Quality of Life Impact of External Beam Radiotherapy for Advanced Thyroid Carcinoma

Abstract

Background:

External beam radiotherapy (XRT) has an established role in the management of recurrent or advanced well-differentiated thyroid carcinoma (WDTC). The goal of this study was to investigate the impact of this additional intervention on the quality of life (QOL) compared with total thyroidectomy (TT), with or without adjuvant radioactive iodine (RAI).

Methods:

A cross-sectional analysis using validated QOL instruments was performed. Patients receiving XRT between 1992 and 2008 for WDTC were identified and offered study participation. The Quality of Life Radiation Therapy Instrument and the Head and Neck Companion Module were administered retrospectively (N=13). For a comparison, patients previously treated with TT (N=11) alone as well as TT with postoperative RAI (N=11) for WDTC were also evaluated.

Results:

Thirty-four patients were included in the analysis. The XRT group reported significant decreases in chewing, swallowing, and appetite, and significant increase in pain, compared with both the RAI group and the TT group. Significant differences were reported for questions with regard to peace of mind, feeling discouraged, saliva, taste, ability to eat regular food, and concerns for the appearance of the neck in both RAI and XRT groups compared with TT patients. Subscale analysis of head and neck specific questions demonstrated significant overall differences for both RAI and XRT groups compared with thyroidectomy alone, with no differences observed between RAI and XRT groups in a direct comparison.

Conclusions:

RAI therapy results in a measurable decrease in head and neck specific QOL measures compared with TT alone. The addition of XRT results in additional measurable morbidity secondary to pain and dysphagia.

Introduction

T hyroid cancer constitutes ∼1% of newly diagnosed cancer cases in the United States, representing about 20,000 cases a year. Well-differentiated thyroid cancer accounts for roughly 90% of these cases (1).

In general, patients with WDTC are considered as having an excellent prognosis. Survival rates at 20 years are estimated to be more than 95%. It is frequently assumed, therefore, that the level of emotional distress is lower in these patients when compared with the overall cancer population and that quality of life (QOL) is comparable to the general population (2). With the increased awareness of the impact of the diagnosis and management of cancer on QOL, attention has been given to the impact of thyroid cancer on QOL. This is particularly significant, as this disease frequently affects young patients in the prime of their life (3).

The mainstay of therapy for WDTC remains surgery, specifically thyroidectomy, with radioactive iodine (RAI) ablation as indicated. Studies of QOL in WDTC to date have focused primarily on the impact of these interventions both during and after treatment as compared with controls from the general population (2,4 –6). There remains, however, a subset of patients with advanced or recurrent disease. Although somewhat controversial, external beam radiotherapy (XRT) is an established treatment option in these patients (1,7 –11). The toxicity and impact of external beam radiation on QOL to the head and neck in the setting of squamous cell carcinoma is well documented (12 –16). This population differs from the thyroid cancer population, which tends to be younger and predominantly female. Similarly, radiation target volumes for thyroid cancer differ when compared with head and neck cancer. As a result, the sequelae and effects on QOL observed for mucosal head and neck cancer cannot be considered to be generalizable to the thyroid population. The goal of this study was to evaluate the impact of XRT on QOL in the setting of advanced or recurrent well-differentiated thyroid carcinoma (WDTC).

Methods

Approval for this study was obtained from the Institutional Review Board at the University of Kentucky. Patients who received external beam radiation for recurrent WDTC at the University of Kentucky, Department of Radiation Oncology, between 1992 and 2008 were identified through clinical records and then offered study participation. Treatment controls were identified through a search of Current Procedural Terminology codes for thyroidectomy performed by participating investigators, and identified patients were offered participation. While patients receiving XRT were contacted directly to maximize enrollment, treatment control group patients were offered participation during routine clinic follow-up visits over a one-year period. The intention was to establish a reference range for a comparison of the radiation group and not to maximally capture data on the thyroidectomy population. Informed consent was obtained in writing, and questionnaire data were collected by mail or during follow-up clinic visits. Chart reviews were accomplished for all participants to gather data about demographic and clinical variables.

