Phase II Randomized Controlled Trial Of Postoperative Intensity Modulated Radiotherapy (IMRT) in Locally Advanced Thyroid Cancers.
Phase: NA
Conditions: Thyroid Cancer Stage IV, Radiation Toxicity
Sponsor: Tata Memorial Hospital

 
 
  
 
 
Phase II Randomised 
Controlled Trial of 
Postoperative Intensity 
Modulated 
Radiotherapy(IMRT) in 
Locally Advanced 
Thyroid Cancers 
Head Neck Oncology 
 
NCT number- not available 
 
Date of document- 13th February 2014 
 
 
 

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Phase II Randomised Controlled Trial of Postoperative Intensity Modulated 
Radiotherapy (IMRT) in Locally Advanced Thyroid Cancers 
 
Background 
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. This is because of the close proximity of the 
thyroid gland to important structures of the aero-digestive tract, like the larynx, trachea, 
esophagus and the recurrent laryngeal nerve. In a disease where life expectancy is good 
despite recurrences, quality of life is greatly compromised by repeated salvage surgeries 
with resection of parts of the aero-digestive tract. 
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.1-4  
The revised ATA (American Thyroid Association) guidelines (2009) recommend use of 
radiotherapy in patients with gross extrathyroidal disease. 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. 

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3. There is no data regarding toxicity of adjuvant RT in any of these studies in any of 
these studies as most have been retrospective in nature.  
As a result, the use of radiotherapy has not become a common clinical practice and 
standard of care, reflecting a lack of prospective data on toxicity and loco-regional 
control in locally advanced thyroid cancers.  
We therefore plan to perform a Phase II randomized controlled trial looking at loco-
regional control and toxicity of adjuvant radiation in locally advanced high risk thyroid 
cancer after surgery with or without radio-iodine ablation. 
This study will help to define the role of this modality in management of thyroid cancer 
and provide prospective data on loco-regional recurrence and toxicity in this group of 
patients.   
 
Aims/Objectives 
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 or without 
radioiodine therapy 
Secondary aim: 
 To assess toxicity (early and late at 2 years) of adjuvant RT in these patients  
 
Design 
Phase II randomized study 
 
Setting 
Tertiary level comprehensive cancer care centre in Western India. 
 
Patients and methods 
All patients undergoing total thyroidectomy for locally advanced differentiated thyroid 
cancer presenting to our hospital will be considered for the study. 

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Inclusion criteria 
A) All patients of thyroid cancer (papillary/follicular/poorly differentiated) who have 
undergone total/completion thyroidectomy at our institute and having at least two of 
the following features (listed below) intra-operatively and/or on histopathology 
1. Gross extrathyroidal spread into soft tissues of the neck, trachea, esophagus, 
recurrent laryngeal nerve (constituting stage T4a) 
2. R1/ shave resections (minimal residual disease) 
3. R2 resections (gross residual disease) 
4. Multiple lymph nodes positive(>2) with perinodal extension at level VI 
B) Normal baseline haematological and biochemical parameters 
Exclusion criteria 
1. Anaplastic or medullary thyroid cancer 
2. Previous history of radiation 
3. Pregnancy 
4. < 18 years 
5. Patient unwilling to participate in the study 
 
Prescreening 
A detailed history including comorbid conditions and performance status of the patient 
will be recorded on presentation. A diagnosis of thyroid carcinoma (excluding anaplastic 
thyroid cancer) will be confirmed in our hospital and documented. 
Patients will have undergone routine surgery in the form of total thyroidectomy/ 
completion thyroidectomy with or without neck dissection, as is standard practice for 
thyroid cancer. If the histopathology report along with the intra-operative findings is 
suggestive of locally advanced thyroid cancer (as defined above), patients will be 
screened for the study (Eligibility checklist, annexure 3). Patients will be explained about 
the trial and written informed consent will be obtained (Informed Consent, annexure 2). 

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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. 
 
Trial schema 
 
Prescreening 
Patients undergoing total thyroidectomy 
for thyroid cancer  
Screening 
If patient has locally advanced thyroid cancer (see inclusion/exclusion 
criteria) 
Consent 
Post operative radiation after 
completion of RAI therapy 
Randomization 
(Differentiated thyroid cancers having 
received RAI therapy at 6-8 weeks) 
No treatment 

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Follow up assessment: 
Patients will be followed up three monthly for the first two years, and 6 monthly 
thereafter.  
 
