DR.Guttler’s Patient Thyroid Blog Posts: Patients’ Treatment Choice for Low Risk Thyroid Cancer. Add RFA to the Discussion.

DR.Guttler’s Patient Thyroid Blog Posts: Patients’ Treatment Choice for Low Risk Thyroid Cancer. Add RFA to the Discussion.

A Quantitative Analysis Examining Patients’ Choice of Active Surveillance or Surgery for Managing Low-Risk Papillary Thyroid Cancer

Abstract

Background: It is important to understand patient preferences on managing low-risk papillary thyroid cancer (PTC).

Methods: We prospectively followed patients with low-risk PTC <2 cm in maximal diameter, who were offered the choice of thyroidectomy or active surveillance (AS) at the University Health Network (UHN), in Toronto, Canada. The primary outcome was the frequency of AS choice (percentage with confidence interval [CI]). Univariate and multivariable analyses were performed to identify predictors of the choice of AS.

Results: We enrolled 200 patients of median age 51 years (interquartile range 42–62). The primary tumor measured >1 cm in 55.5% (111/200) of participants. The AS was chosen by 77.5% [71.2–82.7%, 155/200] of participants. In a backwards conditional regression model, the clinical and demographic factors independently associated with choosing AS included: older age (compared with referent group <40 years)—age 40–64 years—odds ratio (OR) 2.78 [CI, 1.23–6.30, p = 0.014], age ≥65 years—OR 8.43 [2.13–33.37, p = 0.002], and education level of high school or lower—OR 4.41 [1.25–15.53, p = 0.021]; AS was inversely associated with the patient’s surgeon of record being affiliated with the study hospital—OR 0.29 [0.11–0.76, p = 0.012]. In a separate backwards conditional logistic regression model examining associations with psychological characteristics, AS choice was independently associated with a fear of needing to take thyroid hormones after thyroidectomy—OR 1.24 [1.11–1.39, p < 0.001], but inversely associated with fear of PTC progression—OR 0.94 [0.90–0.98, p = 0.006] and an active coping mechanism (“doing something”)—OR 0.43 [0.28–0.66, p < 0.001].

Conclusions: Approximately three-quarters of our participants chose AS over surgery. The factors associated with choosing AS included older age, lower education level, and having a surgeon outside the study institution. Patients’ fears about either their PTC progressing or taking thyroid hormone replacement as well as the level of active coping style were associated with the decision. Our results inform the understanding of patients’ decisions on managing low-risk PTC. Registration: Clinicaltrials.gov NCT03271892.

Introduction

Worldwide, thyroid cancer is the ninth most commonly diagnosed malignancy overall and the fifth most common in women (1). In 2020, it is estimated that more than half a million individuals were diagnosed with this malignancy (1).

The management of small, low-risk papillary thyroid cancer (PTC) has also evolved in recent years, with recent clinical practice guidelines suggesting de-escalation of treatment of low-risk disease (2). Active surveillance (AS) of a malignancy consists of close clinical and diagnostic test follow-up in lieu of immediate surgical or other treatment, with the intention of treatment in the event of disease progression (defined by pre-specified criteria).

The AS of papillary microcarcinoma (PTC 1 cm or smaller) was first initiated in Japan, specifically in Kuma Hospital in 1993 (3) and then in Tokyo in 1995 (4). In recent years, investigators from multiple countries have published reports on AS of small, low-risk PTC (5–9). The authors of the 2015 American Thyroid Association clinical practice guideline on differentiated thyroid cancer management indicated that “studies that examine decision-making and acceptability of an active surveillance approach to thyroid cancer in patients, family members, and clinicians are required to better understand how to implement this novel management approach outside of Japan” (2).

In 2016, we initiated the first prospective observational study in Canada offering patients with low-risk PTC <2 cm in maximal diameter the option of AS or surgery (NCT03271892) (10). We recently published the results of a qualitative analysis of patients’ rationale for choosing AS or surgery, in the first 100 participants enrolled in the study (11). As the recruitment of planned 200 participants for this study is now complete, we present the quantitative analyses examining the primary outcome of how often patients chose AS over surgery (or vice versa).

