Thyroid cancer patient reported outcome measures in clinical practice: analysing acceptability and optimizing recruitment

Patient reported outcomes measures (PROMs) can provide valuable metrics in clinical trials and cancer registries. To ensure relevance, patient participation must be optimized and PROMs be highly acceptable to patients. There are few data reporting methods to maximize recruitment and a lack of consensus regarding appropriate PROMs for thyroid cancer survivors.


Introduction
Despite good physical health-related quality of life (HRQoL); rates of anxiety, depression and fatigue are high in thyroid cancer survivors, particularly when compared to other cancer subtypes with inferior prognosis (e.g., breast and colorectal cancer). 1,2Although HRQoL improves over the first year after treatment, 3,4 long-term detriments persist in many patients. 5,68][9] Given the comparative young age of many thyroid cancer survivors and their long lifeexpectancy, it is vital that more is understood about the psychosocial harms associated with diagnosis and treatment so that wellbeing in this group can be optimized.
1][12] Often limited funding is provided for the administration of PROMs, yet to obtain meaningful and representative data, it is critical to understand the accuracy, comprehensiveness and ease of completion of the surveys, as well as maximize consent and completion rates. 13,14Many prior studies in thyroid cancer cohorts have recruited particular patient groups via social media and internet sites and may be subject to selection bias. 1,6In addition there is no clear survey (generic or disease-specific), or combination of surveys that have been shown to be superior, 15 with concerns that many surveys fail to capture the nuances of the thyroid cancer patient's experience, in particular FCR. 16,17here is a critical gap in the evidence concerning recruitment methods for PROMS to maximize participation of the broader population of thyroid cancer survivors in a real-world clinical setting.There is also a need to assess the acceptability, face validity and feasibility of administration of both generic and thyroid cancer specific PROMs in this broader patient group. 18,19This study examined: (1) Survey consent and completion rates under an enhanced versus standard recruitment model; (2) Pragmatic aspects of two generic and two thyroid cancer specific PROMs administered electronically: including number of items, survey completion rates and readability; (3) The acceptability, comprehensiveness, and face validity of the four measures as reported by thyroid cancer patients through survey follow-up questions and structured interviews.

Patient eligibility
Patients with a new diagnosis of thyroid cancer between January 2020 and December 2021, within the Hunter New England local health district (HNELHD), New South Wales (NSW), Australia, were prospectively invited to complete PROMs utilizing the Research Electronic Data Capture (REDCap ® ) database. 20he HNELHD has an area of 131785km 2 with an estimated population of 920 000, spanning metropolitan, regional and rural areas.Patients were identified either directly via clinician recruitment or via the HNELHD thyroid cancer multidisciplinary team process.Excluded patients were: aged <18 years at the time of diagnosis, those who had insufficient English skills or lacked access to online surveys.Patients with a diagnosis of papillary thyroid microcarcinoma (PTMC) with no adverse features were excluded as local clinical practice is of a restrictive biopsy protocol that avoids biopsy of most nodules <1 cm, and follow-up is not offered to the majority of patients with incidental PTMC.Patients with anaplastic thyroid cancer were also excluded as the median diseasesurvival is less than the study period.The study was prospectively approved by the HNELHD Human Research Ethics Committee (2019/ETH13770) and University of Newcastle Human Research Ethics Committee (H-2021-0097).

Survey tools and administration
Survey tools were selected after a review of the literature.Although Short Form-36 (SF-36) has been utilized more extensively in thyroid cancer survivorship research, 21,22 Short Form-12 is a suitable alternative measure with 12 (compared to 36) items. 23,24European Organization of Research and Treatment of Cancer (EORTC-QLQ-C30) is designed for cancer survivors of any disease subtype and has also been utilized in prior research in thyroid cancer survivors. 4,15,25,26At the time of study design there were only two thyroid cancer specific PROMs that were validated in Phase IV testing: City of Hope Quality of Life-Thyroid Version (COH-TV) and Thyroid Cancer Quality of Life Survey (ThyCaQoL).COH-TV is a 41-item survey that provides an overall wellbeing score, along with sub-scores in four domains (physical symptoms, psychological, social and spiritual well-being).In contrast, ThyCaQoL is a shorter survey with 24 items that evaluates only physical and psychological domains. 15atient Health Questionnaire 4 (PHQ-4) was used as a generalizable ultra-brief anxiety and depression screen.Additional surveys addressing fear of cancer recurrence, FCR (Assessment of Survivor Concerns Scale, ASC) and financial impacts (financial toxicity), Table 1, were included as our prior research in a cohort of longterm thyroid cancer survivors suggested that these issues needed specific investigation. 27Survey measures were repeated at 3-, 6and 12-months.The complete study methodology included 7 survey tools administered at baseline, 3-, 6-and 12-months with the exception of the financial toxicity scale which was administered at only 3-and 12-months.Interviews were piloted with a historical cohort of 8 patients and a further 12 interviews were undertaken with patients who had answered surveys at a minimum of two survey time points (baseline and 3-months).† The 'Simple Measure of Gobbledygook', SMOG readability score is an index that measures how many years of education the average person needs to understand the text presented in each survey.‡ These last three surveys were not analysed for self-reported acceptability or comprehensiveness in this study.

