The HiLo Trial: a Multicentre Randomised Trial of High- versus Low-dose Radioiodine, with or without Recombinant Human Thyroid Stimulating Hormone, for Remnant Ablation after Surgery for Differentiated Thyroid Cancer

Abstract

There are about 1600 newly diagnosed patients with thyroid cancer each year in the UK [1Cancer Research UK Cancer statistics 2005.http://info.cancerresearchuk.org/cancerstats/types/thyroid/incidence/Google Scholar] and an estimated 37 000 in the USA [2American Cancer Society Cancer facts and figures 2008.http://www.cancer.org/docroot/STT/stt_0.aspGoogle Scholar]. Differentiated thyroid cancer is the most common, with a survival rate of 90% at 10 years. After thyroidectomy, most patients, apart from those at very low risk, are given radioactive iodine to ablate any thyroid remnant, according to the current British Thyroid Association national guidelines [3British Thyroid Association Guidelines for the management of thyroid cancer in adults. Royal College of Physicians, London2007Google Scholar]. The usual dose given is 3.7 GBq, but for many years there has been interest in administering a lower dose, such as 1.1 GBq. This has the advantages of reducing the risk of developing a second primary malignancy [4Rubino C. de Vathaire F. Dottorini M.E. et al.Second primary malignancies in thyroid cancer patients.Br J Cancer. 2003; 89: 1638-1644Crossref PubMed Scopus (458) Google Scholar] or permanent dry mouth, a shorter hospital stay, less time in isolation and a lower overall treatment cost. National guidelines are not sufficiently clear on whether a lower activity could be used routinely [3British Thyroid Association Guidelines for the management of thyroid cancer in adults. Royal College of Physicians, London2007Google Scholar, 5The American Thyroid Association Guidelines Taskforce. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer.Thyroid. 2006; 16: 109-142Crossref PubMed Scopus (1730) Google Scholar]. This is not surprising, given that the available evidence does not allow a reliable comparison between 1.1 and 3.7 GBq.A systematic review [6Hackshaw A.K. Harmer C. Mallick U. Haq M. Franklyn J. 131I activity for remnant ablation in patients with differentiated thyroid cancer: a systematic review.J Clin Endocrin Metab. 2007; 92: 28-38Crossref PubMed Scopus (141) Google Scholar], based on 41 studies that examined patient case notes and 12 prospective cohort studies, produced inconclusive results. Some suggested that a low activity had a similar effect as a high activity, whereas others suggested it might have a lower ablation success rate. In a meta-analysis, the pooled ablation success rate was only 10% lower in patients given about 1.1 GBq. The best evidence comes from randomised trials, but there are only six and the comparison of 3.7 and 1.1 GBq was based on a relatively small number of patients [6Hackshaw A.K. Harmer C. Mallick U. Haq M. Franklyn J. 131I activity for remnant ablation in patients with differentiated thyroid cancer: a systematic review.J Clin Endocrin Metab. 2007; 92: 28-38Crossref PubMed Scopus (141) Google Scholar]. However, these results are equivocal, indicating that a large randomised trial is needed.Patients are usually prepared for ablation after withdrawal of thyroid hormone replacement for 2 weeks if they are taking liothyronine (T3) or for 4 weeks if they are on levothyroxine (T4). Alternatively they may have recombinant human thyroid stimulating hormone (rhTSH) by intramuscular injection on each of the 2 days before ablation. There is evidence that using rhTSH can improve quality of life by avoiding the symptoms of hypothyroidism caused by hormone withdrawal, and patients take less time off work. It may also reduce the risk of second malignancies because of faster renal clearance of radioiodine and consequent less radiation exposure to the blood [7Pacini F. Ladenson P.W. Schlumberger M. et al.Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international randomized controlled study.J Clin Endocrinol Metab. 2006; 91: 926-932Crossref PubMed Scopus (358) Google Scholar]. However, the studies that have compared ablation success rates between these two methods have been small, ranging from only 40 to 120 patients and only one study was randomised [7Pacini F. Ladenson P.W. Schlumberger M. et al.Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international randomized controlled study.J Clin Endocrinol Metab. 2006; 91: 926-932Crossref PubMed Scopus (358) Google Scholar]. A recent randomised trial compared 1.8 GBq with 3.7 GBq; all patients received rhTSH, but this equivalence trial was powered to detect a large difference in ablation success rate of at least 20% and as such only 72 patients were included [8Pilli T. Brianzoni E. Capoccetti F. et al.A comparison of 1850 (50 mCi) and 3700 MBq (100 mCi) 131-iodine administered doses for recombinant thyrotropin-stimulated postoperative thyroid remnant ablation in differentiated thyroid cancer.J Clin Endocrinol Metab. 