A comparative study of quality of life in patients with papillary thyroid carcinoma undergoing microwave ablation vs. Total thyroidectomy

Abstract Objective To compare the health-related quality of life (HRQoL) of patients with T1N0M0 papillary thyroid carcinoma (PTC) who underwent microwave ablation (MWA) and those who underwent total thyroidectomy (TT). Materials and methods From February 2018 to February 2022, 180 T1N0M0 PTC patients were enrolled in present study, including 90 in the MWA group and 90 in the TT group, respectively. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and Thyroid Cancer-Specific Quality of Life Questionnaire (THYCA-QoL) were completed by patients to evaluate their HRQoL scores Results According to the results of the EORTC-QLQ-C30, there was a significant difference in the scores of global health, physical, emotional, etc. between the two groups, which indicated that the quality of life in these items in the MWA group was better than those in the TT group (all p < 0.05). According to the results of the THYCA-QoL, all items had significant differences between the two groups except for headache, which demonstrated the thyroid-specific quality of life was higher in the MWA group than in the TT group (all p < 0.05). Conclusion Ultrasound (US)-guided MWA offers a significant advantage in HRQoL over TT in T1N0M0 PTC patients, which provides an important reference for MWA as an alternative strategy to TT.


Introduction
The incidence of thyroid carcinoma continues to rise worldwide.Papillary thyroid carcinoma (PTC), as the most common subtype of thyroid cancer, carries a promising prognosis, low mortality rate, and over 90% 10-year survival rate [1,2].Thyroidectomy is often applied to manage PTC as a traditional method [3,4].However, total thyroidectomy (TT) could affect thyroid function, and patients need to receive lifelong drug replacement therapy [2,5,6].Thermal ablation (TA), including microwave ablation (MWA), radiofrequency ablation (RFA), and laser ablation, has emerged as an alternative option for selected patients with PTC [7][8][9][10].The results of several clinical studies showed that MWA is an effective, safe, and feasible method and has no influence on thyroid function in treating T1N0M0 PTC [11][12][13].
Possibly due to hypothyroidism and drug replacement therapy, PTC survivors after surgery are often reported to have decreased health-related quality of life (HRQoL) compared with the healthy population and even other types of cancer survivors [14][15][16].However, several recent studies reported the outcomes of TA versus surgery and showed that the TA group had a lower complication rate, lower postoperative pain, and a better cosmetic result which indicated that there was a higher posttreatment thyroid-related quality of life in the TA group [9, 17,18].
Considering the longevity of T1N0M0 PTC patients' survival time and a similar therapeutic effect between surgery and MWA posttreatment [19,20], more attention should be given to patients' HRQoL during the choice of treatment.The aim of the present study was to compare the HRQoL outcomes for T1N0M0 PTC patients treated by MWA versus TT.

Patients
This retrospective study was approved by the institutional review board of China-Japan Friendship Hospital.Written informed consent was obtained from each patient and written informed consent for publication of their data was waived by the ethics committee of China-Japan Friendship Hospital.The Clinical Trial Number is ChiCTR-ONC-17010406 (The multicenter study for the thermal ablation of thyroid papillary microcarcinoma), and the registration date was 12 January 2017 0:00:00.
The target population was patients who had undergone US-guided MWA or TT to manage T1N0M0 PTC at China-Japan Friendship Hospital.Patients completed the questionnaires when they came to hospitals for review.The researcher offered assistance to patients who had problems with understanding questionnaires but avoided using any language to affect their judgment.The inclusion criteria were as follows: (1) PTC confirmed by pathology with a maximum diameter �2 cm; (2) no regional lymph node metastasis (LNM) or distant metastasis; (3) no postoperative recurrence or major complications; (4) follow-up time longer than 3 months; and (5) clear thinking and ability to understand and cooperate with the survey.The exclusion criteria were (1) any combination with serious primary disease in the liver, kidney, hematopoiesis, or endocrine system and (2) a history of mental illness, personality disorders, cognitive impairments, or organic brain disease.