Our original hypothesis was that more than half of eligible patients with small, low-risk PTC would opt for AS over surgery (which we defined by a value of >50% for the lower confidence interval [CI] for the percentage of patients choosing AS). We have also explored potential clinical and psychological predictors of the choice of AS over immediate surgery.

Methods

Study design and setting

This is a single-center, prospective, observational cohort study, offering patients the choice of either AS or surgery for primary management of small, low-risk PTC. The study is conducted at University Health Network (UHN), which is a high surgical volume tertiary and quaternary referral center for thyroid cancer care in Toronto, Canada. We previously reported the details of the study methodology (NCT03271892) (10–12), and we have summarized additional research ethics-board approved study protocol changes in Supplementary Table S1).

Participants in the study were free to choose AS or surgery (usual care), and their long-term follow-up is currently in progress (for planned future reporting). The study is approved by the UHN Research Ethics Board (15-8942), and participants in the study provided informed consent for their participation as per institutional guidelines.

Participant eligibility criteria

Eligible participants were consenting, adult patients (age 18 years or older) with an untreated primary PTC measuring <2 cm in maximal diameter that was considered low risk (i.e., neither evidence of metastatic disease nor extrathyroidal extension on clinical exam or imaging), with the primary tumor judged to be in a location that was considered unlikely to be at high risk for invasion of the trachea or the recurrent laryngeal nerve (10). Patients were ineligible if they had another type of thyroid cancer (e.g., poorly differentiated or other non-PTC thyroid malignancy), an absolute surgical indication for other thyroid or parathyroid surgery, or severe comorbidity (with life expectancy <1 year) that would preclude surgery (per most recently approved protocol, summarized in Supplementary Table S1).

Participants were recruited consecutively in participating UHN thyroid cancer clinics, and referrals were accepted from thyroid cancer specialists outside our institution or by self-referral. Each patient identified a preferred surgeon (without institutional affiliation restriction) who was intended to perform the patient’s thyroid cancer surgery, if needed.

AS and surgical study procedures

As previously reported, AS includes periodic ultrasound imaging (at UHN), bloodwork (thyrotropin, free thyroxine, thyroglobulin, thyroglobulin antibody), and clinical assessment at the study hospital, and clear criteria for recommending surgery for disease progression are established (10). Patients may cross over from surgery to AS at any time, if they choose.

Data collection and outcomes

Patient questionnaires were administered at baseline and after the disease management choice was finalized (AS or surgery). The options of AS and surgery were offered to patients after obtaining informed consent and administration of the baseline questionnaires. We provided the patient with written information about the options, supplemented with physician discussion regarding the information. Participants’ thyroid cancer-related medical records were reviewed at baseline and yearly.

Baseline patient reported data included demographic characteristics, past medical history, family history, as well as the following psychological questionnaires: (i) Brief Cope questionnaire [first 19 questions, including the following complete subscales: Self-distraction (doing unrelated activities as a distraction), Active Coping (wanting to do something about the PTC), Denial (trying to deny the PTC is real), Substance Use (turning to drugs or alcohol), Use of Emotional Support (engaging in getting support from others), Behavioral Dysregulation (giving up), and Positive Reframing (trying to look for something positive about the situation) (13,14)], (ii) Fear of Disease Progression—Short Form (15,16), and (iii) Surgical Fear questionnaire (17), which was supplemented with four questions specific to thyroid cancer that were formatted similarly to the original questionnaire (“afraid”—“that my voice may change because of the operation,” “that I will need to take thyroid hormone because of the operation,” “that my blood calcium level will be low because of the operation,” and “of how the scar will look after the operation”).

The following medical decision-making questionnaires were administered at the following time points: baseline—Decision Self-efficacy Scale (DSES) (18,19), which measured the confidence in participating in the decision on PTC management and when the disease management decision was finalized, the Satisfaction with Decision Scale (20) was administered. In an introduction to the DSES questions in our baseline questionnaire, we asked participants to “assume you have been offered the choice of having surgery to remove your thyroid cancer or not having surgery (with close follow-up, called active surveillance).”

