High Dose vs Low Dose I 131 +/- rhTSH for Differentiated Thyroid Cancer (HiLo)

Multicentre Randomised Trial of High Dose Versus Low Dose Radioiodine, With or Without Recombinant Human Thyroid Stimulating Hormone, for Remnant Ablation Following Surgery for Differentiated Thyroid Cancer [HILO]

RATIONALE: Radioactive iodine uses radiation to kill tumor cells. Giving iodine I 131 with or without thyroid-stimulating hormone after surgery may kill any tumor cells that remain after surgery. It is not yet known which dose of iodine I 131 is more effective when given with or without thyroid-stimulating hormone in treating thyroid cancer.

PURPOSE: This randomized phase III trial is studying two different doses of iodine I 131 to compare how well they work when given with or without thyroid-stimulating hormone in treating patients who have undergone surgery for thyroid cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: Head and Neck Cancer
• Intervention / Treatment: Biological: recombinant thyroid-stimulating hormone; Radiation: Radiodine ablation without rhTSH

Detailed Description

OBJECTIVES:

Primary

• Compare the percentage of successful remnant ablation at 6-8 months after administration of high- vs low-dose iodine I 131 with vs without recombinant thyroid-stimulating hormone in patients who have undergone total thyroidectomy for differentiated thyroid cancer.

Secondary

• Compare quality of life in patients treated with these regimens.
• Compare locoregional recurrence in patients treated with these regimens.
• Compare distant metastases, survival, and incidence of second primary malignancies in patients treated with these regimens.

OUTLINE: This is a multicenter, factorial, randomized study. Patients are stratified according to treatment center and disease stage (I vs II vs III vs IVA). Patients are randomized to 1 of 4 treatment arms.

Patients receive thyroid hormone replacement therapy (THRT)* with thyroxine (T4)** or liothyronine sodium (T3). Patients randomized to arm III or IV discontinue THRT 4 weeks (for patients receiving T4) or 2 weeks (for patients receiving T3) prior to remnant ablation.

NOTE: *Some treatment centers may chose to avoid starting THRT in patients randomized to arm III or IV.

NOTE: **Patients receiving T4 may be switched to T3 for 2 more weeks before discontinuing THRT.

• Arm I: Patients receive recombinant thyroid-stimulating hormone (rTSH) intramuscularly on days 1 and 2 and undergo remnant ablation with low-dose iodine I 131 on day 3.
• Arm II: Patients receive rTSH as in arm I and undergo remnant ablation with high-dose iodine I 131 on day 3.
• Arm III: Patients undergo remnant ablation with low-dose iodine I 131 as in arm I.
• Arm IV: Patients undergo remnant ablation with high-dose iodine I 131 as in arm II.

Quality of life is assessed at baseline, day 3 before remnant ablation, and at 3 months.

After completion of study therapy, patients are followed at 3 months, between 6-8 months, and then annually thereafter.

Peer Reviewed and Funded or Endorsed by Cancer Research UK

PROJECTED ACCRUAL: A total of 468 patients will be accrued for this study.

