN 2013 Clinical Practice Guidelines in Oncology, Thyroid Carcinoma. v.2.2013: 1-91 Surgical approach Surgical approach
Indications for total Indications for total thyroidectomy, if any thyroidectomy or present lobectomy, if all present
• Age <15 or >45 • Age 15-45 y • Radiation history • No prior radiation • Known distant mets • No distant metastases • Bilateral nodularity • No cervical LN mets • Extrathyroidal extension • No ETE • Tumor >4cm • Tumor <4cm • Cervical LN mets • No aggressive variant • Aggressive variant
NCCN 2013 Clinical Practice Guidelines in Oncology, Thyroid Carcinoma. v.2.2013: 1-91 Completion thyroidectomy
• Tumor >4cm • Positive margins • Gross extrathyroidal extension • Macroscopic multifocal disease • Confirmed nodal mets • Vascular invasion
NCCN 2013 Clinical Practice Guidelines in Oncology, Thyroid Carcinoma. v.2.2013: 1-91 Postoperative RAI “Low Risk” Patients Tumor 1-4cm No “extensive” extrathyroidal extension No LN on preop US N=237
Postop Tg <1 OR <10 with negative US NPV 100% Postoperative Tg 3 months after surgery by THW
<1ng/mL >10ng/mL N=132 1-10 ng/mL N=20 N=85 4 RxWBS + Neg US 4 LNs by US Neg RxWBS
2 RxWBS + 2 RxWBS - 1 US+ 3 US- Rosario 2011 Thyroid 21: 49-53 Total Thyroidectomy: Low risk PTC, central neck nodes only, no extrathyroidal extension
TSH Stimulated Thyroglobulin Measurement
<1mcg/L 1-5mcg/L >5mcg/L
No Routine RAI Possible RAI Routine RAI
1 RAI 58 No RAI 29 No RAI 6 RAI 9 RAI 1 No RAI
59 NED 1 RAI 14 NED
Vaisman et al 2010 Head & Neck 32: 689-98 Gomez-Hernandez et al 2012 Thyroid 22: 760-1 Evolution of basal Tg after thyroidectomy without RAI
2.0 1.8
1.6 40 Tg
1.4 /mL)
1.2 30 ng ( 1.0
Tg 0.8 20
0.6 Mean Values Mean
0.4 10 Serum Serum
0.2 Percent detectable detectable Percent 0 0 1 2 3 4 5 6 7 No. of pts 78 78 72 61 38 21 17 Years
Durante 2012 JCEM 97: 2748-53 Comparison of side effects with administered activity of 131I
Any symptoms Dry mouth Taste alteration
Salivary gland swelling Saiivary gland pain Excess tearing
50 40 30 20
Percentage 10 0
Grewal et al 2009 J Nucl Med 50: 1605-10 ESTIMABL • Randomized, phase 3 trial of RAI with a 2 x 2 design that compared: − THW versus Thyrogen − Two 131I doses: 1.1 GBq and 3.7 GBq − Included T1-2, N0, N1, Nx, M0 Low rhTSH Low THW High rhTSH High THW
100 97 90 95 95 96 94 96 80 94 70 96 60 50 40 30
Percent patients of Percent 20 10 0 Normal US rhTSH Tg <1ng/mL n=684 Schlumberger et al 2012 NEJM 366 Administration of RAI Papillary Thyroid Carcinoma
RECOMMENDED Selectively NOT recommended • Gross ETE recommended (if all present) • Primary tumor >4cm • Primary tumor 1-4cm • Classic PTC • Known or suspected • High risk histology • Tumor <1cm distant mets • Vascular invasion • Intrathyroidal • Cervical LN mets • No vascular invasion • Minor ETE • Unifocal or multifocal • Multifocality • Appropriate postoperative • Inappropriate Tg postoperative Tg • Clinical N0 • Clinical M0
NCCN 2013 Clinical Practice Guidelines in Oncology, Thyroid Carcinoma. v.2.2013: 1-91 Administration of RAI Follicular/Hurthle Cell Carcinoma
RECOMMENDED Selectively NOT recommended (if any present) recommended (if ALL present) • Gross ETE (if any present) • Tumor <2cm • Primary tumor >4cm • Primary tumor 2-4cm • Intrathyroidal • Known or suspected • High risk histology • No vascular invasion distant mets • Minor vascular invasion • Unifocal or multifocal • Extensive vascular • Cervical LN mets • Appropriate postoperative invasion • Minor ETE Tg • Multifocality • Clinical N0 • Inappropriate • Clinical M0 postoperative Tg
NCCN 2013 Clinical Practice Guidelines in Oncology, Thyroid Carcinoma. v.2.2013: 1-91 Patients being considered for RAI
2-12 wk post- thyroidectomy: no gross residual disease in neck
Total body RAI imaging with TSH stimulation (rhTSH or THW)
Tg<1ng/mL with Suspected or Suspected or negative TgAb and proven thyroid proven RAI RAI imaging bed uptake responsive negative residual tumor
Remnant ablation RAI treatment (100- 30-100mCi No RAI 200mCi) Consider dosimetry for distant mets
NCCN 2013 Clinical Practice Guidelines in Oncology, Thyroid Carcinoma. v.2.2013: 1-91 Follow-up strategies Follow up