Participants were retrospectively administered a 39-item questionnaire consisting of the Quality of Life–Radiation Therapy Instrument (QOL-RTI) and Head and Neck (H&N) Companion Module. Questions 1–24 comprised the QOL-RTI (Table 1) (17), question 25 asked about overall QOL, and questions 26–39 consisted of the H&N Companion Module (Table 2) (18). All questions were scored on a 10-point Likert scale with higher scores indicating better QOL. The total score for the QOL-RTI, the H&N Companion Module, and the complete questionnaire were tabulated. In addition, participants' scores on the four subscales of the QOL-RTI (Functional/Health, Socioeconomic/Family, Emotional/Psychological, and General QOL) were considered (18). Finally, the mean response to each question in the H&N Companion Module was evaluated.

Table 1.

Quality of Life–Radiation Therapy Instrument and Related Subscales

Question number	Question
Functional/health subscale
2	I have a normal appetite.
3	I enjoy good food.
4	I am bothered by nausea.
5	I feel tired.
9	I have skin discomfort in the treatment area.
19	My illness interferes with my ability to take care of myself.
22	I experience pain.
23	My sexual activity is satisfactory.
24	I sleep at night.
Socioeconomic/family subscale
12	I look forward to seeing my friends and family.
13	My healthcare is interfering with my job, school, or other activities.
14	I look forward to getting out and doing things.
15	I feel satisfied with my life.
16	I receive support from the medical team after my cancer.
17	I receive support from my family and friends.
Emotional/psychological subscale
1	My appearance is almost similar as earlier when I was diagnosed as having cancer.
6	My cancer treatments frighten me.
7	I worry about my bills.
8	I feel cheerful.
10	I feel hopeful about my future.
11	I feel discouraged.
18	I receive support from my relationship with God/a “supreme being.”
General quality of life subscale
20	In general, I would say my health is good.
21	I feel in control of my life.

Adapted from Johnson et al. (17)

Table 2.

Head and Neck Companion Module for Quality of Life-Radiation Therapy Instrument

Question number	Question
26	I have pain in my mouth.
27	I have pain in my throat.
28	I have a normal amount of saliva.
29	My saliva is very thick.
30	I have trouble eating or breathing because of mucous in my mouth or throat.
31	I can taste food as a normal person would.
32	I am bothered by how my face and neck look.
33	People have trouble understanding me when I speak.
34	I am bothered by frequent or severe coughing.
35	I can chew as well as ever.
36	I am eating regular food.
37	I am embarrassed to eat in public or with others.
38	I can swallow all food without difficulty (including meat and bread).
39	I can swallow any type of liquid without difficulty.

Adapted from Trotti et al. (18).

Statistical significance was set at p<0.05. Before data analysis, missing data were addressed. If more than half of the questions on a participant's QOL-RTI and/or H&N Companion Module were not completed, all their data were omitted from analysis. If only one to two questions were not answered by a participant, then the samples' average score for that question was used as a replacement. After missing data analysis, nonparametric Kruskal–Wallis tests were used to examine differences in QOL across the three treatment groups (thyroidectomy alone, thyroidectomy with adjuvant RAI, and external beam radiation), with a one-way analysis of variance used to test compiled mean test scores. A priori power analysis indicated that in order to demonstrate a mean difference of three points for individual questions on the H&N Companion Module with an average standard deviation of two, as seen in the report of Trotti et al., seven recurrent WDTC patients treated with external-beam radiation would be needed (18). Power analysis was performed with π=0.80; thus, the probability of a Type I and Type II error was set at 0.05 and 0.20, respectively. Stata 9.0 (College Station, TX) statistical software was used for analysis.

Results

Overall, 34 patients were enrolled in the study and completed survey information sufficiently for inclusion in the analysis. The average age was 50.8±13.2 years. No significant differences in age were observed between the groups. Eighty percent of participants were women. Demographics across study groups are outlined in Table 3. Out of the 36 patients identified at our institution as having received external beam radiation in the management of WDTC, 13 (36.1%) elected to participate. All patients treated with external beam radiation were at least 18 months out from this intervention, with a maximum of 122 months. No significant differences in the distribution of age or sex were observed across groups. Using the date of initial surgery as a baseline, no significant differences were observed across groups with regard to the interval from the date of the first surgery (thyroidectomy) to the date of the interview (p=0.6).

