The EORTC module for quality of life in patients with … · tumours often do not survive 6 months...

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DOI: 10.1530/ERC-16-0530http://erc.endocrinology-journals.org © 2017 Society for Endocrinology

Printed in Great BritainPublished by Bioscientifica Ltd.

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S Singer et al. EORTC QLQ-THY phase III

10.1530/ERC-16-0530

The EORTC module for quality of life in patients with thyroid cancer: phase III

Susanne Singer1,2, Susan Jordan3, Laura D Locati4, Monica Pinto5, Iwona M Tomaszewska6, Cláudia Araújo7, Eva Hammerlid8, E Vidhubala9, Olga Husson10, Naomi Kiyota11, Christine Brannan12, Dina Salem13, Eva M Gamper14, Juan Ignacio Arraras15, Georgios Ioannidis16, Guy Andry17, Johanna Inhestern18, Vincent Grégoire19, Lisa Licitra4 on behalf of the EORTC Quality of Life Group, the EORTC Head and Neck Cancer Group, and the EORTC Endocrine Task Force

1Institute of Medical Biostatistics Epidemiology and Informatics (IMBEI), University Medical Center Mainz, Mainz, Germany2University Cancer Centre, Mainz, Germany3QIMR Berghofer Medical Research Institute, Herston, Australia4Head & Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy5Rehabilitation Unit, Department of Quality of Life, Istituto Nazionale per lo Studio e la Cura dei Tumori ‘Fondazione Giovanni Pascale’ – IRCCS, Naples, Italy6Department of Medical Education, Jagiellonian University Medical College, Krakow, Poland7Service of Surgical Oncology, Instituto Português do Oncologia do Porto Francisco Gentil, Porto, Portugal8Department of Otolaryngology and Head and Neck Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden9Department of Psycho-Oncology, Resource Centre for Tobacco Control, Cancer Institute (WIA), Chennai, Tamil Nadu, India10Department of Medical Psychology, Radboud University Medical Center, Nijmegen, The Netherlands11Department of Medical Oncology and Hematology, Kobe University Hospital, Kobe, Japan12Mount Vernon Cancer Centre, East & North Herts NHS Trust, Northwood, London, UK13Clinical Oncology, Faculty of Medicine, Ain Shams University, Cairo, Egypt14Department of Nuclear Medicine, Medical University of Innsbruck, Innsbruck Institute of Patient-Centred Outcome Research, Innsbruck, Austria15Oncology Departments, Complejo Hospitalario de Navarra, Pamplona, Spain16Oncology Department, Nicosia General Hospital, Nicosia, Cyprus17Surgery Department, Jules Bordet Institute, Brussels, Belgium18Clinic of Otorhinolaryngology, Jena University Hospital, Jena, Germany19Department of Radiation Oncology, Institut de Recherche Experimentale et Clinique, Université Catholique de Louvain, St-Luc University Hospital, Brussels, Belgium

Abstract

The purpose of the study was to pilot-test a questionnaire measuring health-

related quality of life (QoL) in thyroid cancer patients to be used with the European

Organisation for Research and Treatment of Cancer (EORTC) core questionnaire EORTC

QLQ-C30. A provisional questionnaire with 47 items was administered to patients

treated for thyroid cancer within the last 2 years. Patients were interviewed about

time and help needed to complete the questionnaire, and whether they found the

items understandable, confusing or annoying. Items were kept in the questionnaire

if they fulfilled pre-defined criteria: relevant to the patients, easy to understand, not

confusing, few missing values, neither floor nor ceiling effects, and high variance.

A total of 182 thyroid cancer patients in 15 countries participated (n = 115 with papillary,

244

197–207

Correspondence should be addressed to S Singer Email [email protected]

Key Words

f thyroid cancer

f quality of life

f papillary

f follicular

f medullary

f anaplastic

f patient-reported outcomes

http://dx.doi.org/10.1530/ERC-16-0530

mailto:[email protected]

AUTHOR COPY ONLY198Research S Singer et al. EORTC QLQ-THY phase III

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n = 31 with follicular, n = 22 with medullary, n = 6 with anaplastic, and n = 8 with other

types of thyroid cancer). Sixty-six percent of the patients needed 15 min or less to

complete the questionnaire. Of the 47 items, 31 fulfilled the predefined criteria and

were kept unchanged, 14 were removed, and 2 were changed. Shoulder dysfunction

was mentioned by 5 patients as missing and an item covering this issue was added. To

conclude, the EORTC quality of life module for thyroid cancer (EORTC QLQ-THY34) is

ready for the final validation phase IV. Endocrine-Related Cancer (2017) 24, 197–207

Introduction

While thyroid cancer is one of the less common malignancies with an age-standardised rate in Europe of 6.3 per 100,000 per year (3.1 in men and 9.3 in women) (Ferlay et al. 2013), the incidence rates have been rising rapidly in many countries (Amphlett et al. 2013, Husson et al. 2013b, Radespiel-Troger et al. 2014, Carlberg et al. 2016, Morris et al. 2016). Papillary and follicular thyroid cancers have a very good prognosis with 20-year relative survival rates of 95% (Brenner 2002) but the rarer medullary cancers have 10-year survival rates of 75–85% (Pacini et al. 2010, Brown et al. 2011, Wu et al. 2012), and patients with (very rare) anaplastic tumours often do not survive 6 months after diagnosis (Brown et al. 2011).