• Study Type: Interventional
• Enrollment (Actual): 438
• Phase: Phase 3

Contacts and Locations

Study Locations

• United Kingdom
  • England
    • Brighton, England, United Kingdom, BN2 5BE
      • Sussex Cancer Centre at Royal Sussex County Hospital
    • Cambridge, England, United Kingdom, CB2 2QQ
      • Addenbrooke's Hospital
    • Canterbury, England, United Kingdom, CT1 3NG
      • Kent and Canterbury Hospital
    • Cottingham, England, United Kingdom, HU16 5JQ
      • Castle Hill Hospital
    • Derby, England, United Kingdom, DE1 2QY
      • Derbyshire Royal Infirmary
    • Exeter, England, United Kingdom, EX2 5DW
      • Royal Devon and Exeter Hospital
    • Gloucester, England, United Kingdom, GL1 3NN
      • Gloucestershire Royal Hospital
    • Guildford, England, United Kingdom, GU2 7XX
      • St. Luke's Cancer Centre at Royal Surrey County Hospital
    • Ipswich, England, United Kingdom, IP4 5PD
      • Ipswich Hospital
    • Leeds, England, United Kingdom, LS9 7TF
      • Leeds Cancer Centre at St. James's University Hospital
    • Leicester, England, United Kingdom, LE1 5WW
      • Leicester Royal Infirmary
    • London, England, United Kingdom, SW3 6JJ
      • Royal Marsden - London
    • London, England, United Kingdom, SE1 9RT
      • Guy's Hospital
    • Maidstone, England, United Kingdom, ME16 9QQ
      • Maidstone Hospital
    • Manchester, England, United Kingdom, M20 4BX
      • Christie Hospital
    • Middlesbrough, England, United Kingdom, TS4 3BW
      • James Cook University Hospital
    • Newcastle-Upon-Tyne, England, United Kingdom, NE4 6BE
      • Newcastle Upon Tyne Hospitals NHS Trust
    • Northampton, England, United Kingdom, NN1 5BD
      • Northampton General Hospital
    • Northwood, England, United Kingdom, HA6 2RN
      • Mount Vernon Cancer Centre at Mount Vernon Hospital
    • Norwich, England, United Kingdom, NR4 7UY
      • Norfolk and Norwich University Hospital
    • Poole Dorset, England, United Kingdom, BH15 2JB
      • Dorset Cancer Centre
    • Sheffield, England, United Kingdom, S10 2SJ
      • Cancer Research Centre at Weston Park Hospital
    • Stoke-On-Trent, England, United Kingdom, ST4 7LN
      • University Hospital of North Staffordshire
  • Wales
    • Cardiff, Wales, United Kingdom, CF14 2TL
      • Velindre Cancer Center at Velindre Hospital
    • Rhyl, Wales, United Kingdom, LL 18 5UJ
      • Glan Clwyd Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed differentiated thyroid cancer

  • T1-T3, Nx, N0, N1, M0 disease

• Has undergone one- or two-stage total thyroidectomy with or without lymph node dissection

  • All known tumor resected (R0)

• Requires radioiodine remnant ablation

  • Does not require mandatory recombinant thyroid-stimulating hormone

• No Hurthle cell carcinoma or aggressive variants, including any of the following:

  • Tall cell, insular, poorly differentiated disease with diffuse sclerosing
  • Anaplastic or medullary carcinoma

PATIENT CHARACTERISTICS:

• WHO performance status 0-2

• No severe comorbid conditions including, but not limited to, any of the following:

  • Unstable angina
  • Recent heart attack or stroke
  • Severe labile hypertension
  • Dementia
  • Concurrent dialysis
  • Tracheostomy needing care
  • Learning difficulties
  • Inability to comply with radiation protection issues
  • Requirement for frequent nursing or medical supervision that puts staff at risk for unacceptable radiation exposure
• No other cancers except basal cell skin cancer or carcinoma in situ of the cervix
• Not pregnant or nursing
• Negative pregnancy test
• Fertile female patients must use effective contraception during and for 6 months after radioiodine remnant ablation
• Fertile male patients must use effective contraception during and for 4 months after radioiodine remnant ablation

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• More than 3 months since prior contrast CT scan
• No prior iodine I 131 or iodine I 123 pre-ablation scan
• No prior treatment for thyroid cancer (except surgery)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Single

