Iodine or Not (IoN) for Low-risk Differentiated Thyroid Cancer: The Next UK National Cancer Research Network Randomised Trial following HiLo

Abstract

Differentiated thyroid cancer (DTC) is the most common endocrine malignancy. More than 2100 new cases occur each year in the UK [[1]Cancer Research UK, Cancer Statistics. Available at: http://info.cancerresearchuk.org/cancerstats/types/thyroid [accessed 07.11].Google Scholar]. It has the fastest rising incidence of any cancer in the USA with over 48,000 cases annually, and a 2.6-fold increase in incidence between 1973 and 2006 [2American Cancer Society. Cancer facts and figures, Atlanta: American Cancer Society; 2011. pp. 21, P 1–55.Google Scholar, 3National Cancer Institute. http://www.cancer.gov/cancertopics/types/thyroid [accessed 07.11].Google Scholar].Many patients have radioactive iodine (RAI) ablation after surgery, although most guidelines are unable to provide clear recommendations in the absence of randomised studies [4Cooper D.S. Doherty G.M. Haugen B.R. et al.Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer.Thyroid. 2009; 19: 1167-1214Crossref PubMed Scopus (5331) Google Scholar, 5British Thyroid AssociationGuidelines for the management of thyroid cancer.2nd ed. Royal College of Physicians, London2007Google Scholar]. Despite a lack of robust evidence there are some suggestions that its use is increasing, raising concern that patients with low-risk cancer are being over-treated [[6]Haymart M.R. Banerjee M. Stewart A.K. Koenig R.J. Birkmeyer J.D. Griggs J.J. Use of radioactive iodine for thyroid cancer.JAMA. 2011; 306: 721-728Crossref PubMed Scopus (142) Google Scholar]. Most patients with low-risk DTC will probably be cured and it is important to minimise the risk of a radiation-induced second cancer, which may be less curable than DTC itself, and other long-term side-effects [7Iyer N.G. Morris L.G. Tuttle R.M. Shaha A.R. Ganly I. Rising incidence of second cancers in patients with low-risk (T1N0) thyroid cancer who receive radioactive iodine therapy.Cancer. Oct 1, 2011; 117: 4439-4446Crossref PubMed Scopus (224) Google Scholar, 8Mallick U.K. The revised American Thyroid Association management guidelines 2009 for patients with differentiated thyroid cancer: an evidence-based risk-adapted approach.Clin Oncol (R Coll Radiol). 2010; 22 ([Special Issue Thyroid Cancer]): 472-474Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 9Tala H. Tuttle R.M. Contemporary post surgical management of differentiated thyroid carcinoma.Clin Oncol (R Coll Radiol). 2010; 22 ([Special Issue Thyroid Cancer]): 419-429Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar]. Over the years, thyroid clinicians worldwide have been trying to address two questions: (1) what is the lowest effective radioiodine dose for ablation so that treatment morbidity, including the risk of second cancer, can be kept as low as practicable, (2) is it possible to identify a group of low-risk patients in whom ablation can be avoided, without compromising recurrence or survival rates.HiLo was the seminal multicentre randomised phase III clinical trial of high versus low activity radioiodine, with or without recombinant human thyroid stimulating hormone (rhTSH) for remnant ablation. It was the first ever national thyroid cancer trial in the UK, and has answered the first question: namely that low activity (1.1 GBq with rh-TSH or thyroxine withdrawal) is as effective as the standard high activity (3.7 GBq) in low- to intermediate-risk DTC. This has been confirmed by the similar French trial (ESTIMABL). Practice in the UK and internationally will be changing as a result of these studies [[10]Mallick U, Clarke S, Moss L, et al. HiLo: Multicentre randomised phase III clinical trial of high vs low dose radioiodine, with or without recombinant human thyroid stimulating hormone (rhTSH), for remnant ablation for differentiated thyroid cancer. International Thyroid Congress, Paris, France 2010.Google Scholar].The second question has not yet been addressed in a randomised study. Evidence supporting RAI ablation is based on non-randomised studies, with a claimed benefit in recurrence rates and survival [4Cooper D.S. Doherty G.M. Haugen B.R. et al.Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer.Thyroid. 2009; 19: 1167-1214Crossref PubMed Scopus (5331) Google Scholar, 5British Thyroid AssociationGuidelines for the management of thyroid cancer.2nd ed. Royal College of Physicians, London2007Google Scholar, 11Mazzaferri E.L. Jhiang S.M. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer.Am J Med. 1994; 97: 418-428Abstract Full Text PDF PubMed Scopus (2184) Google Scholar]. Other studies and a systematic review suggest, on the contrary, that for low-risk DTC it is doubtful whether disease recurrence (the major outcome under consideration in this group rather than mortality) is significantly reduced by RAI ablation [12Hay I.D. Selective use of radioactive iodine in the postoperative management of patients with papillary and follicular thyroid carcinoma.J Surg Oncol. 2006; 94: 692-700Crossref PubMed Scopus (87) Google Scholar, 13Jonklaas J. Sarlis N.J. Litofsky D. et al.Outcomes of patients with differentiated thyroid carcinoma following initial therapy.Thyroid. 2006; 16: 1229-1242Crossref PubMed Scopus (502) Google Scholar, 14Ross D.S. Litofsky D. Ain K.B. et al.Recurrence after treatment of micropapillary thyroid cancer.Thyroid. 2009; 19: 1043-1048Crossref PubMed Scopus (148) Google Scholar, 15Sawka A.M. Brierley J.D. Tsang R.W. et al.An updated systematic review and commentary examining the effectiveness of radioactive iodine remnant ablation in well-differentiated thyroid cancer.Endocrinol Metab Clin North Am. 2008; 37: 457-480Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar].The very low long-term mortality rate in this group of patients, even without ablation, raises serious doubts whether it can be reduced further and whether a study with sufficient power could in fact be designed to detect a meaningful difference in mortality. This led to the understandable conclusion that a randomised trial of ablation versus no ablation with overall survival as the primary end point is probably unrealistic or virtually impossible [[16]Mazzaferri E. A randomized trial of remnant ablation – in search of an impossible dream?.J Clin Endocrinol Metab. 2004; 89: 3662-3664Crossref PubMed Scopus (31) Google Scholar].However, in recent years routine rhTSH-stimulated thyroglobulin, high-resolution ultrasound and fine needle aspiration cytology have become routine in most centres. These stringent follow-up methods will facilitate the detection of residual disease and recurrence and the estimation of disease-free survival earlier than was possible before [17Vaisman F. Shaha A. Fish S. Tuttle R. Initial therapy with either thyroid lobectomy or total thyroidectomy without radioactive iodine remnant ablation is associated with very low rates of structural disease recurrence in properly selected patients with differentiated thyroid cancer.Clin Endocrinol. 2011; ([Epub ahead of print])https://doi.org/10.1111/j.1365–2265.2011.04002.xCrossref PubMed Google Scholar, 18Schlumberger M. Borget I. Nascimento C. Brassard M. Leboulleux S. Treatment and follow-up of low-risk patients with thyroid cancer.Nat Rev Endocrinol. 2011; 7: 625-628https://doi.org/10.1038/nrendo.2011.133Crossref PubMed Scopus (18) Google Scholar].The Iodine or Not Trial — Objectives and DesignThe Iodine or Not (IoN) Trial is a randomised non-inferiority phase II/III multicentre trial in 570 low-risk patients with DTC. The main objective is to determine whether 5 year disease-free survival is no worse in the patients not having ablation, compared with those who do. The trial will compare total thyroidectomy (TT) and TSH suppression therapy (TSHST) with TT + TSHST + RAI ablation. Some patients might be concerned that the no ablation arm is an inferior option (it delivers two modalities instead of three) and as a consequence might be reluctant to participate. An initial phase II feasibility study will address this. If patient entry is adequate, the trial will proceed to a phase III study.Careful consideration has been given to the definition of ‘low-risk’ based on available risk stratification criteria [[4]Cooper D.S. Doherty G.M. Haugen B.R. et al.Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer.Thyroid. 2009; 19: 1167-1214Crossref PubMed Scopus (5331) Google Scholar]. Eligible patients are those with R0 total thyroidectomy and include:•papillary thyroid cancer with non-aggressive histological features, stages pT1b (1–2 cm), pT2 (2–4 cm), pT3 intrathyroidal only, multifocal microcarcinoma and pN0, pN1a, pNX.