Assessments for patients in RT arm: 
At completion of radiotherapy 
Clinical examination 
Acute toxicity reporting using toxicity criteria (CTC version 3) 
 
3 monthly 
Clinical examination only 
 
6 monthly 
Clinical examination 
USG neck 
Serum thyroglobulin 
Serum TSH 
 
Annually 
QOL EORTC questionnaire will be administered at baseline prior to start of RT and 
annually thereafter. 
 
 
At 2 years 
LENT SOMA late toxicity reporting 
Barium swallow 
 
Assessments of patients in observation arm: 
3 monthly 
Clinical examination only 
 
6 monthly 
Clinical examination 
USG neck 
Serum Thyroglobulin 
Serum TSH 
 
Annually 
QOL EORTC questionnaire 
 
Details of treatment 
Total thyroidectomy: 

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Total thyroidectomy will involve removal of both lobes of the thyroid gland along with 
central compartment clearance. Neck dissection can be added as merited by the stage 
of the thyroid cancer and as per tumor board decision. In recurrent cases, surgery as 
warranted by the disease extent (completion thyroidectomy, thyroid bed recurrence 
excision etc) will be done. 
 
Radio-Iodine treatment:  I-131 ablation of residual tissue will be undertaken using the 
standard approach that exists in our institute. All necessary standard precautions and 
measures for radiation will be adopted. The dosage of I-131 will be based on the sites 
and extent of uptake on the RAI scan, as is the practice in the institute. Locally advanced 
thyroid cancers are administered higher dose of I-131 based upon the extent of disease 
noted at surgery, residual disease after surgery and the histology. 
 
Radiotherapy details:  
Pre-treatment work-up: 
 Dental Care: 
Adequate and appropriate dental care will be given including extraction of carious teeth, 
application of fluoride gel etc.     
 Nutritional Support 
Pre-treatment nutritional counseling will be done. 
Weight reduction > 8%, feeding tube support is recommended  
 
Patient positioning and immobilization: 
Patients will be immobilized in the supine position, using a thermoplastic mask.  
Planning scan: Contrast enhanced planning CT scan of the area of interest with 3mm 
slices on a CT scanner that is networked to the treatment planning system 
 
Treatment volumes and doses: 

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1. Definition of target volumes: Planning target volumes (GTV and CTV) and organ 
at risk volumes will be contoured on each slice. 
 CTV:  Pre-op thyroid Bed 
Involved (+) lymph node areas as defined clinically, radiologically and pathologically 
Potential for subclinical or microscopic involvement 
Further divided into low risk and high risk levels according to dose levels 
High risk: (CTV1/ 56-60):  
Pre-op thyroid bed 
Involved neck nodes 
Low risk: (CTV2/ 50):  
Elective radiation of uninvolved bilateral lymph node regions, encompassing the central  
compartment and level VI nodes, if not already encompassed in CTV1  
 
2. Delineation of nodal CTV:  Various nodal levels will be delineated as per 
established guidelines for contouring. (RTOG, EORTC, DAHANCA guidelines) 
3. PTV:  
A minimum of .5 cm margin will be added to CTV to generate the corresponding PTV 
4. OAR: 
Spinal cord, larynx, brainstem, salivary glands, constrictor muscles, uninvolved oral 
mucosa, base of tongue, uninvolved upper airway 
PRV will be generated appropriately for spinal cord, with 3mm margin. 
 
Target delineation: An isometric margin of 5 mm to be provided to the CTV for final PTV 
and 3mm to organs at risk for planning organ at risk volume (PORV). The GTV will 
include only the primary and involved neck nodes. The delineation of the various 
volumes will be as per consensus guidelines. The priorities and constraints for IMRT plan 
will also be decided on a case to case basis  
 

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Prescription: The goal of the treatment plan would be to encompass the PTV subclinical 
disease with a dose of 54-60 Gy and the PTV of the gross disease with 70-74 Gy while 
sparing as much of the aforesaid critical structures as possible. 
The maximum permissible point doses to the spinal cord will be limited to 46 Gy. IMRT 
planning and delivery will be carried out on the Tomotherapy Hi Art System. 
 
Dose Specification for IMRT 
The prescription dose is the isodose which encompasses at least 95% of the planning 
target volume (PTV). No more than 5% of any planning target volume (PTV) will receive 
>107% of its prescribed dose. No more than 1% of any planning target volume (PTV) will 
receive <95% of its prescribed dose.  
Treatment will be delivered once daily, 5 fractions per week, over 7 weeks. All targets 
will be treated simultaneously. Breaks in treatment should be minimized. The reported 
doses for each PTV shall include the prescription dose as well as the maximum point 
dose, % target volume receiving > 103% and >105% of its prescribed dose and the % 
target volume receiving < 95% of the prescribed dose, and the mean dose to the PTV. 
 
