Title:    Phase II Randomised Controlled Trial of Postoperative Intensity Modulated Radiotherapy (IMRT) in Locally Advanced Thyroid Cancers

Background and rationale: Locally advanced thyroid cancers (AJCC - T4a, N1), are known to have high rates of loco-regional recurrences after conventional treatment with surgery and radioactive iodine therapy. Most patients with recurrences are amenable to salvage surgeries; however these surgeries have very high morbidity. A few retrospective studies have shown that the addition of radiotherapy (RT) after surgery and radioiodine treatment has decreased the loco-regional recurrence rate in locally advanced thyroid cancers (LATC). However, all these studies are retrospective and heterogenous with no clear indications or protocols for radiotherapy  Recommendation 41 of ATA guidelines states that, “The use of external beam irradiation to treat the primary tumor should be considered in patients over age 45 with grossly visible extrathyroidal extension at the time of surgery and a high likelihood of microscopic residual disease, and for those patients with gross residual tumor in whom further surgery or RAI would likely be ineffective.”⁵ Thus the use of adjuvant RT in advanced differentiated thyroid cancer may be considered as standard of care.

However there are certain caveats to this:

1. The level of recommendation is B (‘the strength of the evidence is limited by the number, quality, or consistency of the individual studies’).

2. All the previous studies have been retrospective, with heterogenous patient population, no clearly defined inclusion criteria and end points.

3. There is no data regarding toxicity of adjuvant RT in any of these studies in these studies as most have been retrospective in nature.

 Aims, Objectives and hypotheses:

Primary aim:

• To assess the impact of adjuvant RT on loco-regional control  in patients with locally advanced thyroid cancers who have undergone surgery with radioiodine therapy

Secondary aim:

• To assess toxicity (early and late at 2 years) of adjuvant RT in these patients

Study Methodology

All patients who are willing to participate on the trial and have signed the informed consent form will be randomized to either receive adjuvant external beam RT or no treatment. All patients (irrespective of randomization), will proceed to receive radio-active iodine scanning and therapy as is standard for patients with locally advanced differentiated thyroid cancers. This will be performed between 4-6 weeks after thyroidectomy providing adequate period for thyroid hormone withdrawal, to allow TSH to rise beyond 30microIU/ml. Adjuvant radiotherapy will be administered after radioiodine therapy, within 8-10 weeks of the surgery. Patients in both arms of the trial will be followed up for 5 years.

 Sample size for the study has been calculated considering a 23% decrease in loco-regional recurrence with addition of adjuvant RT, as obtained from a previous study.

Eight patients (5%) have been added to account for lost to follow up. The total sample size is 72 with 36 in each arm

Alpha- 80%

Beta- 0.05