The current standard anti-neoplastic treatment comprises surgery, radioactive iodine (RAI) ablation, radiotherapy and medical therapy, including thyroxine, tyrosine kinase inhibitors and chemotherapy, according to the stage and histological type of the disease. Both disease and treatment can have profound effects on the patients’ quality of life (QoL) (Husson et al. 2011, Gamper & Sztankay 2015, Applewhite et al. 2016).

The most common and significant complications of total thyroidectomy and neck dissection are long-term hypoparathyroidism leading to hypocalcaemia and injury at the laryngeal nerve and its branches leading to vocal cord paresis and voice changes (Ryu et al. 2013). Potential long-term side effects of RAI include xerostomia, nasolacriminal duct stenosis, bone marrow and gonadal deficiency (Husson et al. 2011). Temporary TSH stimulation along with radioiodine ablation as a preparation for radioiodine whole-body imaging and serum thyroglobulin (Tg) measurements can result in severe fatigue, neurological deficiencies, reduced appetite, memory problems and depression (Dow et al. 1997, Gamper et al. 2015). Potential side effects of TSH-suppressive doses of levothyroxine are cardiac tachyarrhythmias, bone demineralisation

and symptoms of hyperthyroidism. With the use of recombinant human thyroid-stimulating hormone (rhTSH), compared with conventional thyroid hormone withdrawal, fewer symptoms occur (Taieb et al. 2009, Lee et al. 2010). However, this treatment is expensive compared to hormone withdrawal and is not administered in all institutions and countries.

Several multi-targeted tyrosine kinase inhibitors (TKI) are currently available for advanced-stage medullary thyroid cancer and radioiodine-refractory papillary and follicular thyroid carcinomas. Their use is commonly associated with a wide range of toxicities that can significantly affect QoL, including hypertension, skin rash and gastrointestinal adverse events (Krajewska et al. 2015, Schlumberger et al. 2015).

Despite this, clinicians sometimes assume that, due to the good prognosis, thyroid cancer patients have less distress than other cancer patients, and that QoL is comparable to the general population as long as patients do not have to undergo thyroxine withdrawal (Dow et al. 1997, Borget et al. 2007). Whilst some studies have found that those with thyroid cancer generally have a QoL that is comparable to people in the general population (Crevenna et al. 2003, Schroeder et al. 2006), others have reported an impaired QoL (Botella-Carretero et al. 2003, Bianchi et al. 2004, Tagay et al. 2005, Tan et al. 2007, Hoftijzer et al. 2008, Singer et al. 2012, Applewhite et al. 2016).

A key weakness of most studies to date has been a lack of specific questionnaires for thyroid-related problems and functioning. Assessments have been done largely using generic instruments. Only few thyroid-specific QoL questionnaires were developed (Dow et al. 1997, Husson et al. 2013a). The European Organisation for Research and Treatment of Cancer (EORTC) therefore created a thyroid-cancer-specific module to be used as a supplement of the quality-of-life core questionnaire EORTC QLQ-C30 (phase I and II of the EORTC



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module development process (Johnson et al. 2011)). This (provisional) module was developed based on two systematic reviews and structured interviews with 110 patients and 57 health care professionals (Singer et al. 2016). In these previous phases, items were derived from a longer list of QoL issues that could be relevant for thyroid cancer patients. The patients and health care professionals rated these issues for relevance and importance, resulting in a list of 47 items with the most important and relevant QoL issues.

The present study was set up to pilot-test this list, representing phase III of the instrument development according to the EORTC module development guidelines (Johnson et al. 2011).

Methods

Study design

The module was pilot-tested in a multi-national cross-sectional study according to the EORTC module development guidelines (Johnson et al. 2011). Patients were eligible if they fulfilled the following criteria: histologically verified thyroid cancer (International Classification of Diseases, version 10, code C73), treatment for thyroid cancer within the last two years, ability to understand and complete the questionnaire (language proficiency and cognitive functioning as judged by the local study coordinator upon inclusion), age 18 years or above, and written informed consent. Patients could be on or off treatment.

