Changing paradigms in the management of

Differentiated Thyroid Cancer

Prof. Hisham Mehanna

Chair of Head and Neck Surgery

Director, Institute of Head & Neck Studies & Education

University of Birmingham

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Changing paradigms

• Incidence rates • Diagnosis • Personalisation of therapy

– Extent of surgery – Radioiodine ablation – Radioiodine dose

• Dynamic risk stratification and follow-up – Surveillance strategies – TSH suppression

• Mortality

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Changing paradigms

• Incidence rates • Diagnosis • Personalisation of therapy

– Extent of surgery – Radioiodine ablation – Radioiodine dose

• Dynamic risk stratification and follow-up – Surveillance strategies – TSH suppression

• Mortality

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Incidence of thyroid cancer UK

Incidence rates doubled in 15 years

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Global Incidence rates

IARC

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Increase in incidence due to increased detection of small sub-clinical disease

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Davies JAMA 2006

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Davies JAMA 2006

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Increase in incidence due to increased detection of small sub-clinical disease

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Personalisation of therapy

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Traditional mainstay of treatment

Total/completion thyroidectomy +/-

Central nodal dissection +

Radioiodine ablation +

TSH suppression

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Case for Total Thyroidectomy

• Retrospective data of large cohorts over long periods (up to 30 year follow-up)

• Mayo Clinic -14,200 patient year experience

Cancer mortality at 25 years HemiT Total T Very low-risk AGES<4 1% 2% Rest AGES>4 65% 35% Hay, Surgery, 1987

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Extent of surgery for low risk DTC

• 20 year cost effectiveness of total vs hemi-thyroidectomy. • Pooled published data and decision analysis (Markov). • Cause-specific mortality same. • BUT recurrence free survival (RFS) higher for total thyroidectomy. • Cost effectiveness:

Hemi Total $ $ 20 year OS 15,155 14,317 20 year RFS 19,916 15,440

Shrime et al, Arch Otol HNS, 2007

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Case for Hemi-thyroidectomy

Ito Hospital, 1088 pts, Hemi-T, no RIA • Median 17.6 yr follow-up

• Multivariate analysis - factors predictive of DSS

– Age>45 – Tumour size>4cm – LN metastasis – Extrathyroidal extension

• None of patients without any of these features died

Matsuzi, World J Surg, 2014

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BTA Guidelines 2014 lobectomy for low risk PTC

• This is relevant for low-risk PTC and FTC with no aggressive features only

• Low-risk DTC: with ALL these features

– Primary less than 4cm in diameter, unifocal disease – <45 years old – No extra-thyroidal extension – No poor histological features – tall cell, sclerosing, widely-invasive (FTC),

angioinvasion (FTC) – No lymph node mets or distant mets – No familial disease

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Role of radioiodine in management of DTC

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Case for Radio-iodine

• Retrospective data of large cohorts over long periods (up to 30 year follow-up)

• Recurrence rate after 131I one third after thyroid hormone

therapy alone (P < 0.001)

• Likelihood of cancer death decreased significantly by – surgery more extensive than lobectomy, and – 131I plus thyroid hormone therapy Mazzaferri, ey al Am J Med, 1995

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Radioiodine in high risk DTC

• In high risk PTC: recommended Tumour >4 cm even without high risk factors evidence for efficacy mainly in >45 year olds , but BTA and ATA also recommends <45 year old Gross extrathyroidal extension regardless of size Incomplete resection Known distant metastasis

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Radioiodine in Papillary Thyroid MicroCarcinoma (PTMC)

RIA did not reduce recurrence in PTMC patients with: multi-focal disease (8% vs 7%) or lymph node metastasis (11% vs 10%)

Hay, Surgery, 2008

Ross, Thyroid, 2009 Sakorafas, Cancer Treat Reviews, 2005

Tumours <1cm and no high risk features: No RIA

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Radioiodine in intermediate risk DTC

