Focus on endocrine neoplasiaJuly 9, 2010

Rome

Furio PaciniDipartimento di Medicina Interna e

Scienze Endocrino-MetabolicheUniversità di Siena

Differentiated thyroid carcinoma:Treatment and follow-up

Thyroid cancer incidence and mortality in USA (1973-2002) and

Italy (1988-2002)

Italian Network of Cancer Registries, 2006

ItalyUSA

APC:USA 3.8%

Italy 4.0%

Thyroid cancer incidence in USA (1973-2002) and Italy (1988-2002)

Italy

USA

Italian Network of Cancer Registries, 2006

Trend incidence of papillary thyroid cancer by size in USA (1988-2002)

CRITICAL STEPS IN THE CRITICAL STEPS IN THE MANAGEMENT OF DTCMANAGEMENT OF DTC

• Surgery • 131I therapy • Short term follow up• Long term follow up

ATA and ETADifferentiated thyroid cancer guidelines: Surgery for cytology diagnostic of malignancy

• Preoperative ultrasound for the contralateral lobe and cervical lymph nodes (central and bilateral) is recommended for all patients undergoing thyroidectomy for suspicious cytology

• Near total or total thyroidectomy should be the initial procedure in any malignancy discovered before surgery.

• Thyroid lobectomy alone may be sufficient treatment for small, isolated, intrathyroidal papillary carcinomas in the absence of cervical nodal metastases, that have been diagnosed at final histology when the surgical procedure had been performed for other indications.

POST-SURGICAL RADIOIODINE POST-SURGICAL RADIOIODINE ABLATIONABLATION

• Rationale:– Ablation: eradication of normal thyroid

remnants– Treatment: irradiation of persistent disease– Total body scan a few days later– Diagnostic scan useless– The combination of serum Tg, post-therapy

WBS and neck ultrasound is a strong predictor of the future outcome.

Metanalysis of radioiodine effectiveness(Sawka et al, J Clin Endocrinol Metab, 2004)Series N Follow-up

(yr)

131I

Effectiveness cancer mortality

131I

Effectiveness cancer recurrence

Ohio State 1510 16.6 P<0.0001 P<0.016

UCSF 187 10.6 NS P<0.0001

Hong Kong 587 9.2 NS

Toronto 382 10.8 NS

Illinois Reg 2282 6.5 NS

Gundersen 177 7.2 NS

Anderson 1599 11 P<0.001

Gustave R. 273 7.3 NS

Mexico 229 5 NS

Pisa 964 12 NS P<0.001

Does post-surgical 131-I decrease DTC recurrence Does post-surgical 131-I decrease DTC recurrence and mortality rates? European Consensus and mortality rates? European Consensus

(Pacini et al. EJE 153:1-10, 2005)(Pacini et al. EJE 153:1-10, 2005)

• Very low-risk patients: Benefitunifocal T1 <1 cm N0 M0 no evidence

• Low-risk patients:T1 >1 cm N0 M0 may decrease

recurrenceT2 N0 M0 but evidence not

definitive

• High-risk patients:any T3 and T4 evidence of decreased any T N1 recurrence and mortalityM1 rate

0

20

40

60

80

100

Ablated Not Ablated

Hypo

rhTSH

0

20

40

60

80

100

Ablated Not Ablated

50 mCi (n=36)

100 mCi (n=36)

100 mCi; hypo vs rhTSH rhTSH; 50 vs 100 mCi

On l-T4 therapy: Measurements of

•Serum Tg and anti-Tg antibodies

•Thyroid hormones and TSH: to assess the appropriate dose of l-T4

FOLLOW-UP: 3 months after ablationFOLLOW-UP: 3 months after ablation

FOLLOW-UP: 8-12 MONTHS AFTER FOLLOW-UP: 8-12 MONTHS AFTER ABLATIONABLATION

• Clinical examination: poorly sensitive

• Neck ultrasonography • Serum Tg determination following

TSH stimulation • (131I-total body scan)

Follow-up of differentiated thyroid Follow-up of differentiated thyroid carcinoma after surgery and carcinoma after surgery and

radioiodine ablation radioiodine ablation

Options

1. After thyroid hormone withdrawal or after rhTSH ??

2. based on stimulated serum Tg measurement alone or in combination with 131-I WBS ??

SERUM Tg DETERMINATIONSERUM Tg DETERMINATION

• Serum Tg is a marker of disease (Van

Herle, 1975), not a disease• Measurement:

– Immunometric assay (IMA)– Standardization: CRM-457– Functional sensitivity < 1ng/mL.

Supersensitive methods (<0.1ng/mL): improved sensitivity but decreased specificity.

– Search for interferences: • Measurement of anti-Tg antibodies.

DETECTABLE Tg LEVEL AFTER DETECTABLE Tg LEVEL AFTER THYROID ABLATION. THYROID ABLATION.