Consecutive patients attending the collaborating institutions were screened for eligibility and asked to participate. The enrolment was monitored monthly by the principal investigator and fed back to the collaborators. We tried to maximise the heterogeneity of the sample in terms of histology, tumour stage and country. Thus, patients with papillary, follicular, medullary and anaplastic cancer were included. Additionally, we aimed to interview at least 15 patients from each of the following cultural areas: Central Europe, Southern Europe, Northern Europe, Eastern Europe, Western Europe, Asia and Australia. As the study evolved, we monitored whether there were sufficient patients in each group. Thereafter, additional patients were enrolled only in groups where patient numbers had not reached our target. We aimed to include 150 patients, including 60 with papillary, 50 with follicular, 30 with medullary and 10 with anaplastic cancer,

in order to create a sample with a good representation of both the rarer and the more frequent types of thyroid cancer.

Data collection

The provisional questionnaire was completed by the patients together with the EORTC QLQ-C30. The questionnaires were administered in the native language of the individual patient. They had been translated beforehand via forward and backward translations according to the EORTC translation guidelines (Dewolf et al. 2009) and coordinated by the EORTC translation unit.

In a debriefing interview, participants were asked whether any item was difficult for them to understand or upsetting, how much time they needed to complete the questionnaire and whether they required any help with it. They were requested to name the most important items they would like to have included in the questionnaire, and to indicate items they found irrelevant. If the questionnaire was lacking a certain item, it was written down using the patients’ wording.

Socio-demographic (age, gender, education) and clinical characteristics (histology, tumour stage, time since diagnosis, treatment, Karnofsky performance status, thyroid hormone status) were documented on case report forms by the interviewer. All clinical data were obtained from the patients’ medical charts.

All procedures performed were in accordance with the ethical standards of the institutional research committees and with the 1964 Helsinki declaration and its later amendments of comparable ethical standards. The study protocol was approved by the local ethical committees in each country. The approval of the principal investigator’s institution was granted on 18 December 2014 (# 837.470.14, 9709). Informed consent was obtained from all individual participants included in the study. The study was registered at the EORTC Quality of Life Group (# EORTC QLQ-THY_Phase III).

Statistical analysis

We calculated frequencies of all item responses together with their range and mean and the percentage of missing values per scale. We counted how often a certain item was mentioned to be upsetting, difficult to understand, relevant, or irrelevant.



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The pre-defined criteria for keeping an item in the questionnaire (according to the EORTC module development guidelines (Johnson et al. 2011)) were: (1) importance (mean >1.5; items had a response format 1–4), (2) prevalence (scores 3 or 4 >50%), (3) neither floor nor ceiling effect (responses 1 or 2 and 3 or 4 >10%, respectively), (4) variance (responses range from 1 to 4), (5) acceptance (<5% of patients stated that the item was upsetting), (6) clarity (<5% of patients stated that the items was difficult to understand), (7) compliance (>95% of the patients completed the item), and (8) relevance (>10% of the patients mentioned the item as especially relevant).

The items were grouped into hypothesised scales, and Cronbach’s alpha and scaling error (percentage of items that correlate higher with a different scale than with its own scale, corrected for overlap) were calculated. If items worked well together in a scale, it was another criterion for keeping them in the questionnaire. It should be noted that these psychometric tests are preliminary and that the final psychometric testing will be done in phase IV of this module development.

We tabulated the results per item together with the number of fulfilled criteria. A multi-national multi-professional group of experts then discussed the results and decided on keeping, removing or changing items. An item was kept when most criteria were fulfilled and the patients had assessed it as relevant. An item was removed when few criteria were fulfilled and only few patients had mentioned the item as highly relevant. An item was changed if it was considered relevant by the patients but at the same time difficult to understand or upsetting. According to the EORTC module development guidelines (Johnson et al. 2011), the group of experts could decide to keep an item even if few criteria were fulfilled when they had sound justification, e.g. when the item was highly relevant to a sub-group of patients.

Relevant issues that participants suggested relevant but were lacking from the questionnaire were translated into English (where necessary), similar issues were grouped together and the number of issues was counted. If a new issue was mentioned by at least 5 patients it was added to the module. If items needed to be changed or added, we searched the EORTC item-library and used existing validated items if available.

We calculated the average time it took to complete the questionnaires and how often help was needed to complete the questionnaires.

Data entry, cleaning and analysis were conducted using STATA (Stata Statistical Software, release 12; StrataCorp, College Station, TX, USA).

Results

Sample characteristics

A total of 182 patients participated in the study; n = 115 with papillary, n = 31 with follicular, n = 22 with medullary, n = 6 with anaplastic and n = 8 with another type of thyroid cancer (Table 1). They were enrolled from 17 institutions in 15 countries (n = 37 from Italy, n = 25 Australia, n = 17 Poland, n = 14 Portugal, n = 13 Germany, n = 13 India, n = 13 Sweden, n = 11 the Netherlands, n = 9 Japan, n = 9 the United Kingdom, n = 7 Egypt, n = 4 Austria, n = 4 Spain, n = 3 Belgium, and n = 3 Cyprus). The median time since diagnosis was 0.8 years. The majority (96%) had a Karnofsky performance status of 70 or higher.