Participants were asked to select whether they favored surgery or AS at this time, before a formal meeting with an investigator about disease management options. High satisfaction with the decision was defined by a score of ≥24/30 on the Satisfaction with Decision Scale (21). All questionnaires were scored as per developers’ instructions, whereas the additional questions specific to thyroid cancer surgical fears were scored on a Likert Scale of 0–10, where 0 means “not at all afraid” and 10 is “very afraid.”

Statistical analyses

We described the clinical and demographic characteristics of the study population (and respective groups of patients choosing AS or surgery), as the frequency (and percentage) for categorical data and the median (with interquartile range) or mean (and standard deviation, SD) for continuous variables. We reported CIs for the primary outcome of frequency of choice of AS (or surgery), and the odds ratios (ORs) in the predictive models. For the univariate analyses, we compared the AS and primary surgical patients’ characteristics by using Wilcoxon Rank-Sum tests for continuous data and Chi-Squared tests or Fisher’s exact tests for categorical data.

We performed multivariable logistic regression analyses predicting the choice of AS. The details of the statistical analyses are provided in the Supplementary Methods S3 and S4. The statistical analyses were performed by experienced statisticians (J.S., W.X.) using SAS 9.4 by (SAS Institute, Cary, NC) and R 4.1.0. We reported two-tailed p-values and consider a value of <0.05 statistically significant.

Results

Description of study participants

We recruited 200 patients from a total of 260 potentially eligible patients screened (Fig. 1). Females comprised 76.0% (153/200) of the study population. The mean age of study participants was 52 years (SD 15, range 20–85 years). Table 1 summarizes the clinical characteristics of participants, and additional descriptive data are summarized in Supplementary Table S2. The mean size of the primary PTC tumor was 11 mm (SD 4), and 56% (111/200) of the primary tumors were larger than a centimeter in maximum diameter (i.e., larger than a microcarcinoma). The institutional affiliation of the patient’s surgeon was the study hospital for 71% of the participants (142/200).

FIG. 1.
FIG. 1. Participant study flow. *Reasons for exclusion were: location considered at risk for tracheal or recurrent laryngeal nerve invasion (n = 23 patients), other malignancy (n = 2, however one patient who had been originally excluded [out of three originally excluded for this indication] opted for study participation after amendment of our study protocol, which is detailed in Supplementary Table S1), cytopathology not papillary or suspicious for papillary thyroid cancer (n = 2), primary tumor ≥2 cm in size (n = 7), nodal metastatic disease noted on baseline imaging at our institution (n = 3), and other indication for thyroid or parathyroid surgery (n = 3 primary hyperparathyroidism).

Table 1. Clinical Characteristics of the 200 Study Participants

Variable All participants (200) Active surveillance (155) Primary surgery (45)
Female sex, n (%) 153 (76.5) 120 (77.4) 33 (73.3)
Median age, years (IQR) 51 (42–62) 53 (44–66) 44 (36–54)
Median size of primary tumor, largest dimension in mm, (IQR) 11 (9–14) 11 (8–13) 13 (9–15)
Primary tumor larger than microcarcinoma, >1 cm in largest dimension, n (%) 111 (55.5) 81 (52.3) 30 (66.7)
Cytologic diagnosis on fine needle biopsy of primary tumor
 PTC, n (%) 142 (71.0) 113 (72.9) 29 (64.4)
 Suspicious for PTC, n (%) 58 (29.0) 42 (27.1) 16 (35.6)
Taking thyroid medication,an (%) 31 (15.5) 22 (14.2) 9 (20.0)
Median baseline thyrotropin concentration, mIU/L (IQR) 1.49 (1.02–2.20) 1.46 (1.02–2.17) 1.78 (1.15–2.39)
Presence of multiple thyroid nodules on ultrasound, n (%) 147 (73.5) 112 (72.3) 35 (77.8)
Thyroid surgeon affiliated with the study hospital, n (%) 142 (71.0) 103 (66.5) 39 (86.7)

aThyroid medication includes either thyroid hormone replacement for treatment of hypothyroidism or anti-thyroid drugs for treatment of hyperthyroidism. The type of thyroid medication taken at baseline was as follows: Levothyroxine (n = 27), methimazole (dose ranges 2.5 mg every other day to 5 mg daily; n = 3), and Natural Desiccated Thyroid (n = 1).