Thyroid cancer patient reported outcomes 2215
Self-reported patient demographic data were collected via the survey (educational and smoking status, and information regarding thyroid hormone replacement).Age, gender, geographical data and body mass index (BMI) were collected from the medical record.Surveys were administered in the following order: SF-12, EORTC-QOL-C30, ThyCaQoL, COH-TV, ASC, Financial Toxicity Scale and PHQ-4.Randomising the order of surveys for repeated measures was not possible with the software available.Participants were asked to rate the generic and disease-specific PROMs for both ease of completion and comprehensiveness directly after each module was completed.Ratings regarding comprehensiveness were not collected for PHQ-4, ASC or financial toxicity scores as these survey tools address specific issues of cancer survivorship.No incentives or reimbursements were offered to participants.

Interviews
Semi-structured telephone interviews were undertaken to allow the nuances of thyroid cancer survivorship to be explored.Interview design was guided by a review of the literature and included an opportunity for patients to freely express their thyroid cancer survivor experience as well as focussing on FCR, financial impacts, family, social and professional support structures and timing and adequacy of information.A pilot of interview technique was undertaken with a historical cohort of 8 thyroid cancer survivors (diagnosed prior to the study period) aiming for diversity of age, gender and stage of disease.All interviews were double coded, the interview script reviewed, and a further 12 interviews were undertaken with participants from the 2021 study cohort who had responded to surveys at a minimum of 2 time points.A purposive, maximum variation sample of patients was recruited aiming for a diverse sample across gender, age, stage of disease and geographical location.Interviews were undertaken with one of two female trained research assistants with at least 1 year of full-time experience in patientcentred study interviews in mixed oncology populations.They were unknown to the participants and not involved in their clinical care.Double coding was undertaken by researchers with different backgrounds (clinical and sociology) utilizing a hybrid model of inductive and realistic codebook thematic analysis as described by Braun and Clarke. 28

Recruitment
The initial (standard) recruitment procedure was based on similar PROMs studies and is summarized in Table 2. 29 However, due to poor recruitment after the first year of the study (also affected by COVID-19), there was a naturalistic opportunity to evaluate an enhanced recruitment strategy to optimize recruitment rates.Enhanced recruitment involved a more personalized, multimodal and time-intensive approach to contacting potential participants.Eligibility screening was performed by a senior clinician and telephone recruitment was undertaken by a research assistant with training equivalent to those who undertook the interviews.Up to three attempts to contact patients were made ensuring that telephone calls were made at differing times of day and on different weekdays.Text messaging was also used where calls were not answered.
Consent was accepted either in written or verbal form (recorded) and study information supplied via email.Consenting patients were sent a survey link via email.Automatic email reminders at all survey time-points were generated and initial non-respondents were contacted to ensure the email address supplied was correct.A maximum of three attempts to contact were made at each time-point.

Analysis
The above methodology summarizes our complete research protocol incorporating repeated surveys administered at four time points over the first year following a thyroid cancer diagnosis, and semistructured interviews administered at a single time point (summarized in Table 1).The data presented in this paper evaluates the effect of enhanced recruitment and focuses on acceptability and face validity of the generic and thyroid cancer-specific surveys at baseline only.The interviews did not aim to assess surveys specifically, but many patients commented voluntarily on the comprehensiveness and acceptability of the surveys and this data has been included as it presented unique input beyond survey data alone.The effect of enhanced recruitment was analysed by comparing consent and completion rates with those of standard recruitment.Clinical and demographic characteristics in each recruitment period were analysed using ANOVA for continuous variables and Chisquared test for categorical variables.Pragmatic aspects of the two generic and two thyroid cancer specific PROMs were reported for surveys including number of items, survey completion rates and readability.The acceptability and face validity of each generic and thyroid cancer specific tool was measured by self-reported participant data reflecting the ease of completion (5-point Likert score) and perceived comprehensiveness (4-point Likert score).Generalized linear mixed models were used to take account of the repeated measures and assess whether surveys were rated differently on ease of use and comprehensiveness.The fatigue effect of multiple surveys was also evaluated.