Table 1 Sample characteristics (n = 182).

Number Percent (%)

Age (in years) <40 41 23 40–49 32 18 50–59 35 19 60–69 39 21 70–79 31 17 80+ 3 2 Unknown 1 1Sex Male 60 33 Female 122 67Education Compulsory or less 55 30 Post-compulsory 70 38 University 53 29 Unknown 4 2Histology Papillary 115 63 Follicular 31 17 Medullary 22 12 Anaplastic 6 3 Other 8 4Tumour stage T1 50 27 T2 38 21 T3 49 27 T4a 21 12 T4b 6 3 Tx 15 8 Unknown 2 1 N0 85 47 N1a 30 16 N1b 33 18 Nx 31 17 Unknown 3 2 M0 124 68 M1 25 14 Mx 32 18



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Table 2 Treatment received by the participants.

Number

Percent (%)

Surgery None 3 2 Hemithyroidectomy 12 7 Partial thyroidectomy 3 2 Total thyroidectomy 161 88 Unknown 3 2Neck dissection No 91 50 Yes 77 42 Unknown 14 8Radioactive

iodine therapyCurrently receiving this

treatment0 0

Last treatment <6 m before interview

35 19

Last treatment ≥6 m before interview

65 36

Never/not yet 79 43 Unknown 3 2Chemotherapy Currently receiving this

treatment0 0


7 4


2 1

Never/not yet 167 92 Unknown 6 3Tyrosine kinase

inhibitorsCurrently receiving this

treatment9 5


2 1


1 1

Never/not yet 164 90 Unknown 6 3

Most of the participants (88%) had had a total thyroidectomy (Table 2), and 55% had been treated with radioactive iodine therapy.

In 42 cases (23%), participants had vocal cord impairment and 29 cases (16%) had parathyroid insufficiency as a result of treatment, transient or permanent.

Time and help needed to complete the questionnaire

A total of 121 patients (66%) needed 15 min or less to complete the questionnaire. Most patients (n = 137, 75%) completed it on their own while it was administered orally in 37 (20%) patients, in n = 8 (4%) the method of administration was not documented.

The majority of patients (n = 109, 60%) required no help, 16% required practical help (such as reading out loud if the patient missed his glasses), 12% required supportive help (such as silently sitting next to the patient while he completes the questionnaire), 7% needed explanations

to help them understand the questions, and in 5% no information about help needed was provided (Table 3).

Evaluation of items

Thirty items could be meaningfully combined to scales with Cronbach’s alpha >0.70 and with a decrease of alpha when the item was removed. The hypothesised scales were: anxiety, body image, cramps, discomfort in the head and neck, dry mouth, fatigue, hair, impact on job or education, joint pain, neuropathological problems, restlessness, shoulder functioning, social support, swallowing, temperature tolerance, voice, and worries about important others.

A total of 34 items fulfilled criterion 1 (mean >1.5). Only one item satisfied criterion 2 (scores 3 and 4 >50%), 38 items fulfilled criterion 3, i.e. they had neither floor nor ceiling effects. In all 47 items, the full range of response categories had been used (criterion 4). All items were well accepted by the patients both regarding criterion 5 (found upsetting by less than 5%) and criterion 6 (found difficult to understand by less than 5%). Nearly all items (n = 45) were completed by >95% of the patients (criterion 7). A minimum of 5 out of these 7 criteria were fulfilled by 38 items (Table 4 for details).

Additional items

The patients mentioned 44 issues they felt were missing in the core questionnaire plus module. Shoulder dysfunction

Table 3 Time and help required for completing the

questionnaire.

Number

Percent (%)

Duration (min) <10 54 30 11–15 67 37 16–20 33 18 21–30 12 7 >30 6 3 Unknown 10 5Form of administration Self-completed 137 75 Orally 37 20 Unknown 8 4Type of help required No help required 109 60 Practical help

required30 16

Supportive help required

21 12

Help with understanding the questionnaire

13 7

Unknown 9 5



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Table 4 Item pilot testing. Results per item, fulfilled criteria and decision by expert group based on the results.