2007; 92: 3542-3546Crossref PubMed Scopus (142) Google Scholar]. Two small studies compared 1.1 GBq with 3.7 GBq using rhTSH and had conflicting results. The randomised study concluded that 1.1 GBq was inferior, but was criticised for the non-standard timing of ablation on day 2; the other study supported its use, but was not randomised. A large randomised trial is also needed to compare the use of rhTSH with standard thyroid hormone withdrawal, especially when 1.1 GBq activity is used.The HiLo trial has therefore been designed to address these two important questions involving remnant ablation: (1) whether 1.1 GBq is as effective as 3.7 GBq in achieving successful ablation and (2) whether rhTSH is as effective as thyroxine withdrawal in preparing patients for ablation using both 3.7 and 1.1 GBq regimens.HiLo is a factorial non-inferiority trial. The target sample size is 468 patients, to be randomised to one of four groups. Patients are randomised to receive either 1.1 or 3.7 GBq after a total thyroidectomy. The main outcome measure is the ablation success rate 6–8 months after treatment. In preparing patients for ablation, patients will have either rhTSH given on each of the 2 days before ablation or withdrawal of thyroid hormone replacement.What is Special about the HiLo Trial?HiLo is the largest trial of thyroid cancer comparing 1.1 and 3.7 GBq and with a power to detect a 10% difference in ablation success rates between the treatment arms. It is also the largest randomised trial comparing rhTSH and thyroxine withdrawal using 1.1 GBq.Methodological flaws of some of the previous studies were a variable extent of surgery leading to a variable remnant size, no pre-ablation scan to enable the assessment of remnant size and dose effect, no fixed timing of the assessment of ablation and the absence of a strict definition of ablation success. These will be avoided in HiLo.Every patient will have a total thyroidectomy by a specialist surgeon and a pre-ablation scan to provide a quantitative estimate of remnant size (using 99m technetium to avoid the effects of stunning). This is important because the size of the remnant is the single most important determinant in assessing success rates of different radioiodine activities for ablation.The success of ablation for patients in this trial has to be assessed between 6 and 8 months after ablation and not earlier or later, in order to standardise the time interval after ablation.In addition, more stringent criteria for assessing ablation success are being used. Cut-off values of the scan uptake and thyroglobulin are clearly defined. Patients will have an I131 scan. They will also have a serum thyroglobulin measurement, by both immunometric and radioimmunoassay, to identify thyroglobulin antibody interference reliably. No other trial has done this before.The trial is being funded by Cancer Research UK and conducted through the National Cancer Research Network. It is the first ever national study for patients with thyroid cancer in the UK. At present, more than 20 centres are recruiting.We would like members of every multidisciplinary thyroid team to consider the suitability of all patients with differentiated thyroid cancer for randomisation into the HiLo trial as soon as the decision is made to give radioiodine ablation. Only with the help of all colleagues can this trial succeed. Interested centres should contact Pablo Alvarez, the trial co-ordinator ( [email protected] ).The results will be used to inform national and international guidelines. They will help to achieve the highest cure rate for differentiated thyroid cancer and to optimise quality of life, and at the same time reduce the risk of developing second malignancies and other late effects.Achieving the highest cure rate with minimal late effects has been the direction of the development of therapy for all curable cancers, such as childhood malignancies and Hodgkin's lymphoma. The outcome of the Hilo trial may permit a step in the same direction.Because differentiated thyroid cancer is a rare cancer, it is important to collaborate with as many centres as possible to ensure the success of the HiLo trial. This will also extend research across the National Cancer Research Network portfolio into the rare cancers. There are about 1600 newly diagnosed patients with thyroid cancer each year in the UK [1Cancer Research UK Cancer statistics 2005.http://info.cancerresearchuk.org/cancerstats/types/thyroid/incidence/Google Scholar] and an estimated 37 000 in the USA [2American Cancer Society Cancer facts and figures 2008.http://www.cancer.org/docroot/STT/stt_0.aspGoogle Scholar]. Differentiated thyroid cancer is the most common, with a survival rate of 90% at 10 years. After thyroidectomy, most patients, apart from those at very low risk, are given radioactive iodine to ablate any thyroid remnant, according to the current British Thyroid Association national guidelines [3British Thyroid Association Guidelines for the management of thyroid cancer in adults. Royal College of Physicians, London2007Google Scholar]. The usual dose given is 3.7 GBq, but for many years there has been interest in administering a lower dose, such as 1.1 GBq. This has the advantages of reducing the risk of developing a second primary malignancy [4Rubino C. de Vathaire F. Dottorini M.E. et al.Second primary malignancies in thyroid cancer patients.Br J Cancer. 2003; 89: 1638-1644Crossref PubMed Scopus (458) Google Scholar] or permanent dry mouth, a shorter hospital stay, less time in isolation and a lower overall treatment cost. National guidelines are not sufficiently clear on whether a lower activity could be used routinely [3British Thyroid Association Guidelines for the management of thyroid cancer in adults. Royal College of Physicians, London2007Google Scholar, 5The American Thyroid Association Guidelines Taskforce. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer.Thyroid. 2006; 16: 109-142Crossref PubMed Scopus (1730) Google Scholar]. This is not surprising, given that the available evidence does not allow a reliable comparison between 1.1 and 3.7 GBq. A systematic review [6Hackshaw A.K. Harmer C. Mallick U. Haq M. Franklyn J. 131I activity for remnant ablation in patients with differentiated thyroid cancer: a systematic review.J Clin Endocrin Metab. 2007; 92: 28-38Crossref PubMed Scopus (141) Google Scholar], based on 41 studies that examined patient case notes and 12 prospective cohort studies, produced inconclusive results. Some suggested that a low activity had a similar effect as a high activity, whereas others suggested it might have a lower ablation success rate. In a meta-analysis, the pooled ablation success rate was only 10% lower in patients given about 1.1 GBq. The best evidence comes from randomised trials, but there are only six and the comparison of 3.7 and 1.1 GBq was based on a relatively small number of patients [6Hackshaw A.K. Harmer C. Mallick U. Haq M. Franklyn J. 131I activity for remnant ablation in patients with differentiated thyroid cancer: a systematic review.J Clin Endocrin Metab. 2007; 92: 28-38Crossref PubMed Scopus (141) Google Scholar]. However, these results are equivocal, indicating that a large randomised trial is needed. Patients are usually prepared for ablation after withdrawal of thyroid hormone replacement for 2 weeks if they are taking liothyronine (T3) or for 4 weeks if they are on levothyroxine (T4). Alternatively they may have recombinant human thyroid stimulating hormone (rhTSH) by intramuscular injection on each of the 2 days before ablation. There is evidence that using rhTSH can improve quality of life by avoiding the symptoms of hypothyroidism caused by hormone withdrawal, and patients take less time off work. It may also reduce the risk of second malignancies because of faster renal clearance of radioiodine and consequent less radiation exposure to the blood [7Pacini F. Ladenson P.W. Schlumberger M. et al.Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international randomized controlled study.J Clin Endocrinol Metab. 2006; 91: 926-932Crossref PubMed Scopus (358) Google Scholar]. However, the studies that have compared ablation success rates between these two methods have been small, ranging from only 40 to 120 patients and only one study was randomised [7Pacini F. Ladenson P.W. Schlumberger M. et al.Radioiodine ablation of thyroid remnants after preparation with recombinant human thyrotropin in differentiated thyroid carcinoma: results of an international randomized controlled study.J Clin Endocrinol Metab. 2006; 91: 926-932Crossref PubMed Scopus (358) Google Scholar]. A recent randomised trial compared 1.8 GBq with 3.7 GBq; all patients received rhTSH, but this equivalence trial was powered to detect a large difference in ablation success rate of at least 20% and as such only 72 patients were included [8Pilli T. Brianzoni E. Capoccetti F. et al.A comparison of 1850 (50 mCi) and 3700 MBq (100 mCi) 131-iodine administered doses for recombinant thyrotropin-stimulated postoperative thyroid remnant ablation in differentiated thyroid cancer.J Clin Endocrinol Metab. 2007; 92: 3542-3546Crossref PubMed Scopus (142) Google Scholar]. Two small studies compared 1.1 GBq with 3.7 GBq using rhTSH and had conflicting results. The randomised study concluded that 1.1 GBq was inferior, but was criticised for the non-standard timing of ablation on day 2; the other study supported its use, but was not randomised. A large randomised trial is also needed to compare the use of rhTSH with standard thyroid hormone withdrawal, especially when 1.1 GBq activity is used. The HiLo trial has therefore been designed to address these two important questions involving remnant ablation: (1) whether 1.1 GBq is as effective as 3.7 GBq in achieving successful ablation and (2) whether rhTSH is as effective as thyroxine withdrawal in preparing patients for ablation using both 3.7 and 1.1 GBq regimens. HiLo is a factorial non-inferiority trial. The target sample size is 468 patients, to be randomised to one of four groups. Patients are randomised to receive either 1.1 or 3.7 GBq after a total thyroidectomy. The main outcome measure is the ablation success rate 6–8 months after treatment. In preparing patients for ablation, patients will have either rhTSH given on each of the 2 days before ablation or withdrawal of thyroid hormone replacement. What is Special about the HiLo Trial?HiLo is the largest trial of thyroid cancer comparing 1.1 and 3.7 GBq and with a power to detect a 10% difference in ablation success rates between the treatment arms. It is also the largest randomised trial comparing rhTSH and thyroxine withdrawal using 1.1 GBq.Methodological flaws of some of the previous studies were a variable extent of surgery leading to a variable remnant size, no pre-ablation scan to enable the assessment of remnant size and dose effect, no fixed timing of the assessment of ablation and the absence of a strict definition of ablation success. These will be avoided in HiLo.Every patient will