•follicular thyroid/Hürthle cell cancer (minimally invasive with capsular invasion only) stages pT1b (1–2 cm) or pT2 (2–4 cm).Patients will be randomised to receive RAI (1.1 GBq) or not, after surgery. Between 6 and 9 months later both groups will have a diagnostic I131 scan, neck ultrasound and stimulated thyroglobulin. Identifying residual disease and recurrence early is crucial. For 5 years patients will have thyroglobulin measured every 6 months while on thyroxine. Neck ultrasound (with fine needle aspiration cytology if required) will be carried out every 6 months in the first year and then annually. Most recurrences are locoregional and will be detected using these techniques.Special Features of the Iodine or Not TrialThe Iodine or Not Trial is a pragmatic trial. It takes into consideration the wide variations in practice that exist in the selection of cases for ablation by multidisciplinary teams. The inclusion criteria are therefore more permissive than the low-risk groupings suggested by the ATA Guidelines 2009 and includes T3 (intrathyroidal), N1a disease and minimally invasive follicular cancers with capsular invasion only up to stage T2. A central expert pathology review of all tissue samples is required. The initial phase II trial will also show whether clinicians are willing to recruit these groups of patients.Preoperative ultrasound assessment for all cases and intra-operative assessment of the central compartment in papillary thyroid cancer cases are strongly recommended. Suitable patients may have bilateral or ipsilateral central compartment node dissection (CCND) if adequate surgical expertise is available, according to current guidelines [[4]Cooper D.S. Doherty G.M. Haugen B.R. et al.Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer.Thyroid. 2009; 19: 1167-1214Crossref PubMed Scopus (5331) Google Scholar]. This is neither universally recommended nor practised and an analysis will be carried out between CCND and no CCND subgroups.All patients will have stimulated thyroglobulin and a pre-ablation technetium-99m scan (additional optional ultrasound) to assess remnant size after surgery. These will be subsequently correlated with recurrence rate to explore their role in risk stratification and for selective ablation in the future [17Vaisman F. Shaha A. Fish S. Tuttle R. Initial therapy with either thyroid lobectomy or total thyroidectomy without radioactive iodine remnant ablation is associated with very low rates of structural disease recurrence in properly selected patients with differentiated thyroid cancer.Clin Endocrinol. 2011; ([Epub ahead of print])https://doi.org/10.1111/j.1365–2265.2011.04002.xCrossref PubMed Google Scholar, 18Schlumberger M. Borget I. Nascimento C. Brassard M. Leboulleux S. Treatment and follow-up of low-risk patients with thyroid cancer.Nat Rev Endocrinol. 2011; 7: 625-628https://doi.org/10.1038/nrendo.2011.133Crossref PubMed Scopus (18) Google Scholar].The thyroglobulin level (or a serial rise in thyroglobulin) is not sufficient on its own for the diagnosis of residual disease and recurrence in this setting [[17]Vaisman F. Shaha A. Fish S. Tuttle R. Initial therapy with either thyroid lobectomy or total thyroidectomy without radioactive iodine remnant ablation is associated with very low rates of structural disease recurrence in properly selected patients with differentiated thyroid cancer.Clin Endocrinol. 2011; ([Epub ahead of print])https://doi.org/10.1111/j.1365–2265.2011.04002.xCrossref PubMed Google Scholar]. Ultrasound with cytological or histological confirmation (guided by suspicious features of malignancy on ultrasound) and occasional functional or cross-sectional imaging will be required to confirm the diagnosis. We will also examine the value of a more sensitive second generation thyroglobulin assay (Beckman-Coulter) in earlier detection of residual and recurrent disease without the need for TSH stimulation [[19]Spencer C. Fatemi S. Singer P. Nicoloff J. Lopresti J. Serum basal thyroglobulin measured by a second-generation assay correlates with the recombinant human thyrotropin-stimulated thyroglobulin response in patients treated for differentiated thyroid cancer.Thyroid. 2010; 20: 587-595Crossref PubMed Scopus (85) Google Scholar]. Translational components of the Iodine or Not Trial will include BRAF V600E mutation analysis and its correlation with disease-free survival, as well as serum and tissue proteomic studies [20Elisei R. Ugolini C. Viola D. et al.BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study.J Clin Endocrinol Metab. 2008; 93: 3943-3949Crossref PubMed Scopus (422) Google Scholar, 21Kim T.H. Park Y.J. Lim J.A. et al.The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis.Cancer. Aug 31, 2011; ([Epub ahead of print])https://doi.org/10.1002/cncr.26500Crossref PubMed Scopus (319) Google Scholar, 22Damante G. Scaloni A. Tell G. Thyroid tumors: novel insights from proteomic studies.Expert Rev Proteomics. 