• In intermediate risk PTC: conflicting evidence

• Selected recommendation only for 1-4 cm tumour confined to

thyroid with a combination of high risk features:

– multiple lymph node metastasis (5), large size of involved nodes (6mm), high ratio of positive to negative nodes (0.7), extracapsular nodal extension

– aggressive histology (tall cell, columnar, insular, solid, poorly differentiated, intrathyroid intravascular invasion)

– widely invasive follicular thyroid cancer – multifocal disease >1 cm size – minimal extra-thyroidal spread

British Thyroid Association, 2014

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ION TRIAL

CI: Prof Mallick

• Multicentre randomised phase II/III trial

• Phase III: to determine whether the 5-year disease-free survival rate among patients who do not have routine Radioactive iodine (RAI) ablation is non-inferior to those who do.

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Eligibility: T1-T3N0/N1, no minimal extracapsular spread, no distant mets Low dose 1.1 GBq versus high dose 3.7GBq RIA Same efficacy: Low dose 85% vs High 88.9% But lower adverse events: low 21% vs 33% Hospitalisation for min 3 days: low 13% vs high 36.3%

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TSH suppression and follow-up

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TSH suppression and follow-up

Traditionally, everyone got full TSH suppression and thyroglobulin life-long follow-up

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Dynamic Risk Stratification

• Determining follow-up intensity and TSH suppression based on risk of recurrence

• Follow-up in those treated with TT and RIA by: – Stimulated Thyroglobulin, and – US scan

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Thyroglobulin measurement

• Stimulated thyroglobulin after rhTSH – Either by rhTSH or withdrawal (TSH>30) – sTg <0.5microg/l 98-99.5% probability disease free – sTg >2 microg/l highly accurate for persistent disease Baudin, JCEM, 2003

• Unstimulated thyroglobulin

– uTg <0.15 98.6% negative predictive value for recurrence

– Cost effective alternative to sTg Malandrino, JCEM, 2011

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Dynamic Risk Stratification

Excellent Response Indeterminate Response Incomplete Response

All the following: -Suppressed and stimulated Tg<1mcg/L -Neck USS without evidence of disease -Cross-sectional and/or nuclear medicine imaging negative (if performed)

Any of the following: -Suppressed Tg<1mcg/ml and stimulated Tg ≥1 and <10mcg/L -Neck USS with nonspecific changes or stable sub-cm lymph nodes -Cross-sectional and/or nuclear medicine imaging with nonspecific changes, not completely normal

Any of the following: -Suppressed Tg≥1mcg/L or stimulated Tg≥10mcg/L -Rising Tg values Persistent or newly identified disease on US -Persistent or newly identified disease on cross-sectional and/or nuclear medicine imaging

Low risk Intermediate Risk High Risk No TSH supp (0.5-2) Annual Tg/Tg Ab US 2-3 yrs

Mild TSH supp 0.1-0.5 More frequent

TSH suppression <0.1 Frequent as appropriate

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Dynamic Risk Stratification

• Good predictor of recurrence – Excellent response: sTg<1 ng/ml, US clear – Incomplete response, sTg>10ng/ml, rising Tg or US shows

structural changes

Low risk group

Inter risk group

High risk group

Excellent response

2% 2% 14%

Incomplete response

13% 41% 79%

Tuttle, Thyroid, 2010

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Papillary Thyroid MicroCarcinoma

• BTA 2007: no completion or radio-iodine

• BTA 2014 guidelines: – no TSH suppression – no follow-up

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Incidental vs non-incidental

Incidental PTMC Discharge, annual TSH Non-incidental PTMC low risk follow-up Mehanna et al, JCEM, 2014

StudyIncidental PTMC

Wada N, 2003Dietlein M,2005Lo CY, 2006Roti E,2006Schonberger J, 2007Sakorafas GH, 2007Gülben K, 2008Pazaitou-Panayiotou K, 2008Lin JD,2008Besic N, 2009Pisanu A, 2009Xu YN, 2010Summary (I-squared = 0%, p = 0.999)