Table 3.

Demographic Data

	Treatment
	TT	TT+RAI	TT+RAI+XRT	Overall
Age (years [mean±SD])	53.5±11.1	51.5±14.2	48.2±14.5	50.9±13.2
Sex (n)
Male	1	4	2	7
Female	9	7	11	28
Diagnosis (n)
Papillary	2	10	12	24
Follicular	1	1	1	3
Benign	7	0	0	7
Additional surgery [n (%)]	0	2 (18%)	6 (46.5%)	8 (23.5%)
Interval from thyroidectomy to interview (days; p=0.6)
Mean±SD	1516±2776	2626±5430	3082±1810	2446±3541
Range	205–9771	23–17,762	316–6970	23–17,762

TT, total thyroidectomy; RAI, radioactive iodine; XRT, external beam radiotherapy; SD, standard deviation.

Cumulative QOL scores are summarized in Table 4. Average overall QOL was reported as 8.2±2.2 on a 10-point scale. No significant differences were observed for overall QOL measures. Assessment of QOL subscales of the QOL-RTI instrument demonstrated no significant differences with regard to functional/health, socioeconomic/family, emotional/psychological, or general QOL categories. Comparisons using the H&N companion module for the QOL-RTI, however, demonstrated significant decreases in overall head and neck specific QOL for both RAI (p=0.02) and XRT (p=0.01) groups when compared with total thyroidectomy (TT) alone.

Table 4.

Quality of Life Scores by Treatment Group

		Treatment
	n	TT	TT+RAI	TT+RAI+XRT	Overall	p-Value
Total QOL	23	219.6±28.5	219.9±27.0	216.9±16.8	218.5±16.8	0.95
Overall QOL (question 25)	25	8.2±2.9	8.2±1.8	8.3±1.9	8.2±2.2	0.7
QOL-RTI	25	148.0±23.4	155.8±21.9	147.1±23.9	150.3±23.9	0.6
Head and neck module	32	65.7±8.2	57.3±7.3	55.9±8.1	59.3±8.7	0.02
Functional/Health	31	44.9±3.7	42.5±12.0	45.0±12.0	44.2±9.9	0.8
Socioeconomic/Family	30	44.0±9.6	48.0±6.1	45.3±4.1	46.0±6.3	0.4
Emotional/Psychological	27	43.4±5.4	46.2±9.9	42.6±9.3	44.0±8.9	0.6
General QOL	33	16.7±5.4	16.9±3.1	14.6±4.8	16.0±4.5	0.4

Values represent mean±SD. Boldface indicates statistical significance (p<0.05).

QOL, quality of life; QOL-RTI, Quality of Life–Radiation Therapy Instrument.

No significant differences were reported with regard to the questions concerning the overall QOL (p=0.7). Using the QOL-RTI, decreases in QOL were reported with regard to peace of mind (p=0.006), feeling discouraged (p=0.02), and pain (p=0.02). Decreased QOL was observed in both RAI and XRT groups with regard to peace of mind and feeling discouraged when compared with surgery alone. Patients in the RAI group also reported a decreased ability to enjoy good food (p=0.03) compared with thyroidectomy patients, which was not observed in the XRT group (p=0.20). Patients receiving XRT reported decreased QOL secondary to pain (p=0.003), decreased appetite (p=0.03), and religious support systems (p=0.04) compared with thyroidectomy patients, which was not observed in the RAI group.

Using head and neck specific questions, decreased QOL was observed in both RAI and XRT groups with regard to normal saliva (p=0.005), normal taste (p=0.04), ability to eat regular food (p=0.008), and concerns regarding the appearance of the neck (p=0.008). These results were significant in a direct comparison of both RAI and XRT to TT. In addition, patients treated with XRT reported decreased QOL with regard to chewing (p=0.02) and swallowing (p=0.001) that was not observed in RAI patients.