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q 31 Have you had sudden attacks of tiredness? 0.85 0.80 1 2.0 1 0.27 0 0.73 1 1–4 1 0.00 1 0.01 1 1.00 1 6 1 0.14 0.01 1 1 1 1 keepq 32 Have you felt mentally exhausted? 0.85 0.81 1 1.9 1 0.23 0 0.76 1 1–4 1 0.00 1 0.01 1 0.99 1 6 1 0.16 0.02 1 1 1 1 keepq 33 Have you felt physically exhausted? 0.85 0.77 1 2.0 1 0.29 0 0.71 1 1–4 1 0.00 1 0.01 1 0.99 1 6 1 0.15 0.01 1 1 1 1 keepq 34 Has your sleep pattern been disrupted? n.a. 0 1.9 1 0.26 0 0.74 1 1–4 1 0.00 1 0.00 1 1.00 1 6 1 0.08 0.00 0 1 0 0 removeq 35 Have you felt refreshed when waking up? 0.85 0.87 0 2.9 1 0.64 1 0.35 1 1–4 1 0.01 1 0.03 1 0.99 1 7 1 0.05 0.00 0 1 0 0 removeq 36 Have you had pain in your throat? 0.71 0.60 1 1.5 0 0.12 0 0.88 1 1–4 1 0.00 1 0.01 1 1.00 1 5 1 0.05 0.01 0 1 0 1 keepq 37 Have you had any discomfort in your neck? 0.71 0.66 1 1.9 1 0.24 0 0.76 1 1–4 1 0.00 1 0.00 1 1.00 1 6 1 0.10 0.01 0 1 0 1 keepq 38 Have you had problems breathing? n.a. 0 1.3 0 0.05 0 0.95 0 1–4 1 0.00 1 0.01 1 1.00 1 4 0 0.05 0.01 0 0 0 0 removeq 39 Have food and drink tasted different from usual? n.a. 0 1.3 0 0.09 0 0.91 0 1–4 1 0.00 1 0.00 1 1.00 1 4 0 0.04 0.03 0 0 0 0 removeq 40 Have you had problems talking to other people because of your voice? 0.91 0.89 1 1.5 1 0.14 0 0.86 1 1–4 1 0.00 1 0.00 1 1.00 1 6 1 0.08 0.02 0 1 0 1 removeq 41 Have you had problems with hoarseness? 0.91 0.90 1 1.6 1 0.17 0 0.83 1 1–4 1 0.00 1 0.02 1 1.00 1 6 1 0.08 0.01 0 1 0 1 keepq 42 Has your voice sounded different as a result of your disease or treatment? 0.91 0.88 1 1.8 1 0.20 0 0.79 1 1–4 1 0.00 1 0.00 1 0.99 1 6 1 0.10 0.01 0 1 0 1 keepq 43 Have you had a tired voice? 0.91 0.90 1 1.7 1 0.20 0 0.79 1 1–4 1 0.00 1 0.01 1 0.99 1 6 1 0.09 0.01 0 1 0 1 keepq 44 Have you had thin or lifeless hair as a result of your disease or treatment? 0.90 0.83 1 1.6 1 0.20 0 0.80 1 1–4 1 0.00 1 0.01 1 1.00 1 6 1 0.07 0.08 0 1 0 1 keepq 45 Have you lost any hair? 0.90 0.84 1 1.6 1 0.15 0 0.85 1 1–4 1 0.00 1 0.01 1 1.00 1 6 1 0.05 0.07 0 1 0 1 keepq 46 If you have lost any hair: Have you been upset by the loss of your hair? 0.90 0.89 1 2.0 1 0.28 0 0.72 1 1–4 1 0.01 1 0.00 1 0.43 0 5 1 0.06 0.04 0 1 0 1 removeq 47 Have you had problems swallowing liquids? 0.82 0.73 1 1.3 0 0.07 0 0.92 0 1–4 1 0.00 1 0.00 1 0.99 1 4 0 0.05 0.02 0 0 0 0 removeq 48 Have you had problems swallowing pureed food? 0.82 0.71 1 1.2 0 0.03 0 0.95 0 1–4 1 0.00 1 0.00 1 0.98 1 4 0 0.05 0.02 0 0 0 0 removeq 49 Have you had problems swallowing solid food? 0.82 0.85 0 1.4 0 0.10 0 0.89 0 1–4 1 0.00 1 0.00 1 0.99 1 4 0 0.08 0.01 0 0 0 0 keepa

q 50 Have you had a dry mouth? n.a. 0 1.8 1 0.20 0 0.78 1 1–4 1 0.00 1 0.00 1 0.98 1 6 1 0.07 0.01 0 1 0 0 keepq 51 Have you had problems tolerating heat or cold? n.a. 0 1.8 1 0.24 0 0.75 1 1–4 1 0.00 1 0.00 1 0.99 1 6 1 0.10 0.00 0 1 0 0 keepq 52 Have you felt physically less attractive as a result of your disease or treatment? n.a. 0 1.6 1 0.15 0 0.84 1 1–4 1 0.01 1 0.01 1 0.99 1 6 1 0.07 0.02 0 1 0 0 keepq 53 Have you felt restless or agitated? 0.66 1 1.8 1 0.22 0 0.77 1 1–4 1 0.00 1 0.00 1 0.99 1 6 1 0.07 0.01 0 1 0 1 keepq 54 Have you had a rapid heartbeat? 0.66 1 1.5 0 0.10 0 0.89 1 1–4 1 0.00 1 0.00 1 0.99 1 5 1 0.07 0.02 0 1 0 1 keepq 55 Have you worried about your ability to have children? n.a. 0 1.2 0 0.06 0 0.88 0 1–4 1 0.00 1 0.01 1 0.95 0 3 0 0.03 0.06 0 0 0 0 removeq 56 Have you had pain in your shoulder? n.a. 0 1.8 1 0.23 0 0.77 1 1–4 1 0.00 1 0.01 1 1.00 1 6 1 0.04 0.03 0 1 0 0 changeb