Critical Normal Structures 
DVHs must be generated for all critical normal structures and the unspecified tissues. 
Dose constraints to normal tissues should be as follows: 
Brainstem 50 Gy 
Spinal cord 46 Gy 
Mandible 70 Gy 
Unspecified tissue outside the targets: < 110% of the prescribed dose to PTV70 
 
Planning Goals for IMRT: Salivary Glands 
Parotid glands: 
1) Mean dose to either parotid < 26 Gy or 
2) At least 50% of the either parotid gland will receive < 30 Gy or 

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3) At least 20 cc of the combined volume of both parotid glands will receive < 20Gy. 
 
Plan evaluation: Cumulative dose volume histograms (DVHs) will be computed for PTV 
and each PORV to assist in plan evaluation. Plans will be evaluated with respect to 
conformal avoidance of organs at risk, conformity index, homogeneity index and DVHs.  
 
Toxicity 
Acute toxicity will be assessed by physical examination, interim history and laboratory 
assessments. 
Radiotherapy related early toxicity will be recorded as per the National Cancer Institute 
Common Terminology Criteria (NCI CTC), version 3. These will be documented in the 
radiotherapy form of the CRF. Any Grade 3/4 toxicity will be considered an event. 
Late toxicity will be collected at the end of two years using the LENT SOMA scale for late 
toxicity. (Annexure 4) 
Details of adjuvant radiation treatment will be collected in the radiotherapy form of the 
CRF (Annexure 1) 
 
Statistical analysis and sample size calculation 
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.6 
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 
Delta- 23% decrease in loco-regional recurrence with the addition of adjuvant RT 
A two-sided log rank test with an overall sample size of 64 subjects (of which 32 are in 
group 1 and 32 are in group 2) achieves 80% power at a 0.05 significance level to detect 
a difference of 0.23 between 0.70 and 0.93--the proportions surviving in groups 1 and 2 
respectively. Patients will enter the study during an accrual period of 3 years. A follow-

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up period of 5 years is assumed to have 5% loss from group 1 and a 5% loss from group 
two. 
 
Stratification: Patients will be stratified as 
R2 vs. R1/R0 
 
Main research variables 
Primary end point 
Loco-regional recurrence 
Secondary endpoints 
1. Acute toxicity 
2. Late toxicity 
3. Quality of life 
 
Assessment of Endpoints 
Primary Endpoint 
Loco-regional control: Recurrence will be defined as presence of histologically proven 
(FNAC/Biopsy) thyroid cancer recurrence in  
a. Thyroid bed 
b. Lymph nodes at levels II-VI 
Tools used for this diagnosis: clinical examination, USG and FNAC 
 
Secondary endpoints 
1. Acute toxicity will be assessed using the CTC version 3 on a weekly basis till conclusion 
of RT. Patient will also be assessed at 3 months for acute toxicity 
2. Late toxicity: Using the LENT SOMA scale for late toxicity of radiotherapy 
Barium swallow will be done to assess strictures, swallowing dysfunction and 
penetration-aspiration score (PAS) at the end of two years 

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3. Quality of Life: This will be assessed using the QOL- HN35, QLQC 30 questionnaires. 
These will be administered at baseline (before starting RT) and at 1 and 2 years of 
completion of RT. 
 
Investigation time table for patients on RT arm 
 
 
Ethical Considerations: This study will be conducted in accordance with applicable laws 
and regulations including, the International Conference on Harmonization Guideline for 
Good Clinical Practice (GCP) and the ethical principles that have their origins in the 
Declaration of Helsinki. Patients will be consented using the HSRC/HEC approved ICF 
before any procedures specified in the protocol are performed. 
 
Investigations Pre-
Rx 
Week1 Week2 Week3 Week4 Week5 Week6 Week7 At 
conclusion 
of RT 
3mths 6mths 1yr 2yr 
Clinical exam 
x 
- 
- 
- 
- 
- 
- 
- 
x 
x 
x 
x 
x 
Toxicity 
scoring 
- 
x 
x 
x 
x 
x 
x 
x 
x 
x 
- 
- 
- 
Hemoglobin 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
WBC 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
S creatinine 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
S electrolytes 
x 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
S TSH 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
x 
x 
S Tg 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
x 
x 
USG neck 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
x 
x 
QOL 
questionnaire 
x 
- 
- 
- 
- 
- 
- 
- 
- 
x 
- 
x 
x 
Ba swallow 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
LENT SOMA 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
x 
- 
x 

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Discussion 
Thyroid cancer accounts for about 2% of all newly diagnosed cancers every year. An 
overwhelming majority of these (>90%) are differentiated cancers, consisting of 
papillary, follicular, or mixed papillary-follicular histologies. Moreover a large number of 
these are low to intermediate risk thyroid cancers, which in general have excellent 
outcome. The mainstay of treatment is surgery, complemented by radioactive remnant 
ablation as mandated by histology and clinical risk factors. 
 