Discussion

Well-differentiated thyroid cancer remains primarily a surgical disease. The vast majority of cases are effectively managed with thyroidectomy and RAI ablation. It is the management of the ∼10% of patients with locally advanced or recurrent disease that remains controversial (1). Given the absence of prospective clinical trials, no true consensus exists as to who is a candidate for XRT, and the approach frequently differs across centers (7,10). According to American Thyroid Association guidelines, the use of external beam irradiation for treating the primary tumor should be considered in patients older than age 45 with grossly visible extrathyroidal extension at the time of surgery and a high likelihood of microscopic residual disease, and for those patients with gross residual tumor in whom further surgery or RAI would likely be ineffective (19). Given doses of up to 70 Gy and target volumes that extend from the hyoid to the aortic arch which include both cervical nodal basins, it is not surprising to observe toxicities that are comparable to those observed in the management of squamous cell carcinoma of the head and neck (8).

There is some evidence to suggest little difference in QOL measures in patients treated for WDTC with standard therapy when compared with treatment control groups, particularly population-based controls (6,20). However, significant differences in QOL in patients with well-differentiated thyroid cancer, and even thyroid disease in general, have been previously observed. Measurable differences have even been observed in QOL in patients with Hashimoto's thyroiditis without cancer that could be correlated with anti-thyroperoxidase levels (21). In patients undergoing RAI therapy in a hypothyroid state, significant increases in the prevalence of anxiety have been observed (22,23). Detectable improvement in depression related scores has been associated with improvement in serologic improvement in thyroglobulin levels during follow up (24).

More long-term changes have also been observed (4,25,26). Lee et al. reported a decrease in QOL across all functional domains in Korean survivors of differentiated thyroid cancer compared with treatment controls, particularly with regard to anxiety, depression, and fatigue (27). Using health-related QOL measures, Pelttari et al. demonstrated a decrease in measures of sleeping, speech, and distress in thyroid cancer patients who were an average of more than 12 years out from initial therapy when compared with a normal population (28). However, overall QOL measures were found to be comparable for both groups.

Multiple predictors have been shown to be associated with QOL changes in patients with WDTC. Frequently observed side effects of RAI therapy in WDTC affecting QOL include xerostomia, sialadenitis, fatigue, and weight gain (29). Taieb et al. found no significant changes in QOL at 9 months after RAI therapy when compared with baseline using the functional assessment of chronic illness and therapy instrument. However, higher QOL scores were observed in males, age <45 years, “married” status, and recombinant human thyrotropin stimulation (30). Using the University of Washington QOL questionnaire, Almeida et al., likewise demonstrated improved QOL scores on several subscales (31). Furthermore, patients who had modified neck dissection reported worse chewing and shoulder scores than their selective paratracheal node dissection counterparts. Patients receiving more than 150 mCi of RAI reported significantly worse pain, swallowing, chewing, speech, taste, anxiety, and composite scores (31). Additional concerns for impaired QOL have been observed in the elderly as well as the poorly educated (3). There is some evidence to suggest that the duration of cure may result in the return of QOL measures to baseline with long-term follow up (5).

The literature on QOL in WDTC, for the most part, is focused on the impact of surgery and RAI therapy on QOL measures compared with normal treatment controls. In general, it would appear that there is a measurable, but minor impact on QOL in these series. It would appear that the greatest impact results not from the surgery itself but more from the side effects of RAI as well as the emotional discourse arising from the cancer diagnosis itself. This study is one of the few, if not the only study, that measures the effects of the additional impact of XRT on QOL in these patients. Measurable differences in taste, salivary quality, peace of mind, and the appearance of the neck were observed in patients with previous thyroid surgery and RAI. The additional QOL burden of XRT in the setting of advanced WDTC would appear to include concerns with pain, decreased appetite, chewing, and swallowing that are not observed in the thyroid cancer population. These are issues that would be frequently observed in populations treated with XRT for upper aerodigestive tract head and neck cancer. Despite differences in treatment protocols and treatment ports in these patients, it would appear that patients with WDTC are not immune to these sequelae.