q 57 Have you felt as though there was a knot in your throat? 0.71 0.62 1 1.6 1 0.15 0 0.85 1 1–4 1 0.00 1 0.01 1 0.99 1 6 1 0.09 0.01 0 1 0 1 keepq 58 Have you worried about a possible recurrence of the disease? 0.53 0.59 0 2.3 1 0.38 0 0.61 1 1–4 1 0.02 1 0.01 1 0.99 1 6 1 0.15 0.00 1 1 1 0 keepq 59 Have you worried about having to come off your thyroid hormone tablets? 0.53 0.34 1 1.4 0 0.10 0 0.85 1 1–4 1 0.01 1 0.04 1 0.95 1 5 1 0.03 0.03 0 1 0 1 changeq 60 Have you worried about having to take drugs for the rest of your life? 0.53 0.36 1 1.6 1 0.15 0 0.85 1 1–4 1 0.00 1 0.01 1 1.00 1 6 1 0.06 0.03 0 1 0 1 keepq 61 Has weight gain been a problem for you? n.a. 0 1.8 1 0.21 0 0.76 1 1–4 1 0.00 1 0.03 1 0.97 1 6 1 0.07 0.03 0 1 0 0 removeq 62 Has weight loss been a problem for you? 0.75 1 1.2 0 0.05 0 0.93 0 1–4 1 0.00 1 0.03 1 0.98 1 4 0 0.04 0.03 0 0 0 0 removeq 63 Have you worried about losing weight? 0.75 1 1.3 0 0.08 0 0.91 0 1–4 1 0.00 1 0.00 1 0.99 1 4 0 0.03 0.03 0 0 0 0 removeq 64 Have you had pain in your joints? n.a. 0 2.0 1 0.28 0 0.72 1 1–4 1 0.00 1 0.01 1 1.00 1 6 1 0.06 0.02 0 1 0 0 keepc

q 65 Have you had problems with your teeth? n.a. 0 1.5 1 0.12 0 0.87 1 1–4 1 0.00 1 0.00 1 0.99 1 6 1 0.03 0.03 0 1 0 0 removeq 66 Have you had tingling or numbness in your fingers or toes? 0.66 1 1.6 1 0.14 0 0.85 1 1–4 1 0.00 1 0.01 1 0.99 1 6 1 0.06 0.07 0 1 0 1 keepq 67 Have you had tingling or numbness around your mouth? 0.66 1 1.2 0 0.04 0 0.96 0 1–4 1 0.00 1 0.01 1 0.99 1 4 0 0.03 0.06 0 0 0 0 keepq 68 Have you had any muscle cramps? n.a. 0 1.6 1 0.19 0 0.80 1 1–4 1 0.00 1 0.01 1 0.99 1 6 1 0.04 0.04 0 1 0 0 keepd

q 69 Have you found it upsetting to see those close to you distressed as a result of your disease or treatment? 0.91 0.90 1 1.9 1 0.26 0 0.73 1 1–4 1 0.03 1 0.01 1 0.99 1 6 1 0.12 0.02 1 1 1 1 keepq 70 Have you worried about the future of people who are important to you? 0.91 0.90 1 2.3 1 0.36 0 0.62 1 1–4 1 0.03 1 0.02 1 0.97 1 6 1 0.11 0.02 1 1 1 1 keepq 71 Have you worried about disrupting the lives of those close to you? 0.91 0.87 1 2.2 1 0.37 0 0.61 1 1–4 1 0.04 1 0.02 1 0.98 1 6 1 0.10 0.01 1 1 1 1 removee