MWA procedure
Before ablation, contrast-enhanced US (CEUS) examination was used to evaluate the extent of the target tumor and its enhancement mode.The procedure was performed under local anesthesia.Patients were maintained in a supine position with the neck extended.The ablation site was routinely sterilized and draped with sterile towels.A mixture of 2% lidocaine and 0.9% normal saline (1:3) was administered at the intended puncture point as local anesthesia.An 18gauge core needle (Hakko Medical) was inserted along the thyroid capsule into the fascial space between the thyroid lobe bearing the tumor and the adjacent critical structures.Then, normal saline was injected to separate the fascial space and keep the surrounding critical structures far from the thyroid lobe to avoid heat injury.The separation distance was generally greater than 4 mm and maintained by continuous and slow injection of normal saline during ablation [21].A cooled MWA antenna with a 3-mm active tip (Intelligent Basic Type Microwave Tumor Ablation System, Nanjing ECO Microwave System) was inserted into the targeted tumor under US guidance; A multipoint ablation strategy was employed; the power was 30 W, and the radiation time was 15-20 s at each point.The ablation was terminated when the hyperechoic zone covered the entire tumor.CE US was performed to evaluate the ablation effect approximately 3 min later.Representative images of the ablation process are shown in Figure 1.

Surgery procedure
The patient was placed in a supine position with the neck fully extended.After successful general anesthesia, the operation site was routinely sterilized and draped with sterile towels.The surgical strategy for TT followed the American Thyroid Association Management guidelines [2].An approximately 5-8cm transverse neck incision was made above the sternal notch.After the recurrent laryngeal nerve (RLN) and parathyroid gland were identified and protected, the thyroid gland was removed.

Demographic and clinical characteristics
Demographic and clinical characteristics included age, sex, marital status, education status, family history of thyroid cancer, comorbidities, and follow-up time.

EORTC-QLQ-C30
The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) was adopted as a valid measurement of the quality of life for cancer patients.It consists of 5 functional scales (physical, role, cognitive, emotional, and social), 3 symptom scales (fatigue, pain, nausea, and vomiting), 6 single-item common symptoms (dyspnea, loss of appetite, insomnia, constipation, diarrhea, and financial difficulties), and global health status (GHS) subscales.The time frame of the questions is the previous week, and each item is scored on a four-point response scale ranging from 1, "not at all" to 4, "very much", except the global status scale, which is scored on a seven-point modified linear analog scale ranging from 1, "very poor" to 7, "excellent".After linear transformation, all scales and single-item measures range in score from 0-100.A higher score on the functional scales and global status scale means a better level of functioning and HRQoL, whereas a higher score on the symptom scales and single item corresponds to more discomfort and complaints [22].Additionally, the QLQ-C30 summary score is used to measure the overall HRQoL and is calculated with the means of all scales except the global health scale and financial difficulties scale.It ranges from 0-100, with a lower score indicating poorer HRQoL [23].

Thyroid cancer-specific quality of life questionnaire
The Thyroid Cancer-Specific Quality of Life questionnaire (THYCA-QoL), as a methodologically developed questionnaire, was used to assess thyroid-specific symptoms in thyroid cancer survivors.The questionnaire consists of seven symptom scales (neuromuscular, voice, concentration, sympathetic, throat/mouth, psychological and sensory problems) and six single items (problems with scar, feeling chilly, tingling hands/feet, gained weight, headache, less interest in sex), with a time frame of the previous week (except for less interest in sex item, which is four weeks), and each item is scored on a four-point response scale ranging from 1, "not at all", to 4, "very much".Scores were linearly transformed to a 0-100 scale.A higher score on this scale means more symptoms and complaints [24].

Statistical analyses
Propensity score matching was used to control for confounding factors between the two groups.Continuous data are presented as the means ± SDs if the data fit a normal distribution or as medians with 25-75% IQRs if the data did not fit a normal distribution.Categorical variables are presented as frequencies (percentages).Demographic and clinical characteristics were compared by v 2 statistics between groups.A nonparametric test (Kruskal-Wallis) was used to compare the different scales of EORTC QLQ-C30 and THYCA-QoL between groups.All statistical analyses were calculated with 26.0 SPSS statistical software.p < 0.05 was considered statistically significant.