have a total thyroidectomy by a specialist surgeon and a pre-ablation scan to provide a quantitative estimate of remnant size (using 99m technetium to avoid the effects of stunning). This is important because the size of the remnant is the single most important determinant in assessing success rates of different radioiodine activities for ablation.The success of ablation for patients in this trial has to be assessed between 6 and 8 months after ablation and not earlier or later, in order to standardise the time interval after ablation.In addition, more stringent criteria for assessing ablation success are being used. Cut-off values of the scan uptake and thyroglobulin are clearly defined. Patients will have an I131 scan. They will also have a serum thyroglobulin measurement, by both immunometric and radioimmunoassay, to identify thyroglobulin antibody interference reliably. No other trial has done this before.The trial is being funded by Cancer Research UK and conducted through the National Cancer Research Network. It is the first ever national study for patients with thyroid cancer in the UK. At present, more than 20 centres are recruiting.We would like members of every multidisciplinary thyroid team to consider the suitability of all patients with differentiated thyroid cancer for randomisation into the HiLo trial as soon as the decision is made to give radioiodine ablation. Only with the help of all colleagues can this trial succeed. Interested centres should contact Pablo Alvarez, the trial co-ordinator ( [email protected] ).The results will be used to inform national and international guidelines. They will help to achieve the highest cure rate for differentiated thyroid cancer and to optimise quality of life, and at the same time reduce the risk of developing second malignancies and other late effects.Achieving the highest cure rate with minimal late effects has been the direction of the development of therapy for all curable cancers, such as childhood malignancies and Hodgkin's lymphoma. The outcome of the Hilo trial may permit a step in the same direction.Because differentiated thyroid cancer is a rare cancer, it is important to collaborate with as many centres as possible to ensure the success of the HiLo trial. This will also extend research across the National Cancer Research Network portfolio into the rare cancers. HiLo is the largest trial of thyroid cancer comparing 1.1 and 3.7 GBq and with a power to detect a 10% difference in ablation success rates between the treatment arms. It is also the largest randomised trial comparing rhTSH and thyroxine withdrawal using 1.1 GBq. Methodological flaws of some of the previous studies were a variable extent of surgery leading to a variable remnant size, no pre-ablation scan to enable the assessment of remnant size and dose effect, no fixed timing of the assessment of ablation and the absence of a strict definition of ablation success. These will be avoided in HiLo. Every patient will have a total thyroidectomy by a specialist surgeon and a pre-ablation scan to provide a quantitative estimate of remnant size (using 99m technetium to avoid the effects of stunning). This is important because the size of the remnant is the single most important determinant in assessing success rates of different radioiodine activities for ablation. The success of ablation for patients in this trial has to be assessed between 6 and 8 months after ablation and not earlier or later, in order to standardise the time interval after ablation. In addition, more stringent criteria for assessing ablation success are being used. Cut-off values of the scan uptake and thyroglobulin are clearly defined. Patients will have an I131 scan. They will also have a serum thyroglobulin measurement, by both immunometric and radioimmunoassay, to identify thyroglobulin antibody interference reliably. No other trial has done this before. The trial is being funded by Cancer Research UK and conducted through the National Cancer Research Network. It is the first ever national study for patients with thyroid cancer in the UK. At present, more than 20 centres are recruiting. We would like members of every multidisciplinary thyroid team to consider the suitability of all patients with differentiated thyroid cancer for randomisation into the HiLo trial as soon as the decision is made to give radioiodine ablation. Only with the help of all colleagues can this trial succeed. Interested centres should contact Pablo Alvarez, the trial co-ordinator ( [email protected] ). The results will be used to inform national and international guidelines. They will help to achieve the highest cure rate for differentiated thyroid cancer and to optimise quality of life, and at the same time reduce the risk of developing second malignancies and other late effects. Achieving the highest cure rate with minimal late effects has been the direction of the development of therapy for all curable cancers, such as childhood malignancies and Hodgkin's lymphoma. The outcome of the Hilo trial may permit a step in the same direction. Because differentiated thyroid cancer is a rare cancer, it is important to collaborate with as many centres as possible to ensure the success of the HiLo trial. This will also extend research across the National Cancer Research Network portfolio into the rare cancers.