2009; 6: 363-376Crossref PubMed Scopus (11) Google Scholar, 23Cheng S. Serra S. Mercado M. Ezzat S. Asa S.L. A high-throughput proteomic approach provides distinct signatures for thyroid cancer behavior.Clin Cancer Res. 2011; 17: 2385-2394Crossref PubMed Scopus (62) Google Scholar].CollaborationsThe feasibility phase II trial will last for 12–18 months. The Trial Management Group and the National Cancer Research Institute Thyroid Cancer subgroup invite all clinicians engaged in the management of thyroid cancer to participate. We also welcome international collaboration with colleagues from other countries.For more information please contact the Iodine or Not trial co-ordinator, Colin Lunt, at [email protected] .IoN Trial Management Group: Ujjal Mallick, Sandy Beare, Carol Evans, Kate Farnell, Sharon Forsyth, Georgina Gerrard, Allan Hackshaw, Clive Harmer, Barney Harrison, Steve Hyer, Sarah J. Johnson, Catherine Lemon, Val Lewington, Colin Lunt, Laura Moss, Kate Newbold, Alice Nicol, Chris Nutting, Nick Reed, Tim Stephenson, Jonathan Wadsley, John Watkinson and Beng Yap. Differentiated thyroid cancer (DTC) is the most common endocrine malignancy. More than 2100 new cases occur each year in the UK [[1]Cancer Research UK, Cancer Statistics. Available at: http://info.cancerresearchuk.org/cancerstats/types/thyroid [accessed 07.11].Google Scholar]. It has the fastest rising incidence of any cancer in the USA with over 48,000 cases annually, and a 2.6-fold increase in incidence between 1973 and 2006 [2American Cancer Society. Cancer facts and figures, Atlanta: American Cancer Society; 2011. pp. 21, P 1–55.Google Scholar, 3National Cancer Institute. http://www.cancer.gov/cancertopics/types/thyroid [accessed 07.11].Google Scholar]. Many patients have radioactive iodine (RAI) ablation after surgery, although most guidelines are unable to provide clear recommendations in the absence of randomised studies [4Cooper D.S. Doherty G.M. Haugen B.R. et al.Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer.Thyroid. 2009; 19: 1167-1214Crossref PubMed Scopus (5331) Google Scholar, 5British Thyroid AssociationGuidelines for the management of thyroid cancer.2nd ed. Royal College of Physicians, London2007Google Scholar]. Despite a lack of robust evidence there are some suggestions that its use is increasing, raising concern that patients with low-risk cancer are being over-treated [[6]Haymart M.R. Banerjee M. Stewart A.K. Koenig R.J. Birkmeyer J.D. Griggs J.J. Use of radioactive iodine for thyroid cancer.JAMA. 2011; 306: 721-728Crossref PubMed Scopus (142) Google Scholar]. Most patients with low-risk DTC will probably be cured and it is important to minimise the risk of a radiation-induced second cancer, which may be less curable than DTC itself, and other long-term side-effects [7Iyer N.G. Morris L.G. Tuttle R.M. Shaha A.R. Ganly I. Rising incidence of second cancers in patients with low-risk (T1N0) thyroid cancer who receive radioactive iodine therapy.Cancer. Oct 1, 2011; 117: 4439-4446Crossref PubMed Scopus (224) Google Scholar, 8Mallick U.K. The revised American Thyroid Association management guidelines 2009 for patients with differentiated thyroid cancer: an evidence-based risk-adapted approach.Clin Oncol (R Coll Radiol). 2010; 22 ([Special Issue Thyroid Cancer]): 472-474Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar, 9Tala H. Tuttle R.M. Contemporary post surgical management of differentiated thyroid carcinoma.Clin Oncol (R Coll Radiol). 2010; 22 ([Special Issue Thyroid Cancer]): 419-429Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar]. Over the years, thyroid clinicians worldwide have been trying to address two questions: (1) what is the lowest effective radioiodine dose for ablation so that treatment morbidity, including the risk of second cancer, can be kept as low as practicable, (2) is it possible to identify a group of low-risk patients in whom ablation can be avoided, without compromising recurrence or survival rates. HiLo was the seminal multicentre randomised phase III clinical trial of high versus low activity radioiodine, with or without recombinant human thyroid stimulating hormone (rhTSH) for remnant ablation. It was the first ever national thyroid cancer trial in the UK, and has answered the first question: namely that low activity (1.1 GBq with rh-TSH or thyroxine withdrawal) is as effective as the standard high activity (3.7 GBq) in low- to intermediate-risk DTC. This has been confirmed by the similar French trial (ESTIMABL). Practice in the UK and internationally will be changing as a result of these studies [[10]Mallick U, Clarke S, Moss L, et al. HiLo: Multicentre randomised phase III clinical trial of high vs low dose radioiodine, with or without recombinant human thyroid stimulating hormone (rhTSH), for remnant ablation for differentiated thyroid cancer. International Thyroid Congress, Paris, France 2010.Google Scholar]. The second question has not yet been addressed in a randomised study. Evidence supporting RAI ablation is based on non-randomised studies, with a claimed benefit in recurrence rates and survival [4Cooper D.S. Doherty G.M. Haugen B.R. et al.Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer.Thyroid. 2009; 19: 1167-1214Crossref PubMed Scopus (5331) Google Scholar, 5British Thyroid AssociationGuidelines for the management of thyroid cancer.2nd ed. Royal College of Physicians, London2007Google Scholar, 11Mazzaferri E.L. Jhiang S.M. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer.Am J Med. 1994; 97: 418-428Abstract Full Text PDF PubMed Scopus (2184) Google Scholar]. Other studies and a systematic review suggest, on the contrary, that for low-risk DTC it is doubtful whether disease recurrence (the major outcome under consideration in this group rather than mortality) is significantly reduced by RAI ablation [12Hay I.D. Selective use of radioactive iodine in the postoperative management of patients with papillary and follicular thyroid carcinoma.J Surg Oncol. 2006; 94: 692-700Crossref PubMed Scopus (87) Google Scholar, 13Jonklaas J. Sarlis N.J. Litofsky D. et al.Outcomes of patients with differentiated thyroid carcinoma following initial therapy.Thyroid. 2006; 16: 1229-1242Crossref PubMed Scopus (502) Google Scholar, 14Ross D.S. Litofsky D. Ain K.B. et al.Recurrence after treatment of micropapillary thyroid cancer.Thyroid. 2009; 19: 1043-1048Crossref PubMed Scopus (148) Google Scholar, 15Sawka A.M. Brierley J.D. Tsang R.W. et al.An updated systematic review and commentary examining the effectiveness of radioactive iodine remnant ablation in well-differentiated thyroid cancer.Endocrinol Metab Clin North Am. 2008; 37: 457-480Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar]. The very low long-term mortality rate in this group of patients, even without ablation, raises serious doubts whether it can be reduced further and whether a study with sufficient power could in fact be designed to detect a meaningful difference in mortality. This led to the understandable conclusion that a randomised trial of ablation versus no ablation with overall survival as the primary end point is probably unrealistic or virtually impossible [[16]Mazzaferri E. A randomized trial of remnant ablation – in search of an impossible dream?.J Clin Endocrinol Metab. 2004; 89: 3662-3664Crossref PubMed Scopus (31) Google Scholar]. However, in recent years routine rhTSH-stimulated thyroglobulin, high-resolution ultrasound and fine needle aspiration cytology have become routine in most centres. These stringent follow-up methods will facilitate the detection of residual disease and recurrence and the estimation of disease-free survival earlier than was possible before [17Vaisman F. Shaha A. Fish S. Tuttle R. Initial therapy with either thyroid lobectomy or total thyroidectomy without radioactive iodine remnant ablation is associated with very low rates of structural disease recurrence in properly selected patients with differentiated thyroid cancer.Clin Endocrinol. 2011; ([Epub ahead of print])https://doi.org/10.1111/j.1365–2265.2011.04002.xCrossref PubMed Google Scholar, 18Schlumberger M. Borget I. Nascimento C. Brassard M. Leboulleux S. Treatment and follow-up of low-risk patients with thyroid cancer.Nat Rev Endocrinol. 2011; 7: 625-628https://doi.org/10.1038/nrendo.2011.133Crossref PubMed Scopus (18) Google Scholar]. The Iodine or Not Trial — Objectives and DesignThe Iodine or Not (IoN) Trial is a randomised non-inferiority phase II/III multicentre trial in 570 low-risk patients with DTC. The main objective is to determine whether 5 year disease-free survival is no worse in the patients not having ablation, compared with those who do. The trial will compare total thyroidectomy (TT) and TSH suppression therapy (TSHST) with TT + TSHST + RAI ablation. Some patients might be concerned that the no ablation arm is an inferior option (it delivers two modalities instead of three) and as a consequence might be reluctant to participate. An initial phase II feasibility study will address this. If patient entry is adequate, the trial will proceed to a phase III study.Careful consideration has been given to the definition of ‘low-risk’ based on available risk stratification criteria [[4]Cooper D.S. Doherty G.M. Haugen B.R. et al.Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer.Thyroid. 