Demographic and clinical characteristics
The demographic and clinical characteristics are described in Table 1.Data from 544 patients with PTC who underwent MWA or TT from February 2018 to February 2022 were viewed.After the exclusion of 216 patients who did not meet the inclusion criteria, 328 patients were included among them.A total of 125 patients who underwent MWA (125/328, 38.1%; mean age, 44 years ± 13; 31 men, 94 women) were divided into the MWA group, and 203 patients who underwent TT (203/308, 61.9%; mean age, 49 years ± 14; 42 men, 161 women) were divided into the TT group.The median follow-up time was 18 months (IQR, 3-30 months).After propensity score matching, 180 patients were ultimately included, with 90 in each group (Figure 2).After propensity score matching, there was no significant difference in baseline between the two groups.
On the symptom scale, the scores for fatigue and pain in the MWA group were lower than those in the TT group.The scores of fatigue in MWA vs. TT were 11.11 (IQR, 0.00-22.22)vs. 22.22 (IQR,, p < 0.001, and the scores of pain in MWA vs. TT were 0.00 (IQR, 0.00-0.00)vs. 0.00 (IQR, 0.00-16.67),p ¼ 0.004.These results showed that there were more fatigue and pain symptoms in the patients in the TT group than in those in the MWA group.In the single items, insomnia, constipation, and financial difficulties scores in the MWA group were lower than those in the TT group.The scores of insomnia in MWA vs. TT were 0.00 (IQR, 0.00-33.33)vs. 33.33(IQR, 0.00-33.33);p ¼ 0.021, they were 0.00 for constipation in MWA vs. TT (IQR, 0.00-0.00)vs. 0.00 (IQR, 0.00-33.33);p ¼ 0.048, and were 0.00 (IQR, 0.00-0.00)vs. 0.00 (IQR, 0.00-33.33)for financial difficulties in MWA vs. TT; p < 0.001.(Table 2).These results demonstrated that patients had more problems with insomnia and financial difficulties in the TT group than in the MWA group.

The results of THYCA-QoL
According to statistical analysis, except for the headache scale, other scales had significant differences between the  two groups (all p < 0.05), including neuromuscular, voice, concentration, etc. (Table 3).

The results of oncological outcome
According to the statistical analysis, the technical success rates were 100% in both groups.According to the follow-up data, there were no significant differences in disease progression, metastasis-free survival, overall survival, and local tumor control between the two groups (Table 4).