Despite a relatively small sample population, measurable differences in radiation specific QOL measures were observed in patients with WDTC treated with XRT. The available population sample of patients treated with XRT within a single institution would be anticipated to be relatively small. As with all voluntary studies, there exists the potential of bias arising from characteristics of patients who are more likely to participate in these types of studies. All patients treated with XRT for WDTC were offered study inclusion. No significant trends in clinical or demographic differences were observed between participants and nonparticipants. The population of treatment control patients treated with thyroidectomy alone or thyroidectomy with RAI would certainly represent a much larger potential sample pool. The intention of this study was to perform a pilot exploration of the effects of XRT on QOL in these patients. Given the finite and small sample size of this group, it was anticipated that the primary limitation of this investigation would be sample size. It was not the goal of the study to precisely quantify QOL in the thyroidectomy patient, and, therefore, attempts were not made to maximize the participation of these patients. However, it was necessary to have at least some reference values for a comparison to determine the relative significance of QOL changes with XRT. Sample size calculations determined that a clinically significant difference, determined to be three points on a ten-point Likert scale, could be observed with a sample size of seven per group. With more than 10 patients in each group, the observed differences would be expected to be valid. Given the pilot nature of the study, only a sufficient number of subjects that were necessary to draw conclusions of merit were included. Most of these patients were enrolled in clinics during routine long-term follow up over a one-year period. These occurrences, with regard to patient enrollment, can be considered nothing other than random. No other systematic attempts at the enrollment of treatment controls were performed. A multi-center study with a pooled sample population of radiotherapy patients may add to the robustness of the findings of these preliminary data simply by increasing the number of patients treated with external beam radiation.

Patients who undergo external beam radiation for thyroid cancer, by definition, would be expected to have more advanced disease. As a result, in addition to XRT and RAI, they are more likely to have undergone additional surgical procedures beyond TT. In this study, 46.5% of patients treated with external beam radiation underwent additional surgery as well. It is difficult to determine which of the observed effects on QOL observed in this group can be attributed to the radiation, and which can be attributed to, or exacerbated by, the additional surgery. Although it is unlikely that additional surgery is associated with observed salivary issues and dysphagia, there is undoubtedly some effect on observed differences in pain, appearance, and emotional indices.

No significant differences in the period of time from surgery to the date of the interview were observed across groups. All patients receiving XRT were at least 18 months out from this intervention. What is important to note is that these data do not reflect the time from RAI, last surgical procedure, or date of XRT. Given the nature of well-differentiated thyroid cancer, these therapies can occur over many years, and may not accurately reflect the intervention most significantly affecting QOL.

Despite the observed impact of both RAI and XRT on QOL, observed overall QOL scores were not significantly different across groups. Although no “normal control” populations were used for a comparison, there is good evidence to suggest that patients undergoing TT alone have QOL profiles similar to the normal population. As a result, it would appear that despite aggressive intervention and observed discrete head and neck and radiation specific differences in QOL, for the most part, this population is doing relatively well overall.

As seen from the number of instruments used to measure QOL in the thyroid cancer population noted earlier, there would appear to be some controversy as to the optimal means for measuring QOL in these patients. A comparison of head and neck cancer-related questionnaires reveals significant overlaps (32). However, no unique, ideal questionnaire exists, and instrument selection depends on the population to be studied as well as the intervention of interest. In general, the thyroid cancer population is perceived as having a relatively high QOL, comparable to the normal population, and higher than most other cancers, including head and neck cancers (28,31). The aim of this study was not to compare the thyroid cancer population to the general population, but rather the thyroid cancer population treated with XRT to thyroid cancer patients requiring treatment with less invasive modalities. For these reasons, a radiation-specific questionnaire was utilized. The QOL-RTI and the H&E companion module have been demonstrated to be useful, validated instruments for measuring QOL in the head and neck cancer population (17,18). Using this instrument, discrete, radiation-specific alterations in QOL were observed in WDTC cancer patients, in addition to those symptoms expected with RAI alone.

In conclusion, in the well-differentiated thyroid cancer patient population, there is a measurable impact on QOL measures with adjuvant therapy. In addition to changes observed in populations treated with RAI, patients with advanced disease requiring external beam radiation demonstrate additional QOL decrement in the areas of pain and swallowing. Larger studies of this finite population may provide further insights into these findings.

Footnotes

Disclosure Statement

The authors have nothing to disclose that would create a conflict of interest in connection with the submitted article.

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