A fraction of all thyroid cancers are high risk group, which are associated with a graver 
outlook, and are therefore presumably helped by intensification of adjuvant therapy. 
Management of the approximately 10% of patients presenting with locally advanced 
disease remains controversial. It is in these cancers, that the role of adjuvant 
radiotherapy (RT) may come into picture. 
 
Indications for adjuvant radiotherapy generally include high risk presentations involving 
local invasion or encasement of surrounding structures (e.g. trachea, esophagus, larynx, 
mediastinum, and/or great vessels) with evidence of residual microscopic or gross 
disease, especially if it is iodine non-avid. Support for the use of adjuvant RT in these 
scenarios comes from several studies which have shown that that curative dose of 
radiotherapy can reduce the 25–50% loco-regional recurrence rates reported for 
surgery alone. However, this data comes from retrospective studies, with variable 
inclusion criteria.1-4,6  
 
Furthermore, some older evidence suggests that adjuvant radiotherapy may not 
necessarily improve treatment outcomes especially in R2 resections. This has led to 
continuing controversy regarding the utility of adjuvant RT, especially for patients 
following their first surgical procedure and/or with microscopic residual disease. 
 

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Radiotherapy is associated with certain acute as well as long term toxicities, a fact that 
should be borne in mind, while incorporating this modality in treatment. Most of the 
literature reporting on adjuvant RT in thyroid cancers has not detailed the associated 
toxicity.  
 
We therefore endeavor to conduct a phase II randomised controlled trial to analyse the 
loco-regional control and toxicity in a well-defined group of advanced thyroid cancers. 
We believe that the results of our prospective study will help delineate our clinical 
policy towards these high risk thyroid cancers.  
 
Summary 
Adjuvant RT in advanced thyroid cancers has been investigated in numerous studies, all 
of which have unfortunately been retrospective. Some retrospective studies have had 
several matching inclusion criteria and have shown a benefit in loco-regional control 
with the addition of adjuvant radiotherapy. However a few older reports have reported 
no benefit with adjuvant RT. Any benefit obtained from the addition of adjuvant RT will 
have to be counterbalanced against the toxicity associated thereof. There is a need to 
conduct a prospective randomised trial evaluating the toxicity and the disease free 
survival advantage obtained from adjuvant RT in advanced thyroid cancers.  

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References: 
1. 
Ford D, Giridharan S, McConkey C, Hartley A, Brammer C, Watkinson JC, et al. 
External beam radiotherapy in the management of differentiated thyroid cancer. Clin 
Oncol (R Coll Radiol) 2003;15(6):337-41. 
2. 
Terezakis SA, Lee KS, Ghossein RA, Rivera M, Tuttle RM, Wolden SL, et al. Role 
of external beam radiotherapy in patients with advanced or recurrent nonanaplastic 
thyroid cancer: Memorial Sloan-kettering Cancer Center experience. International 
journal of radiation oncology, biology, physics 2009;73(3):795-801. 
3. 
Schwartz DL, Lobo MJ, Ang KK, Morrison WH, Rosenthal DI, Ahamad A, et al. 
Postoperative external beam radiotherapy for differentiated thyroid cancer: 
outcomes and morbidity with conformal treatment. International journal of radiation 
oncology, biology, physics 2009;74(4):1083-91. 
4. 
Brierley J, Tsang R, Panzarella T, Bana N. Prognostic factors and the effect of 
treatment with radioactive iodine and external beam radiation on patients with 
differentiated thyroid cancer seen at a single institution over 40 years. Clinical 
endocrinology 2005;63(4):418-27. 
5. 
Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Revised 
American Thyroid Association management guidelines for patients with thyroid 
nodules and differentiated thyroid cancer. Thyroid : official journal of the American 
Thyroid Association 2009;19(11):1167-214. 
6. 
Farahati J, Reiners C, Stuschke M, Muller SP, Stuben G, Sauerwein W, et al. 
Differentiated thyroid cancer. Impact of adjuvant external radiotherapy in patients 
with perithyroidal tumor infiltration (stage pT4). Cancer 1996;77(1):172-80.