Non - incidental PTMCWada N, 2003Roti E,2006Lo CY, 2006Schonberger J, 2007Cappelli C, 2007Pazaitou-Panayiotou K, 2008Lin JD, 2008Besic N, 2009Pisanu A, 2009Abboud B, 2010Sugitani I, 2010Xu YN, 2010Ito Y, 2010Moon HJ,2011Summary (I-squared = 89.6%, p < 0.001)

Recurrenceproportion

1/1550/200/750/520/540/271/810/302/1260/1070/730/544/854

6/2594/19113/1103/1348/1023/10220/2097/1473/760/1221/561/12332/105912/288173/2669

0.0060.0000.0000.0000.0000.0000.0120.0000.0160.0000.0000.0000.000

0.0230.0210.1180.2310.4710.1250.0960.0480.0390.0000.3750.0080.0300.0420.079

lower0.0000.0000.0000.0000.0000.0000.0000.0000.0020.0000.0000.0000.000

0.0080.0060.0640.0500.3700.0270.0590.0190.0080.0000.2490.0000.0210.0220.049

95% CIsupper0.0350.1680.0480.0680.0660.1280.0670.1160.0560.0340.0490.0660.011

0.0500.0530.1940.5380.5720.3240.1440.0960.1110.2650.5150.0440.0420.0720.109

wgts%20.5 0.911.0 5.4 5.8 1.6 5.7 1.9 8.722.210.5 5.8100

10.210.1 7.1 1.3 4.8 2.9 8.8 9.1 8.1 3.4 3.410.110.610.0100

0 0.1 0.2 0.3 0.4 0.5

Recurrence Proportion

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Increase in incidence due to increased detection of small sub-clinical disease

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Increase due to small subclinical tumours?

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Rates of nodules >4cm increasing rapidly too!

Male Female <1cm 4.0% 8.6% >4cm 3.9% 5.7%

Annual Percentage increase in USA

Chen Cancer 2009; Zhu Thyroid 2009

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Thyroid cancer incidence increased dramatically in >45 compared to <45 in same period in USA

Chen, Cancer, 2009 females males

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Period and birth cohort effect = unlikely to be just detection bias!

male

female Zhu,Thyroid, 2009

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Mortality has not changed?

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Global thyroid mortality rates

If we were detecting subclinical disease mortality rates would remain the same Thyroid mortality rates are decreasing in most countries May be our management is getting better May be by identifying cancers earlier we are preventing mortality

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In UK 10% absolute improvement in survival in a decade

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Changing paradigms

• Incidence rates • Diagnosis • Personalisation of therapy

– Extent of surgery – Radioiodine ablation – Radioiodine dose

• Dynamic risk stratification and follow-up – Surveillance strategies – TSH suppression

• Mortality

www.inhanse.org

Clinical trials Anjola Awofisoye Gemma Jones June Jones Alison Edmonds Vicki Smith Lynda Wagstaff Nicky Graham Paul Nankivell

Translational Adrian Fisk Sean James Chris McCabe Davy Rapozo Sally Roberts Max Robsinon Vicki Smith Gosia Wiench Ciaran Woodman

Warwick CTU Janet Dunn Tessa Fulton-Lieuw Jo Grummet Chris McConkey Dharmesh Patel Joy Rahman

Clinical Ijaz Ahmed Andrew Hartle Huw Griffiths Chris Jennings Tim Martin Hisham Mehanna Janet O’Connell Linda Orr Sat Parmar Paul Pracy Paul Sanghera James Good Prav Praveen John Watkinson Kristien Boelaert Anthony Kong

Patients Collaborators

InHANSE team

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Clinical trials and effectiveness

Experimental and translational medicine

Quality of life

Institute of Head and Neck Studies and Education