q 72 Have you worried how those close to you will cope with your illness and treatment? 0.91 0.88 1 2.1 1 0.32 0 0.66 1 1–4 1 0.03 1 0.01 1 0.98 1 6 1 0.12 0.01 1 1 1 1 keepq 73 Have you worried that you will be a burden to others? 0.91 0.90 1 2.1 1 0.32 0 0.66 1 1–4 1 0.02 1 0.01 1 0.99 1 6 1 0.10 0.01 1 1 1 1 keepq 74 Have you had any problems with your job or your education because of your disease or treatment? n.a. 0 1.7 1 0.18 0 0.80 1 1–4 1 0.00 1 0.01 1 0.97 1 6 1 0.09 0.02 0 1 0 0 keepq 75 Have you felt supported by your doctors? 0.84 0.70 1 1.8 1 0.19 0 0.79 1 1–4 1 0.01 1 0.02 1 0.98 1 6 1 0.18 0.01 1 1 1 1 keepq 76 Have you felt supported by other health care professionals (e.g. nurse)? 0.84 0.71 1 1.9 1 0.21 0 0.75 1 1–4 1 0.01 1 0.02 1 0.96 1 6 1 0.12 0.01 1 1 1 1 keepq 77 Have you felt supported by your family members or friends? 0.84 0.87 0 1.5 0 0.12 0 0.86 1 1–4 1 0.00 1 0.01 1 0.98 1 5 1 0.14 0.00 1 1 1 0 keep

akeep because of anaplastic patients, add “choked when swallowing”; bchange in: dysfunction in the shoulder; cbecause of TKI; dbecause of TKI; etoo many items on the same issue



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was mentioned 5 times, face and neck sensitivity 3 times, and menstruation problems 2 times (Table 5).

Decision on items

The multi-professional group of experts decided, based on the pre-defined criteria and on clinical experience, to

remove 14 items, keep 31, change 2 and add 1, resulting in 34 items (Table 6). Two of these new items were taken from the EORTC item-library, one item was re-worded. This item was discussed in detail in the group and was changed because patients found it important, but difficult to understand. The experts decided to add more information so that patients would better understand the

Table 5 Issues mentioned as missing by the participants.

Topic

Missing issue

Frequency of mentioning

Shoulder Shoulder dysfunction 5 Upper limb pain and function 1Eyes Eyesight impaired 1 Dry eyes 1 Bilateral lacrimation 1 Problems with light 1 Painful and dry eyes 1Hearing Understanding surroundings and

doctors1

Deafness 1Cognition Executive/cognitive functioning 1 Memory loss 1 Problems with finding words 1Sensitivity Face and neck sensitivity 3Menstruation Menstruation problems 2Pain Headaches/migraine 1 Muscle pain 1 Joint pain 1Emotional Need to defend oneself against

the opinion that thyroid cancer is not a serious disease

1

Pressures of work 1 Need for further treatment 1 Dependent on thyroid

medication1

Stress 1 Positive lifestyle change after

cancer1

Information Information tends to be mainly for women, not men

1

To understand information given before operation

1

Financial problems

Cost of expensive investigations, how to solve financial problems

1

Effect of disease on financial situation

1

Body image Aesthetics 1 Scars left by treatment 1Fatigue Stamina 1Other Sexual functioning, relationship

with the husband1

Skin problems (dry, psoriasis) 1 Stomach and intestine problems 1 Metastatic disease questions

missing1

Over-reactive mucosa 1 Satisfaction with treatment plan 1 Timing of diagnosis and stay of

treatment1

Table 6 The items of the EORTC QLQ-THY34.

q 31 Have you had sudden attacks of tiredness?q 32 Have you felt mentally exhausted?q 33 Have you felt physically exhausted?q 34 Have you had pain in your throat?q 35 Have you had any discomfort in your neck?q 36 Have you had problems with hoarseness?q 37 Has your voice sounded different as a result of your

disease or treatment?q 38 Have you had a tired voice?q 39 Have you had thin or lifeless hair as a result of your

disease or treatment?q 40 Have you lost any hair?q 41 Have you had problems swallowing solid food?q 42 Have you choked when swallowing?q 43 Have you had a dry mouth?q 44 Have you had problems tolerating heat or cold?q 45 Have you felt physically less attractive as a result of your

disease or treatment?q 46 Have you felt restless or agitated?q 47 Have you had a rapid heartbeat?q 48 Have you had problems raising your arm or moving it

sideways?q 49 Have you felt as though there was a knot in your

throat?q 50 Have you worried about a possible recurrence of the

disease?q 51 Have you worried about having to come off your

thyroid hormone replacement tablets to prepare for a radioiodine body scan or radioiodine treatment?

q 52 Have you worried about having to take drugs for the rest of your life?

q 53 Have you had pain in your joints?q 54 Have you had tingling or numbness in your fingers or

toes?q 55 Have you had tingling or numbness around your

mouth?q 56 Have you had any muscle cramps?q 57 Have you found it upsetting to see those close to you

distressed as a result of your disease or treatment?q 58 Have you worried about the future of people who are

important to you?q 59 Have you worried how those close to you will cope with

your illness and treatment?q 60 Have you worried that you will be a burden to others?q 61 Have you had any problems with your job or your

education because of your disease or treatment?q 62 Have you felt supported by your doctors?q 63 Have you felt supported by other health care

professionals (e.g. nurse)?q 64 Have you felt supported by your family members or

friends?