IQR, interquartile range; PTC, papillary thyroid cancer.

Choice of AS or surgery

The percentage of patients choosing AS was 77.5% [CI, 71.2–82.7%, 155/200], and the percentage choosing immediate surgery was 22.5% [17.3–28.8%, 45/200]. Most of the participants (78.0%, 156/200) indicated on their baseline questionnaire that they favored the AS option. The baseline mean Decision Self-efficacy Scale score was 93.4/100 (SD 9.6), generally reflecting a high level of the participants’ confidence in the ability to participate in medical decision making.

Further, the mean Decision Self-efficacy Scale values did not differ significantly between patients choosing AS and surgery (p = 0.540). Most participants (86.0%, 172/200) reported making the final disease management decision themselves, and the rest indicated that it was a shared with their physician (14.0% of participants, 28/200). The majority of the participants (96% 192/200) reported high satisfaction with their decision based on the Satisfaction with Decision Scale, and there was no significant difference between those choosing AS and surgery (p = 0.686).

An important consideration regarding patients’ choice of AS or surgery is the durability of the decision. This may include consideration of how often patients changed their mind in response to the study physician’s initial encounter or during follow-up. At baseline, before the formal meeting with a study investigator, 78.0% of patients (156/200) reported that they favored the choice of AS and the rest favored surgery.

Participants’ decisions rarely changed after formally meeting with a study investigator, as three patients (1.5%), who initially favored surgery, ultimately chose AS and four patients (2.0%), who initially favored AS, ultimately chose surgery. All 45 patients who ultimately chose surgery underwent surgery. Of the 155 patients who chose AS, 9 patients (5.8%) crossed over to surgery due to personal choice, in the absence of any change in follow-up surveillance testing (median follow-up 29 months, range 9–65 months).

Within the same follow-up time frame, an additional two patients (1.2%) crossed over to surgery due to a change in personal preference after receiving information on potential changes from baseline on surveillance neck ultrasound imaging (but without a confirmed diagnosis of disease progression at the time). The latter two individuals indicated that they had been considering crossing over to surgery before their routine imaging, but they experienced heightened concerns about potential disease progression after receiving their test results and elected to immediately proceed with surgery.

Predictors of the choice of AS

We constructed two backwards conditional logistic regression models examining factors predicting choice of AS (in lieu of surgery), including (i) participants’ demographic and clinical characteristics (Table 2), and (ii) participants’ baseline psychological characteristics (Table 3). The fit of these models was good (respective C-statistics 0.758 and 0.792).

Table 2. Results of Univariate and Multivariable Analyses of Clinical and Demographic Factors Predicting the Choice of Active Surveillance