• Serum Tg and Tg antibodies every 6 months • Periodic neck US • Stimulated Tg (if given RAI) • DxWBS in high risk pts with RAI avid mets or abnormal Tg/TgAb Cardiovascular mortality in DTC
Hesselink et al 2014 J Clin Oncol 31: 4046-53 Levels of TSH suppression
Serum TSH mU/L 0.1 0.5 1.0 2.0 No RAI or Low risk, biochemical but Disease-free several years no structural disease Residual disease or Disease-free, low risk of high risk for recurrence recurrence
NCCN 2013 Clinical Practice Guidelines in Oncology, Thyroid Carcinoma. v.2.2013: 1-91 Serum Tg levels often decline for years after surgery and RAI
Padovani et al 2012 Thyroid 22: 778-783 Trend in Tg Antibody is predictive of recurrence risk
100 Median 90 disappearance 75 4 years 80
60 40
35 concentration 40 25
TgAb 20
0 TgAb Trend Category>50% fall fromCategory initial CategoryStable (<50%Category >50% rise 1 value 2 change)3 4 Disease detected <3% disease ~20% disease ~40% disease during follow up
Modified from: Spencer et al 2013 Best Pract & Res Clin Endo & Met 27: 701-12 Pacini et al 1988 Acta Endo 119: 373-80 Rubello et al 1990 J Endo Invest 13: 737-42 Chung et al 2002 Clin Endo 57: 215-21 Gorges et al 2005 Eur J Endo 153: 49-55 Seo et al 2010 Clin Endo 72: 558-63 Kim et al 2008 JCEM 93: 4683-9 Liquid Chromatography- Tandem Mass Spectrometry
Tryptase • Measures Tg independent of TgAb • Prospective studies ongoing • Limit of detection 0.5- 1.0ng/mL Follow up Ultrasonography Proportion of patients showing novel LN mets
Ito et al 2014 Thyroid 24: 27-34 Observation of small nodal disease
• 166 patients with 1 or more suspicious US feature – 70% had 2 or more suspicious US features – 33 (20%) growth of ≥3mm – 15 (9%) growth of ≥5mm – 22 (13%) had surgery – 23 (14%) nodes disappeared – 1.5mm/yr median growth – 0 local complications – 0 disease-related mortality
Robenshtok et al 2012 JCEM 97: 2706-13 Stimulation testing Likelihood of recurrent disease based on rhTSH stimulated Tg
80 80 70 60 50 40 30 11 20 3 10 Percentage patients of Percentage 0 Group 1 Tg≤0.5 Group 2 Tg 0.6- Group 3 Tg > ng/mL 2.0 ng/mL 2.0 ng/mL n=68 n=19 n=20
Kloos 2010 JCEM 95: 5241-48 Value of repeat rhTSH stimulated Tg values in initially negative patients
TP FP TN FN NPV PPV Sensitivity Specificity (%) (%) (%) (%) Tg1 0 0 272 6 97.8 NA NA 100 Tg2 5 4 268 1 99.6 55.5 83.3 98.5 Tg3 2 1 75 0 100 66.6 100 98.7 Tg4 1 0 50 0 100 100 100 100 Tg5 1 0 16 0 100 100 100 100 Tg6 0 0 6 0 100 NA NA 100 Tg7 0 0 5 0 100 NA NA 100
Klubo-Gwiezdzinska et al 2011 Clin Endocrin 74: 111-7 Criteria for absence of persistent tumor
After total or near-total thyroidectomy and remnant ablation (RAI), disease-free status comprises ALL of the following:
1. No clinical evidence of tumor. 2. Negative US 3. Undetectable serum Tg levels during TSH suppression and <2ng/mL after stimulation in the absence of interfering antibodies. 4. If RAI imaging performed, this shows no residual disease
NCCN 2013 Clinical Practice Guidelines in Oncology, Thyroid Carcinoma. v.2.2013: 1-91 Refractory Disease Selumetanib: RAI redifferentiating agent
Protocol: 124I-PET N=20 patients Selumetanib 75mg BID x 4 w 8 received RAI 124I-PET RAI-stop selumetanib Re-evaluate at 2m, 6m
Ho et al 2013 NEJM 368: 623-32 Sorafenib Phase III DECISION Trial • N=417 patients • Median PFS 10.8months sorafenib vs 5.8 months placebo • Stable disease >6m: 42% in treatment, 33% in placebo • Median overall survival has not been reached • 70% placebo pts started open-label sorafenib
Brose et al 2013 JCO supplement-ASCO abstract Indications for sorafenib
• Progressive disease not amenable to surgical removal, radiation, or radioiodine therapy • ≥ 20% change in target lesion (>1cm) in 6-12 month • Not eligible for clinical trial or clinical trial not available • RAI refractory disease • Disease progression within 6-12 months after treatment • Documented disease with no RAI uptake on RxWBS • >600mCi of 131I with progressive disease Future Directions
• Redifferentiating agents + RAI • Targeted agent for the offending mutation (eg BRAF inhibitor in BRAF+ pts) • Combination therapy with two (or more) TKIs • TKI + RAI • TKI + traditional chemotherapy Questions?