2009; 19: 1167-1214Crossref PubMed Scopus (5331) Google Scholar]. Eligible patients are those with R0 total thyroidectomy and include:•papillary thyroid cancer with non-aggressive histological features, stages pT1b (1–2 cm), pT2 (2–4 cm), pT3 intrathyroidal only, multifocal microcarcinoma and pN0, pN1a, pNX.•follicular thyroid/Hürthle cell cancer (minimally invasive with capsular invasion only) stages pT1b (1–2 cm) or pT2 (2–4 cm).Patients will be randomised to receive RAI (1.1 GBq) or not, after surgery. Between 6 and 9 months later both groups will have a diagnostic I131 scan, neck ultrasound and stimulated thyroglobulin. Identifying residual disease and recurrence early is crucial. For 5 years patients will have thyroglobulin measured every 6 months while on thyroxine. Neck ultrasound (with fine needle aspiration cytology if required) will be carried out every 6 months in the first year and then annually. Most recurrences are locoregional and will be detected using these techniques. The Iodine or Not (IoN) Trial is a randomised non-inferiority phase II/III multicentre trial in 570 low-risk patients with DTC. The main objective is to determine whether 5 year disease-free survival is no worse in the patients not having ablation, compared with those who do. The trial will compare total thyroidectomy (TT) and TSH suppression therapy (TSHST) with TT + TSHST + RAI ablation. Some patients might be concerned that the no ablation arm is an inferior option (it delivers two modalities instead of three) and as a consequence might be reluctant to participate. An initial phase II feasibility study will address this. If patient entry is adequate, the trial will proceed to a phase III study. Careful consideration has been given to the definition of ‘low-risk’ based on available risk stratification criteria [[4]Cooper D.S. Doherty G.M. Haugen B.R. et al.Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer.Thyroid. 2009; 19: 1167-1214Crossref PubMed Scopus (5331) Google Scholar]. Eligible patients are those with R0 total thyroidectomy and include:•papillary thyroid cancer with non-aggressive histological features, stages pT1b (1–2 cm), pT2 (2–4 cm), pT3 intrathyroidal only, multifocal microcarcinoma and pN0, pN1a, pNX.•follicular thyroid/Hürthle cell cancer (minimally invasive with capsular invasion only) stages pT1b (1–2 cm) or pT2 (2–4 cm). Patients will be randomised to receive RAI (1.1 GBq) or not, after surgery. Between 6 and 9 months later both groups will have a diagnostic I131 scan, neck ultrasound and stimulated thyroglobulin. Identifying residual disease and recurrence early is crucial. For 5 years patients will have thyroglobulin measured every 6 months while on thyroxine. Neck ultrasound (with fine needle aspiration cytology if required) will be carried out every 6 months in the first year and then annually. Most recurrences are locoregional and will be detected using these techniques. Special Features of the Iodine or Not TrialThe Iodine or Not Trial is a pragmatic trial. It takes into consideration the wide variations in practice that exist in the selection of cases for ablation by multidisciplinary teams. The inclusion criteria are therefore more permissive than the low-risk groupings suggested by the ATA Guidelines 2009 and includes T3 (intrathyroidal), N1a disease and minimally invasive follicular cancers with capsular invasion only up to stage T2. A central expert pathology review of all tissue samples is required. The initial phase II trial will also show whether clinicians are willing to recruit these groups of patients.Preoperative ultrasound assessment for all cases and intra-operative assessment of the central compartment in papillary thyroid cancer cases are strongly recommended. Suitable patients may have bilateral or ipsilateral central compartment node dissection (CCND) if adequate surgical expertise is available, according to current guidelines [[4]Cooper D.S. Doherty G.M. Haugen B.R. et al.Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer.Thyroid. 2009; 19: 1167-1214Crossref PubMed Scopus (5331) Google Scholar]. This is neither universally recommended nor practised and an analysis will be carried out between CCND and no CCND subgroups.All patients will have stimulated thyroglobulin and a pre-ablation technetium-99m scan (additional optional ultrasound) to assess remnant size after surgery. These will be subsequently correlated with recurrence rate to explore their role in risk stratification and for selective ablation in the future [17Vaisman F. Shaha A. Fish S. Tuttle R. Initial therapy with either thyroid lobectomy or total thyroidectomy without radioactive iodine remnant ablation is associated with very low rates of structural disease recurrence in properly selected patients with differentiated thyroid cancer.Clin Endocrinol. 