Variable Univariate analysis Multivariable analysis (final model)
OR [CI]a Global p-value OR [CI] Global p-value
Male sex (compared with female) 0.80 [0.37–1.72] 0.570
Age category, years (compared with <40 years)
 40–64 Years 2.33 [1.09–4.95] 0.028 2.78 [1.23–6.30], p = 0.014 0.004
 ≥65 Years 8.72 [2.32–32.73] 0.001 8.43 [2.13–33.37], p = 0.002
Marital status (compared with single)
 Married/common-law 0.75 [0.28–1.98], p = 0.558 0.121
 Divorced, separated, or widowed 6.00 [0.67–53.83], p = 0.109
 Have children 0.92 [0.40–2.11] 0.852
 Responsible for children <18 years of age 0.39 [0.20–0.77] 0.007
Education completed (compared with > than high school)
 High school or lower 6.09 [1.80–20.64] 0.004 4.41 [1.25–15.53] 0.021
Employment status (compared with employed)
 Not employed 1.47 [0.71–3.03] 0.294
 Birth country (compared with Canada) 1.10 [0.57–2.14] 0.773
Ethnicity (compared with White)
 Asian, South-East Asian 0.97 [0.44–2.12], p = 0.936 0.452
 Bi-racial 0.49 [0.04–5.69], p = 0.572
 Black 0.49 [0.09–2.87], p = 0.433
 Hispanic 0.25 [0.01–4.10], p = 0.330
 Middle Eastern 0.29 [0.09–0.94], p = 0.039
Primary tumor larger than microcarcinoma, >1 cm in largest dimension (compared with microcarcinoma) 0.55 [0.27–1.10] 0.089
Primary tumor cytology suspicious for PTC (compared with positive for PTC) 0.67 [0.33–1.36] 0.273
Thyroid cancer family history (compared with no family history)
 Unknown 0.60 [0.17–2.03], p = 0.407 0.103
 Yes 0.41 [0.18–0.96], p = 0.039
Time since enrollment (months) 0.98 [0.96–1.00] 0.040
Thyroid surgeon affiliated with the study hospital (compared with having an outside surgeon) 0.30 [0.12–0.77] 0.012 0.29 [0.11–0.76] 0.012

ap-Value listed for each category, if more than one category of a variable was examined in the model.

CI, confidence interval; OR, odds ratio.

Table 3. Results of Univariate and Multivariable Analyses of Patient-Reported Outcome Questionnaires Predicting the Choice of Active Surveillance

Patient-reported outcome questionnaire Univariate analysis Multivariable analysis (variables in final model)
OR [CI] Global p-value OR [CI] Global p-value
Fear of Progression (Short Form)—total score 0.94 [0.91–0.97] <0.001 0.94 [0.90–0.98] 0.006
Surgical Fear Questionnaire—total score 1.00 [0.99–1.02] 0.846
Fear of voice changing because of the operation 0.97 [0.88–1.07] 0.566
Fear of needing to take thyroid hormone because of the operation 1.10 [1.01–1.21] 0.038 1.24 [1.11–1.39] <0.001
Fear of blood calcium level being low because of the operation 0.97 [0.88–1.07] 0.503
Fear of how the scar will look after the operation 0.98 [0.89–1.08] 0.670
Brief Cope questionnaire subscale
 Self-distraction 0.59 [0.43–0.83] 0.002
 Active coping (“doing something,” “taking action”) 0.41 [0.28–0.61] <0.001 0.43 [0.28–0.66] <0.001
 Denial 0.63 [0.38–1.06] 0.082
 Substance use 0.98 [0.34–2.79] 0.968
 Use of emotional support 0.53 [0.36–0.79] 0.002
 Behavioral dysregulation (“giving up”) 0.29 [0.11–0.74] 0.010
 Positive reframing 0.89 [0.63–1.27] 0.530

Demographic and clinical variables independently associated with the choice of AS included: age 40–64 years (compared with <40 years)—OR 2.78 [1.23–6.30, p = 0.014], age ≥65 years—(compared with <40 years) OR 8.43 [2.13–33.37, p = 0.002], and education level of high school or lower—OR 4.41 [1.25–15.53, p = 0.021]; however, the choice of AS was inversely associated with the surgeon of record being affiliated with the study institution—OR 0.29 [0.11–0.76, p = 0.012] (Table 2).

Psychological factors independently associated with the choice of AS included: agreement with a statement “I am afraid that I will need to take thyroid hormone because of the operation”—OR 1.24 [1.11–1.39, p < 0.001], but inversely associated with Fear of Disease Progression SF total score—OR 0.94 [0.90–0.98, p = 0.006] and the Brief Cope-Active Coping subscale (reflected agreement with statements indicating “concentrating my efforts on doing something about the situation …” and “taking action to make the situation better”)—OR 0.43 [0.28–0.66, p < 0.001].