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item, even though it resulted in a rather lengthy question: ‘Have you worried about having to come off your thyroid hormone replacement tablets to prepare for a radioiodine body scan or radioiodine treatment?’. This new item was subsequently translated into the several languages used in this study. This process was coordinated by the EORTC translation unit. The item mentioned as missing by the patient (‘shoulder dysfunction’) was taken from the item-library, the wording is ‘Have you had problems raising your arm or moving it sideways?’.

Patients treated with tyrosine kinase inhibitors (TKI)

In the sample, there were 9 patients who received TKIs at the time of the study and 3 had received it previously. Hence, 12 patients (7%) had received TKI treatment. Since they are often treated for long periods of time, we did some additional analyses for this group. We found that the ranking of the mean was similar in patients with and without TKI. However, the TKI patients reported more frequently problems with thin or lifeless hair (mean 1.9). Hair loss was rated as relevant by 2 of the patients. Compliance rates per item were similar to the entire sample. When asked for what items they missed from the questionnaire, the majority (n = 11) said nothing was missing. One patient said the only problem for her was that she always ruminates about being dependent on medication.

Discussion

The purpose of this study was to pilot-test the newly developed EORTC module measuring QoL in thyroid cancer patients. We wanted to check whether patients understood and accepted the wording of the items, whether they found the content relevant and whether anything important was missing from the questionnaire. The second aim was to shorten the module without compromising its comprehensiveness.

The patient responses confirmed that the QoL issues identified in phase I of this module development (Singer et al. 2016) are relevant and important to patients. Most of the items were well accepted by the patients. Only one item (‘Have you worried about having to come off your thyroid hormone tablets?’) was considered relevant but difficult to understand by some patients. Its wording was changed to ‘Have you worried about having to come off your thyroid hormone replacement tablets to prepare for a radioiodine body scan or radioiodine treatment?’. Our expert group discussed this new

wording extensively. While it is now a relatively lengthy item and we usually try to keep items as short as possible, we found that the old item was difficult to understand. This was not because of ‘difficult words’ but because of the complex treatment captured by it. Patients need to understand what is meant by an item in a questionnaire without needing to ask a study nurse or clinician for help in completing it. It was therefore decided to add more information to this item.

Further, compliance in completing the items was high. This is especially important as low completion rates of QoL tools are a major challenge in clinical trials (Kopp et al. 2003, Ediebah et al. 2013, Johnston et al. 2013, Bottomley et al. 2014). In order to increase the likelihood of high completion rates, we shortened the module to 34 items, in accordance with the EORTC module development guidelines (Johnson et al. 2011).

Interestingly, a considerable number of patients said they felt there should be more items on shoulder functioning which was why we added another item on this issue. This is in line with a recent study (Roerink et al. 2017) which found that more than half of the thyroid cancer survivors suffer from shoulder problems.

A limitation of our study was that we were able to include only a few patients with anaplastic thyroid cancer. This type of disease is very rare and its prognosis is poor (Brown et al. 2011, Amphlett et al. 2013, Husson et al. 2013b), making it difficult to enrol patients. Our aim had been to include at least 10 patients but we managed to include only 6. Hence, the perspective of this patient group may be under-represented in our module. Although we assume that the type of disease has no major effect on how well patients can understand an item or whether they find it upsetting or annoying, it is possible that the relevance and completion rates might differ as patients with different disease experience different side effects.

Few patients had received chemotherapy as this type of treatment is rarely given to patients with thyroid cancer. The treatment received by the patients in this study reflects therefore the usual situation in this patient group.

Patients who had received tyrosine kinase inhibitors responded similarly to the module than the patients who had received different treatments. However, they reported more problems with lifeless and thin hair and rated hair loss as relevant. Moreover, one of the patients highlighted the problem of having to take medication for a longer period of time.

A strength of this study was that we included patients from Europe, Asia, Australia and Africa. This allowed us



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to ensure that the module is well accepted in patients with different cultural backgrounds and languages. The heterogeneity of the sample in terms of histology, treatment and stage of disease enables the use of this module in different settings and treatment lines.

In summary, the EORTC quality of life module for thyroid cancer consisting of 34 items is now pilot-tested and ready for the final international field validation in phase IV. It is available in the following languages: Arabic, Chinese, Dutch, English, French, German, Greek, Hebrew, Hindi, Japanese, Italian, Polish, Portuguese, Spanish and Tamil.

Declaration of interestThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

FundingThis study was generously funded by the European Organisation for Research and Treatment of Cancer, Quality of Life Group (# THY III).

AcknowledgementsThe authors would like to acknowledge the work of the anonymous colleagues who reviewed the grant proposal and the study report. They are grateful to the EORTC QLG Executive Committee for reviewing the study report and this paper.

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Received in final form 31 January 2017Accepted 21 February 2017Accepted Preprint published online 21 February 2017


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