2011; ([Epub ahead of print])https://doi.org/10.1111/j.1365–2265.2011.04002.xCrossref PubMed Google Scholar, 18Schlumberger M. Borget I. Nascimento C. Brassard M. Leboulleux S. Treatment and follow-up of low-risk patients with thyroid cancer.Nat Rev Endocrinol. 2011; 7: 625-628https://doi.org/10.1038/nrendo.2011.133Crossref PubMed Scopus (18) Google Scholar].The thyroglobulin level (or a serial rise in thyroglobulin) is not sufficient on its own for the diagnosis of residual disease and recurrence in this setting [[17]Vaisman F. Shaha A. Fish S. Tuttle R. Initial therapy with either thyroid lobectomy or total thyroidectomy without radioactive iodine remnant ablation is associated with very low rates of structural disease recurrence in properly selected patients with differentiated thyroid cancer.Clin Endocrinol. 2011; ([Epub ahead of print])https://doi.org/10.1111/j.1365–2265.2011.04002.xCrossref PubMed Google Scholar]. Ultrasound with cytological or histological confirmation (guided by suspicious features of malignancy on ultrasound) and occasional functional or cross-sectional imaging will be required to confirm the diagnosis. We will also examine the value of a more sensitive second generation thyroglobulin assay (Beckman-Coulter) in earlier detection of residual and recurrent disease without the need for TSH stimulation [[19]Spencer C. Fatemi S. Singer P. Nicoloff J. Lopresti J. Serum basal thyroglobulin measured by a second-generation assay correlates with the recombinant human thyrotropin-stimulated thyroglobulin response in patients treated for differentiated thyroid cancer.Thyroid. 2010; 20: 587-595Crossref PubMed Scopus (85) Google Scholar]. Translational components of the Iodine or Not Trial will include BRAF V600E mutation analysis and its correlation with disease-free survival, as well as serum and tissue proteomic studies [20Elisei R. Ugolini C. Viola D. et al.BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study.J Clin Endocrinol Metab. 2008; 93: 3943-3949Crossref PubMed Scopus (422) Google Scholar, 21Kim T.H. Park Y.J. Lim J.A. et al.The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis.Cancer. Aug 31, 2011; ([Epub ahead of print])https://doi.org/10.1002/cncr.26500Crossref PubMed Scopus (319) Google Scholar, 22Damante G. Scaloni A. Tell G. Thyroid tumors: novel insights from proteomic studies.Expert Rev Proteomics. 2009; 6: 363-376Crossref PubMed Scopus (11) Google Scholar, 23Cheng S. Serra S. Mercado M. Ezzat S. Asa S.L. A high-throughput proteomic approach provides distinct signatures for thyroid cancer behavior.Clin Cancer Res. 2011; 17: 2385-2394Crossref PubMed Scopus (62) Google Scholar]. The Iodine or Not Trial is a pragmatic trial. It takes into consideration the wide variations in practice that exist in the selection of cases for ablation by multidisciplinary teams. The inclusion criteria are therefore more permissive than the low-risk groupings suggested by the ATA Guidelines 2009 and includes T3 (intrathyroidal), N1a disease and minimally invasive follicular cancers with capsular invasion only up to stage T2. A central expert pathology review of all tissue samples is required. The initial phase II trial will also show whether clinicians are willing to recruit these groups of patients. Preoperative ultrasound assessment for all cases and intra-operative assessment of the central compartment in papillary thyroid cancer cases are strongly recommended. Suitable patients may have bilateral or ipsilateral central compartment node dissection (CCND) if adequate surgical expertise is available, according to current guidelines [[4]Cooper D.S. Doherty G.M. Haugen B.R. et al.Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer.Thyroid. 2009; 19: 1167-1214Crossref PubMed Scopus (5331) Google Scholar]. This is neither universally recommended nor practised and an analysis will be carried out between CCND and no CCND subgroups. All patients will have stimulated thyroglobulin and a pre-ablation technetium-99m scan (additional optional ultrasound) to assess remnant size after surgery. These will be subsequently correlated with recurrence rate to explore their role in risk stratification and for selective ablation in the future [17Vaisman F. Shaha A. Fish S. Tuttle R. Initial therapy with either thyroid lobectomy or total thyroidectomy without radioactive iodine remnant ablation is associated with very low rates of structural disease recurrence in properly selected patients with differentiated thyroid cancer.Clin Endocrinol. 