However, general fear of surgery, fear of hypocalcemia, fear of changes in voice, and fear of the appearance of the surgical scar were not significantly independently associated with the choice of AS (Table 3). Further, coping by denial, self-distraction, or behavioral dysregulation (giving up) were not significantly independently associated with the choice of AS (Table 3).

Discussion

Our primary finding is that in this a Canadian population of 200 patients with low-risk PTC <2 cm in maximal diameter who enrolled in a study offering the choice of AS or surgery, 77.5% [71.2–82.7%, 155/200] of individuals chose to undergo AS. Our study population reported a high level of confidence in medical decision making, a high rate of involvement deciding on primary PTC management, and ultimately the participants’ decision satisfaction level was generally high.

We found that older individuals and those with less formal education were more likely to select AS over surgery. There is substantial evidence supporting the association of older age with preference for AS in men with low-risk prostate cancer (22). However, there is a limited, conflicting literature on the association between education level and choice of AS for low-risk prostate cancer (22). The choice of AS may differ among malignancies, which may be subject to different patient demographics, prognosis, and AS protocol procedures. More research is needed to understand any relationship between education level and choice of AS for the management of PTC.

We observed that the rate of preference for AS varied significantly by the affiliation of the patient’s surgeon. Of the 142 patients who reported having a surgeon affiliated with the study hospital, 72.5% chose AS whereas 89.7% of the 58 patients whose surgeon was affiliated with an outside hospital chose AS. The most likely explanation is that patients who were originally seen by thyroid cancer specialists in outside institutions and who strongly preferred AS were more likely to agree with a referral to our institution. There may also be a potential influence of practice setting on the choice of AS.

In a recently published Ontario administrative database study examining low-risk prostate cancer disease management, Timilshina et al. reported that men who received oncologic care from a provider affiliated with an academic center or regional cancer center were less likely to undergo AS, compared with men receiving oncology care from providers in other settings (23). However, in a recent thyroid specialty physician survey study, McDow et al. reported that an academic tertiary care practice setting was not significantly associated with the physician’s recommendations for AS of PTC (24). Our study was not designed to examine the influence of physician practice setting on patient choice of AS, but our findings highlight the importance of exploring this issue in future AS implementation research.

Psychological factors are important factors influencing patients’ choice of AS. Our participants who had a greater fear of PTC progression or those with an active coping style (wanting to do something about their situation) were more likely to choose surgery, whereas those who had a greater fear of needing to take thyroid hormone after surgery were more likely to choose AS. These findings generally confirm those of previously published mixed methods and qualitative research (11,25). However, in a recent thyroid specialist physician survey, only 13–20% of physicians reported believing that the patient’s thyroid cancer disease management preference is influenced “a great deal” by concern about “the need for life-long medication” (24).

Thus, there may be some physician underappreciation of patients’ concerns about the potential need to take thyroid hormone treatment after thyroidectomy.

An important strength of our study is its prospective design and completeness of the dataset. Some limitations of this research include the single-center design, the need for protocol amendments in the course of the study (in response to patient and physician interest in expanding the eligibility criteria as well as the COVID-19 pandemic, as detailed in Supplementary Table S1), and the lack of available validated questionnaires for some thyroidectomy-specific surgical fear outcomes that were important to explore (e.g., fear of having to take thyroid hormone treatment after thyroidectomy).

As our study included patients referred from thyroid cancer specialists outside of the study hospital, our results are also subject to potential referral bias. Further, our study population was exclusively conducted in residents of the Greater Toronto Area, which may limit the external generalizability of our findings to other populations. Another potential limitation is that we focused on patient perspectives on PTC management decision making and did not examine their physicians’ perceptions nor formally audio nor video record any patient–physician interactions.

In conclusion, in our study, about three-quarters of patients with small, low-risk PTC chose AS in lieu of immediate surgery. The decision to accept AS was made in in the context of life stage (e.g., older age), and it reflected the preference of a health state of avoiding surgery and the potentially having to take thyroid hormone replacement, over living with a small, low-risk PTC. We are continuing to follow our study population and plan to report long-term patient outcomes in the future as part of an expanded multi-center, pan-Canadian study (26).

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