Eustatia-Rutten, Clin Endocrinol, 61: 61, 2004Eustatia-Rutten, Clin Endocrinol, 61: 61, 2004

010

2030

4050

6070

8090

100

Tg/T4 Tg/WD Tg/rhTSH

Sens (%)Spec (%)

The sensitivity of serum Tg determination is improved by 15-20% following TSH stimulation.

SIGNIFICANCE OF DETECTABLE Tg/TSH AT 1 YEARSIGNIFICANCE OF DETECTABLE Tg/TSH AT 1 YEAR

Haugen2002

Mazzaferri2002

Robbins 2002

Torlontano 2003

Pacini2003

Baudin 2003

n 83 107 109 92 294 256

Tg/TSH>1 ng/ml(%)

17 19 17 15 15 14

Disease detected

6 8.4 8.2 3.3 7.8 3.5

Neck / Distant

4.8/1.2 3.7/4.7 4.6/3.7 3.3/0 6.1/1.7 1.9/1.6

NED 9.6 10.3 9.2 12 7.1 10.9

J Clin Endocrinol Metab. 2002, 87:1499-501

Series Patients(n)

Stimulus False neg. Tg

(WBS+/Tg-)

False neg. WBS

(WBS-/Tg+)

Robbins 366 rhTSH 54/175 (31%)

75/191 (39%)

Pacini 315 hypo 0/315 (0%) Not included

Cailleux 256 hypo 0/210 (0%) 46/46 (100%)

Mazzaferri 107 rhTSH 0/68 (0%) 39/39 (100%)

Torlontano 99 rhTSH 0/78 (0%) 21/21 (100%)

Pacini 72 rhTSH 0/41 (0%) 20/31 (64.5%)

All 1215 54/887 (6.1%)

201/328 (61.2%)

Metanalysis of the rate of false negative stimulated Tg and WBS

STUDY INFORMATION:

Reference

Pacini

Frasoldati

Torlontano

N1/Pts

27/340

51/494

38/456

METHOD:

Tg/TSH

85% (rhTSH)

57% (WD)

82% (WD)

131I TBS

21%

45%

34%

Neck US

70%

94%

100%

Neck US+Tg/TSH

96%

99.5%

100%

DETECTION OF NECK RECURRENCESDETECTION OF NECK RECURRENCES

Combination of neck US and Tg/TSH determination.

USE OF rhTSH.USE OF rhTSH.

• The benefits in terms of QOL of rhTSH over withdrawal are obvious.

• Is the sensitivity of serum Tg similar following rhTSH and withdrawal?

0102030405060708090

100

Perc

en

t

rhTSH Testing: Metastatic Cancer Detection Rate

100100

77

100 97

8088

6757

2 105Serum Thyroglobulin (ng/mL)

rhTSH whole-body scan and Tg rhTSH Tg

Tg on thyroid hormone therapy

Haugen BR, Pacini F, Reiners C, et al: Haugen BR, Pacini F, Reiners C, et al: J Clin Endocrinol MetabJ Clin Endocrinol Metab. . 1999;84:38771999;84:3877

1

10

100

Peak rhTSH Tg Hypo Tg

Tg ng/ml

p= 0.001

Correlation between peak rhTSH-Tg and hypo-Tg

(31 patients, Department of Endocrinology, Pisa)

CONCLUSION: ELEVATED SERUM Tg CONCLUSION: ELEVATED SERUM Tg LEVELS.LEVELS.

• Some months after initial treatment, detectable serum Tg (<5-10ng/mL) may be produced by:– irradiated cells that will disappear in 2/3 of cases (Baudin, Pacini,

Torlontano, Toubeau), and serum Tg will decrease– neoplastic cells that will progress, and serum Tg will increase.

• A control TSH-stimulated Tg obtained some months (or years) later will differentiate these two groups of patients.

• The most relevant parameter is the trend of Tg level, rather than its level.

LOW RISK PATIENTS: UNDETECTABLE LOW RISK PATIENTS: UNDETECTABLE STIMULATED SERUM Tg AT 8-12 MONTHSSTIMULATED SERUM Tg AT 8-12 MONTHS

• False negative results are rare (excellent NPV)

• LT4 dose can be decreased to achieve a low-normal serum TSH level (0.5-2.5 µU/mL)

• Patients are followed up on a yearly basis on replacement L-T4 treatment.

• In the absence of abnormalities, no other testing is warranted.

ETA ATA

Persistent disease TSH <0.1 mU/L

Evidence of remissionlow risk replacement

high risk suppressive duration 3-5 years

ETA and ATA guidelines: l-T4 therapy suppressive vs replacement

CONCLUSIONSCONCLUSIONS

• Follow up based on neck US and Tg/TSH is all we need for nearly 80% of the patients (the low risk)

• Other diagnostic and treatment modalities in selected cases at risk of recurrence or metastases.