Survey consent and completion rates
Recruitment started in February 2020 but was paused prior to any patients being contacted due to the COVID-19 pandemic and resulting Australian government restrictions.The first eligible patients were contacted for recruitment from June 2020 shortly after NSW emerged from its first COVID-19 lockdown.Patient contact, consent and survey completion rates for SF-12, the first survey presented, are summarized in Table 2. Across the 2 years, there were 6 patients who were deemed ineligible due to lack of access to the internet and 2 who had insufficient English language skills to complete the surveys.A significantly higher proportion of patients completed at least one survey in 2021 under enhanced recruitment (37/62, 60%) compared to in 2020 under standard recruitment (19/64, 30%, P = 0.0007, 95% confidence interval of difference (13, 47%)).There was no significant difference in age, gender, insurance status, geography or stage of disease, between responders and non-responders in either year, Table 3. these generic tools.Acceptability was numerically higher for the thyroid-cancer specific survey measures: 54% (ThyCaQol) and 52% (COH-TV) respectively, however differences in reported levels of confidence for each PROM did not reach statistical significance (P = 0.14).Patients who completed all surveys were also asked to rate their satisfaction with the questionnaires collectively (scores of 0-10 with higher scores indicating higher levels of satisfaction).Only 2 patients (4%) rated scores below 5, 19 (40%) were neutral (score 5), 13 (27%) rated scores of 6 or 7, and 14 (29%) rated scores of 8-10, suggesting that the combination of tools was more acceptable and comprehensive than any survey tool in isolation.
Analysis of free-text comments within the surveys, and feedback obtained during the telephone interviews raised several concerns regarding the questionnaires.Patients found surveys difficult to answer in the pre-operative period or when active surveillance was undertaken.The study team recognized this in 2020 and altered recruitment such that patients were recruited after surgery.Despite this change, some patients still reported difficulty answering questionnaires if they had been recommended a completion thyroidectomy or radioactive iodine treatment and underwent these close to the time of the survey.Respondents also commented that the surveys did not capture the effects of delays in care or of telehealth consultations, a situation that affected many in this study due to its co-incident timing with the COVID-19 pandemic: 'COVID had a big impact, not being able to see someone, you could not speak at length'.
The qualitative data also suggested that although many patients found the combination of surveys comprehensive, they struggled to answer them purely from the perspective of their thyroid cancer.They expressed concerns that their self-reported HRQoL reflected other concurrent diagnoses or financial or social stressors rather than their thyroid cancer outcomes: 'I struggled with the surveys, I'd provide a response and want to give a commentary to explain it' or 'The surveys definitely covered off all the broad categories in terms of mental health, physical wellbeing and relationships.It was the more nuanced responses to some of those questions where it's a bit more complex than just a one to five, yes or no'.Other important issues raised that were not captured by survey data alone included a scarcity of timely and appropriate patient information, and a lack of offer of and access to psychological support.

Discussion
Thyroid cancer incidence is increasing and despite excellent disease-free survival, many patients experience psychological and social detriments that impair their ability to regain their prediagnosis level of functioning.An ideal PROM would assess patient-centred priorities in a reliable, measurable and actionable format that would also be reproducible at different timepoints. 13he administration of a such a measure, coupled with optimised participation and completion rates can provide robust longitudinal HRQoL data which will inform cancer survivorship research.Surveys must also be comprehensive without compromising readability levels or being excessively complex or lengthy (number of items). 30inimisation of response burden to both patients and staff is also critical to the integration of HRQoL measures in clinical research, registries and practice.This study adds to the body of literature assessing HRQoL in thyroid cancer survivors but is unique in that it directly compares both generic and disease-specific thyroid cancer tools and in addition triangulates acceptability data with patient interviews.