Discussion
The incidence of PTC is increasing worldwide.MWA, as a minimally invasive, safe, and effective treatment, has a similar therapeutic effect compared with traditional surgical treatment for selected patients [25,26].HRQoL is an important endpoint in medical and health research and has been shown to be a strong predictor of survival [27].Therefore, possible impairments in HRQoL during the patients' posttreatment should be of considerable concern.
Compared with surgery including TT, hemithyroidectomy, endoscopic thyroidectomy, RFA as a thermal ablation has shown favorable outcomes on HRQoL in patients with papillary thyroid microcarcinoma [28][29][30].In this regard, a comparative study between RFA and surgery for papillary thyroid microcarcinoma showed that patients in the surgery group suffered more adverse effects than those in the RFA group, especially those who underwent TT.Additionally, the patients in the surgery group suffered more problems with scarring, which was one of the major causes of quality of life decline in the surgery group [31].However, there have been no reports on MWA versus TT for HRQoL in patients with T1N0M0 PTC.Two questionnaires were applied in the present study.The EORTC QLQ-C30 questionnaire is considered to assess general HRQoL in cancer patients, while the THYCA QoL is an instrument to measure specific aspects of HRQoL in thyroid cancer.The combination of these two questionnaires would be more beneficial to assess all major dimensions of HRQOL in thyroid cancer survivors.
The results of our study indicated that there were several significant differences in the EORTC QLQ-C30 questionnaire and the THYCA-QoL questionnaire between the two groups.According to the statistical analysis of the EORTC QLQ-C30 questionnaire and the THYCA-QoL questionnaire, the HRQoL of patients in the MWA group was obviously higher than that of patients in the TT group.Two reasons may explain these results.The first reason is that there was less trauma in the MWA group than in the TT group [32].The extent of the trauma of TT includes trauma to the skin, subcutaneous fascia, muscular layer, and thyroid itself.The above structures involve blood vessels, nerves, lymph vessels, etc.The structures and function of these tissues are inevitably impaired and even lost, especially for nerves and lymph vessels [33][34][35].These reasons could lead to diverse impacts on the patient's HRQoL in the TT group, such as scales of pain, voice, throat/mouth, sympathetic, scar, etc., as mentioned in the EORTC QLQ-C30 and THYCA-QoL questionnaires.Compared with TT, the extent of the trauma of MWA only includes two parts.One is the puncture wound, which only causes little damage along the needle track.The other is thermal energy from microwaves.MWA can target the nodes precisely under ultrasound guidance in real-time, and the thermal field is confined to the thyroid capsule.Moreover, the surrounding tissues will be protected by consistent injection of isolation fluid along the thyroid capsule to avoid thermal damage [21,25].Therefore, the impact of MWA on surrounding structures is mild, which contributes to fewer symptoms and has less influence on HRQoL after MWA.
The second reason is the different influences on thyroid function between MWA and TT.Several studies have shown that MWA has almost no influence on thyroid function [36] and even enhances immune function temporarily [37].MWA targets the nodes precisely and damages very few surrounding tissues.Therefore, the patients' thyroid function had no obvious variation, and there was no need to have thyroxine replacement therapy after MWA.In contrast, the thyroid function of patients after TT tends to be almost lost or completely lost due to partial or total removal of the thyroid gland.Therefore, most patients need to receive lifelong thyroxine replacement therapy.For patients with normal thyroid function, the secretion of thyroxine is exactly in accordance with human body metabolism because of the precise feedback and regulatory function of the thyroid [38].However, patients with thyroid dysfunction always take a certain dose of thyroxine every day and lose feedback and regulate the function of the thyroid.Thus, they often suffer from slight hyperthyroidism or hypothyroidism, which certainly results in various thyroid dysfunction symptoms, such as symptoms of fatigue, gained weight, emotional changes, neuromuscular symptoms, psychological symptoms, and chilly feelings, as mentioned in the EORTC QLQ-C30 and THYCA-QoL questionnaires.
A few limitations of our study should be acknowledged.First, this was a retrospective study, and our results may be affected by selection bias despite applying statistical analysis of propensity score matching.Second, there were no preoperative HRQoL scores in the two groups; thus, we cannot evaluate the difference in HRQoL pre-and post-operation in the two groups.
In conclusion, this study showed a significant advantage of HRQoL in T1N0M0 PTC patients treated with MWA over those treated with TT.Our study provides an important reference for patients to choose between MWA and TT.

Figure 1 .
Figure 1.Images of a 52-year-old woman with papillary thyroid carcinoma in the right lobe treated with microwave ablation.(A) Ultrasound showed a hypoechoic tumor in the right lobe (white arrows).(B) The hydro dissection technique (blue arrows) was used to keep the thyroid lobe far from the carotid artery, trachea, and nerves to guarantee the safety of ablation.(C) The microwave ablation antenna was precisely inserted into the tumor (blue arrows) and the ablation zone showed a hyperechoic pattern in the tumor around the antenna tip (white arrows).(D) Postablation CE-US image showed no enhancement in the tumor (white arrows).
Unless otherwise specified, data are numbers of patients, with percentages in parentheses.MWA: microwave ablation; PSM: propensity score matching; TT: total thyroidectomy.� Statistically significant.⬆Data are means ± SDs. ⬇Data are medians, with IQRs in parentheses.

Table 2 .
Comparation of EORTC-QLQ-30 in patients with PTC who underwent MWA vs. those who underwent TT.

Table 3 .
Comparation of THYCA-QoL in patients with PTC who underwent MWA vs. those who underwent TT.

Table 4 .
Oncological outcome in the MWA group and the TT group.