2011; ([Epub ahead of print])https://doi.org/10.1111/j.1365–2265.2011.04002.xCrossref PubMed Google Scholar, 18Schlumberger M. Borget I. Nascimento C. Brassard M. Leboulleux S. Treatment and follow-up of low-risk patients with thyroid cancer.Nat Rev Endocrinol. 2011; 7: 625-628https://doi.org/10.1038/nrendo.2011.133Crossref PubMed Scopus (18) Google Scholar]. The thyroglobulin level (or a serial rise in thyroglobulin) is not sufficient on its own for the diagnosis of residual disease and recurrence in this setting [[17]Vaisman F. Shaha A. Fish S. Tuttle R. Initial therapy with either thyroid lobectomy or total thyroidectomy without radioactive iodine remnant ablation is associated with very low rates of structural disease recurrence in properly selected patients with differentiated thyroid cancer.Clin Endocrinol. 2011; ([Epub ahead of print])https://doi.org/10.1111/j.1365–2265.2011.04002.xCrossref PubMed Google Scholar]. Ultrasound with cytological or histological confirmation (guided by suspicious features of malignancy on ultrasound) and occasional functional or cross-sectional imaging will be required to confirm the diagnosis. We will also examine the value of a more sensitive second generation thyroglobulin assay (Beckman-Coulter) in earlier detection of residual and recurrent disease without the need for TSH stimulation [[19]Spencer C. Fatemi S. Singer P. Nicoloff J. Lopresti J. Serum basal thyroglobulin measured by a second-generation assay correlates with the recombinant human thyrotropin-stimulated thyroglobulin response in patients treated for differentiated thyroid cancer.Thyroid. 2010; 20: 587-595Crossref PubMed Scopus (85) Google Scholar]. Translational components of the Iodine or Not Trial will include BRAF V600E mutation analysis and its correlation with disease-free survival, as well as serum and tissue proteomic studies [20Elisei R. Ugolini C. Viola D. et al.BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study.J Clin Endocrinol Metab. 2008; 93: 3943-3949Crossref PubMed Scopus (422) Google Scholar, 21Kim T.H. Park Y.J. Lim J.A. et al.The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis.Cancer. Aug 31, 2011; ([Epub ahead of print])https://doi.org/10.1002/cncr.26500Crossref PubMed Scopus (319) Google Scholar, 22Damante G. Scaloni A. Tell G. Thyroid tumors: novel insights from proteomic studies.Expert Rev Proteomics. 2009; 6: 363-376Crossref PubMed Scopus (11) Google Scholar, 23Cheng S. Serra S. Mercado M. Ezzat S. Asa S.L. A high-throughput proteomic approach provides distinct signatures for thyroid cancer behavior.Clin Cancer Res. 2011; 17: 2385-2394Crossref PubMed Scopus (62) Google Scholar]. CollaborationsThe feasibility phase II trial will last for 12–18 months. The Trial Management Group and the National Cancer Research Institute Thyroid Cancer subgroup invite all clinicians engaged in the management of thyroid cancer to participate. We also welcome international collaboration with colleagues from other countries.For more information please contact the Iodine or Not trial co-ordinator, Colin Lunt, at [email protected] .IoN Trial Management Group: Ujjal Mallick, Sandy Beare, Carol Evans, Kate Farnell, Sharon Forsyth, Georgina Gerrard, Allan Hackshaw, Clive Harmer, Barney Harrison, Steve Hyer, Sarah J. Johnson, Catherine Lemon, Val Lewington, Colin Lunt, Laura Moss, Kate Newbold, Alice Nicol, Chris Nutting, Nick Reed, Tim Stephenson, Jonathan Wadsley, John Watkinson and Beng Yap. The feasibility phase II trial will last for 12–18 months. The Trial Management Group and the National Cancer Research Institute Thyroid Cancer subgroup invite all clinicians engaged in the management of thyroid cancer to participate. We also welcome international collaboration with colleagues from other countries. For more information please contact the Iodine or Not trial co-ordinator, Colin Lunt, at [email protected] . IoN Trial Management Group: Ujjal Mallick, Sandy Beare, Carol Evans, Kate Farnell, Sharon Forsyth, Georgina Gerrard, Allan Hackshaw, Clive Harmer, Barney Harrison, Steve Hyer, Sarah J. Johnson, Catherine Lemon, Val Lewington, Colin Lunt, Laura Moss, Kate Newbold, Alice Nicol, Chris Nutting, Nick Reed, Tim Stephenson, Jonathan Wadsley, John Watkinson and Beng Yap. We thank many colleagues from the UK and abroad for helpful discussions. Conflict of Interest StatementAll four authors have attended Genzyme advisory board meetings and have received honoraria in the past. All four authors have attended Genzyme advisory board meetings and have received honoraria in the past.