Survey tools
The use of generic PROMs allows the opportunity to compare scores in the study population to the population at large (SF-12) or to other oncology cohorts (EORTC-QLQ-C30).However, many common HRQoL issues for thyroid cancer survivors are not well captured by these tools.This is reflected in this study; despite the EORTC-QLQ-C3O and SF-12 being reportedly easy to use, less than 50% of participants felt that either generic survey tool comprehensively assessed their HRQoL in respect to their thyroid cancer.As a result, studies including PROMs in thyroid cancer survivorship should not use generic HRQoL survey tools in isolation.
At the time of design of this study there were only two available thyroid cancer specific HRQoL tools that had been validated in Phase IV testing.ThyCaQoL is designed to be used in conjunction with EORTC-QLQ-C30, but even in combination, concerns have been raised that a comprehensive assessment is not obtained. 7,15hese concerns were validated in this study, with only 54% of patients reporting confidence in ThyCaQoL to capture the HRQoL effects of their cancer diagnosis.A newer HRQoL module specific Note: At the completion of each survey tool patients were asked: (1) How easy or difficult the tool was to complete; and (2) how confident they were in the tool's ability to fully capture the way their cancer diagnosis has impacted their quality of life.For statistical analysis, responses were aggregated into a 3-point scale for ease of use (easy/very easy, neither, difficult/very difficult) and a 2-point scale reflecting confidence (confident/very confident, not/somewhat confidentcharacterized as low and high confidence respectively).† Two responses missing.
to thyroid cancer (EORTC-QLQ-THY34) is being developed that aims to prioritize HRQoL detriments that are of importance to patients.It is undergoing Phase IV testing and may provide a more nuanced assessment in future studies. 31ps in PROMs in thyroid cancer survivors In this study only 38%-54% of patients felt that any survey tool fully captured the impact of their cancer diagnosis and its effect on their quality of life.These results confirm that the breadth of thyroid cancer survivorship is incompletely assessed with current PROMs used in isolation.Fear of cancer recurrence (FCR) has been identified as a driver of HRQoL detriments amongst thyroid cancer survivors. 7Of the generic and disease-specific tools utilized in this study, only COH-TV addresses this issue specifically.The assessment of survivor concerns scale (ASC) was designed to assess FCR specifically in oncology populations. 32It has recently been used in another thyroid cancer study (published after recruitment commenced in this trial) in conjunction with EORTC QLQ-C30 and THY34. 33Fear of cancer recurrence was a prominent issue in that trial and was only highlighted by the addition of the ASC tool.It is vital that FCR is identified and addressed in this population group as there is emerging evidence of the success of interventions for FCR in other cancer subtypes. 34

Recruitment
Although PROMs have been widely utilised in clinical trials, there are many barriers to their widespread implementation into clinical practice. 18,19In particular, maximizing recruitment and retention of participants in a clinical cohort is important to any HRQoL study to ensure results are representative.This study represents recruitment of a geographically selected cohort (mixed metropolitan and regional) and hence is likely to be more representative of the population at large, more closely reflecting a real-world clinical setting.Recruitment rates were enhanced by refinements to the screening of participants (ensuring that all eligible patients were identified) and by utilizing the skills of a research assistant trained in patientcentred interviews to recruit and retain patients.This, in addition to email reminders, the use of text messages and varying both the day and time of day where emails and phone calls were made was essential to improved recruitment rates in the second half of this study.These lessons will be of value to any researcher wishing to incorporate HRQoL assessment into their trials or registries.

Limitations
This study was limited by the number of participants.Despite attempts to maximize recruitment, several respondents declined to participate.Others provided consent but failed to open the survey link or completed only a small number of questions.Despite further attempts to contact these participants, survey response rates increased only marginally.Incentives were not used but could be considered in future studies.Larger numbers could have been achieved by recruitment outside of our local health district, but we felt this might affect the accuracy of screening of patients, participation rates and hence the representativeness of the cohort and generalisability of the results.It is also possible that this study is underpowered to assess potential differences in confidence levels across the surveys and that results could have been subject to pre-conditioning given the use of multiple sequential questionnaires.Finally, the effect of the COVID-19 pandemic and lockdown restrictions may have influenced the results of this study.It should be noted that strict government restrictions existed for 13 weeks in 2021 compared to 8 weeks 2020 in our geographical area.Recruitment across the entirety of this study was likely affected by the COVID-19 pandemic with limited ability to recruit patients face to face at any stage.It is beyond the data of this study to speculate further, but we acknowledge that the pandemic affected both access to health care and patient well-being.Nevertheless, it is important to reflect on this study's finding that participants were comfortable completing more than one measure and were able to complete these PROMs in approximately 20 min.Rather than a focus on selecting one 'gold-standard' PROM specifically for thyroid cancer patients and survivors, future research and health professionals may decide to incorporate several tools, providing they are not repetitive nor too time-consuming.It remains possible that even a combination of surveys provides an incomplete assessment, hence, the opportunity for an open-ended or qualitative element should be strongly considered.

Conclusion
HRQoL detriments are common in thyroid cancer survivors and no single survey tool is sufficient to assess the depth and breadth of these issues.Studies incorporating PROMs should consider choosing at least a generic, thyroid-cancer specific and fear of cancer recurrence tool to maximise comprehensive assessment.The involvement of specialized staff in patient-centred care is essential to optimizing recruitment.

Table 1
Summary of complete study methodology

Table 2
Comparison of research methods under standard (2020) versus enhanced (2021) recruitment

Table 4
Self-reported acceptability for different tools at baseline