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1.1Gbq with rhTSH; Patients receive 1.1GBq dose of radioactive iodine and rhTSH	Biological: recombinant thyroid-stimulating hormone; Recombinant thyroid stimulating hormone (rhTSH) should be given at a dose of 0.9mg by intramuscular injection on two consecutive days before ablation.
Experimental: 3.2 GBq with rhTSH; Patients receive 3.2GBq dose of radioactive idodine and rhTSH	Biological: recombinant thyroid-stimulating hormone; Recombinant thyroid stimulating hormone (rhTSH) should be given at a dose of 0.9mg by intramuscular injection on two consecutive days before ablation.
Experimental: 1.1GBq without rhTSH; Patients only receive 1.1GBq dose of radioactive iodine and no rhTSH	Radiation: Radiodine ablation without rhTSH; Patients in this group do not receive rhTSH pre ablation.
Experimental: 3.2GBq without rhTSH; Patients only receive 3.2GBq dose of radioactive iodine and no rhTSH	Radiation: Radiodine ablation without rhTSH; Patients in this group do not receive rhTSH pre ablation.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients with successful remnant ablation at 6-9 months	The percentage of patients who have a successful remnant ablation at 6-9 months after radioiodine administration.	6-9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Quality of life as measured by the SF-36 questionnaire at baseline, the day of ablation, and at 3 months	Quality of life as measured by the SF-36 questionnaire at baseline, the day of ablation, and at 3 months	Baseline to 3 months
Locoregional recurrence		During and post treatment
Distant metastases	After the 5 year follow up period, patients will be follwed at hospital according to routine practice.	Baseline to 5 years after randomisation of final patient
Survival		Until patient death
Incidence of second primary malignancy	After the 5 year follow up period, patients will be follwed at hospital according to routine practice.	Baseline to 5 years after last patient is randomised

Collaborators and Investigators

• Sponsor: University College, London
• Investigators: Study Chair: Ujjal K. Mallick, MD, Newcastle-upon-Tyne Hospitals NHS Trust

Publications and helpful links

General Publications

• Mallick U, Harmer C, Yap B, Wadsley J, Clarke S, Moss L, Nicol A, Clark PM, Farnell K, McCready R, Smellie J, Franklyn JA, John R, Nutting CM, Newbold K, Lemon C, Gerrard G, Abdel-Hamid A, Hardman J, Macias E, Roques T, Whitaker S, Vijayan R, Alvarez P, Beare S, Forsyth S, Kadalayil L, Hackshaw A. Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer. N Engl J Med. 2012 May 3;366(18):1674-85. doi: 10.1056/NEJMoa1109589.
• Dehbi HM, Mallick U, Wadsley J, Newbold K, Harmer C, Hackshaw A. Recurrence after low-dose radioiodine ablation and recombinant human thyroid-stimulating hormone for differentiated thyroid cancer (HiLo): long-term results of an open-label, non-inferiority randomised controlled trial. Lancet Diabetes Endocrinol. 2019 Jan;7(1):44-51. doi: 10.1016/S2213-8587(18)30306-1. Epub 2018 Nov 27.

Study record dates

Study Major Dates

• Study Start (Actual): November 1, 2006
• Primary Completion (Actual): June 1, 2011
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: December 20, 2006
• First Submitted That Met QC Criteria: December 20, 2006
• First Posted (Estimated): December 22, 2006

Study Record Updates

• Last Update Posted (Estimated): December 19, 2023
• Last Update Submitted That Met QC Criteria: December 12, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: stage IV papillary thyroid cancer; stage IV follicular thyroid cancer; stage II follicular thyroid cancer; stage II papillary thyroid cancer; stage I follicular thyroid cancer; stage I papillary thyroid cancer; stage III follicular thyroid cancer; stage III papillary thyroid cancer
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Site; Endocrine System Diseases; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Thyroid Diseases; Thyroid Neoplasms; Physiological Effects of Drugs; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormones
• Other Study ID Numbers: UCL/05/83; CRUK-HILO-BRD/05/83 (Other Grant/Funding Number: Cancer Research UK); ISRCTN56078540 (Registry Identifier: ISRCTN); EU-20665; CTA-20363/0217/001/0001 (Other Identifier: Regulatory Authority Number); 2005-003687-37 (EudraCT Number)