An assessment of quality of life for early phase after adjuvant radiotherapy in breast cancer survivors: a Korean multicenter survey (KROG 14–09)

The population of our study consisted of patients diagnosed with breast cancer, treated with definite surgery followed by adjuvant radiotherapy, regardless of any other adjuvant. We performed a questionnaire survey to patients who visited the outpatient clinic and corresponded to the periods of 3 months before and after 1, 2, and 3 years after completion of radiotherapy. For example, the population in the 1st year group visited from 9 to 15 months after completion of radiotherapy. The included patients in our study were who; 1) successfully completed planned radiotherapy; 2) were aged between 20 and 70 at the initiation of radiotherapy; 3) were able to communicate in the Korean language and 4) agreed to answer our questionnaire. Exclusion criteria were those who; 1) had any locoregional recurrence or metastasis during or after radiotherapy; 2) had a history of any malignancy except non-melanoma skin cancer; 3) had a disability below Eastern Cooperative Oncology Group performance scale 2 due to physical problem other than breast cancer; and 4) is male.

The population size of our study was estimated using our country and United States cancer statistics. In the year 2011 in South Korea, the newly diagnosed breast cancer patients totaled 15,356, and 2063 people died due to breast cancer. Based on the above values, we assumed that about 13,000 breast cancer patients survived each year [9]. According to the Surveillance, Epidemiology, and End Results Program data of United States, 51% patients with early breast cancer (stage I or II) and 44% of advanced breast cancer (stage III or IV) received adjuvant radiotherapy [10]. Considering this, we expect that about 50% of breast cancer patients would receive adjuvant radiotherapy in South Korea, and we presumed that the number was about 6500 patients each year. Regarding that our exclusion criteria may exclude about 500 patients in each year group, we can estimate that the parent population would be about 6000 patients in a year. With this estimation and the following formula, we calculated the size of sample for our study.

(Confidence level 90% z_a/2 = 1.65, Confidence level 95% z_a/2 = 1.96, Confidence level 99% z_a/2 = 2.54, N = parent population).

As we used a confidence level of 95% and sampling error of +/−5%, we calculated that 384 patients was the sample size needed per year. Consequently, the ideal size of sample for 3 years is 1152. Hence, our goal was to perform our survey to about 1100 patients. However, due to the characteristic of clinical follow-up that the rate of regular checkup is declining as time passes, we applied sample errors and set the sample sizes as followed; 1) 317–474 survivors at the 1st year with +/−4.5–5.5% sample error; 2) 227–317 survivors at the 2nd year with +/−5.5–6.5% sample error; and 3) 170–227 survivors at the 3rd year with +/−6.5–7.5% sample error.

The QoL of study participants was assessed using the 5-dimensional questionnaire by EuroQol group (EQ-5D) to evaluate general health-related QoL and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–breast cancer specific module (EORTC QLQ-BR23) to evaluate characteristic QoL of breast cancer patients.

The EQ-5D, a validated questionnaire translated into Korean, [11] is a widely-used questionnaire to evaluate general health status in 5 categories (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). Each category was assessed by 3-grade Likert scale: 1, No problem; 2, some or moderate problems; 3, extreme problems (EQ-5D-3 L). In addition, each category was also assessed on a visual analogue scale (VAS) where the endpoints are classified as follows: ‘the best imaginable health state’ =100 and the ‘worst imaginable health state’ =0 (EQ-5D-VAS).

The EORTC QLQ-BR23 instrument comprised of 23 questions, which can be divided into 8 categories and 2 areas which are functional (body image, future perspective, and sexual activities and enjoyment) and symptomatic (arm symptom, breast symptoms, side effects of systematic therapy, and upset by hair loss). Each question is scored on a 4-point Likert scale from 1 (not at all) to 4 (very much), and we arranged the data to the above-mentioned categorical basis and linearly transformed them into scores from 0 to 100; a higher score represented better satisfaction with their QoL. The Korean version of EORTC QLQ-BR23 has been tested in a previous study and was shown to be a valid measurement to assess QoL of breast cancer patients [12].

A researcher in each institution filled out the clinical factors, such as the time of surveillance, type of breast surgery, type of axillary surgery (axillary dissection, sentinel lymph node dissection, or none), chemotherapy, hormone therapy, target therapy, and the extent of radiotherapy. The sociodemographic factors and QoL were acquired by the self-administration method from patients. As for personal and sociodemographic factors, age, body mass index, menopausal status before diagnosis of breast cancer, periodic medication (cardiovascular, diabetic, and psychotropic drug), employment status, household income, education status, hobbies, alcohol consumption, smoking, and use of health supplement were considered.

In addition, the questionnaire of Global physical activity question (GPAQ) of the World Health Organization (WHO) to assess physical activeness was performed. The GPAQ was developed by the WHO for physical activity surveillance in many countries. It collects information on physical activity participation in activity at work, travel to and from places, and recreational activities. The questionnaire is comprised of questions asking about the number of days when a certain degree of activity is performed, and the actual time spent for the activity during the day, for last 7 days. The GPAQ was assorted into 3 grades according to total time of activity, which is calculated by multiplying the ‘number of days with certain activity per week’ and ‘actual time of activity in the day’.

The numerical values calculated through the above method were used for QoL analysis as a variable named physical activity. The GPAQ has been validated and applied in diverse studies worldwide including Asian countries [13, 14].

We assorted our study participants into 3 groups according to their surveillance period after the end of radiotherapy, which were the 1st year group (9–15 months), the 2nd year group (21–27 months), and the 3rd year group (33–39 months) from the end of radiotherapy. A chi-square test was performed to evaluate distribution of clinical and sociodemographic variables according to surveillance period.

For missing value control, we regarded clinical factors as missing value that chemotherapy less than 3 cycles, target therapy or hormone therapy less than 6 months. If each category of EQ-5D-VAS is only omitted with written EQ-5D-3 L, the omitted EQ-5D-VAS was replaced according to the median VAS for same grade of each category. In GPAQ, if our participants answered as ‘I do not know/I am not sure’ to the question asking actual time of activities, we replaced with median value of responders.

To identify which category of QoL is mostly deteriorated after breast cancer treatment, Cochran–Mantel–Haenszel analysis to assess the EQ-5D-3 L and multiple comparison test after Kruskal-Wallis analysis to assess EQ-5D-VAS and EORTC QLQ-BR23 were conducted.

From August 2014 to September 2015, 1156 women from 17 hospitals consented and answered questionnaire. With regard to the surveillance period, 587 (58.1%), 332 (30.7%) and 231 (11.2%) patients were corresponded to the first, second and third year group, respectively. The sampling errors with 95% confidence level of the first, second and third year groups were estimated as 3.8, 5.2 and 6.3%, respectively. The surveillance period was missed in 6 questionnaires.

The clinical characteristics of study participants are shown in Table 1. Breast conserving surgery was performed in 91.9% of cases and patients with advanced stage of III or higher were in 11.4% of cases. Radiation field included the regional lymph nodes in 75% of cases and boost to tumor bed was performed in 89.7% of cases. Median dose to whole breast/chest wall and boost was 50.4 Gy and 10.0 Gy, respectively. Assorted by surveillance period, there was no statistically significant difference except for the variables of age and hormone therapy. The difference of age distribution may be reflected by the character of our study and as the surveillance period increases, the median age (50.0, 51.8 and 52.1 years at first, second and third year group, respectively) increases. Regarding hormone therapy, we have more study participants who did not received hormone therapy in the first year group than other groups (29.1 vs. 19.5 vs. 18.6) since some patients in first year group had received hormone therapy for less than 6 months and were considered as missing values. The sociodemographic status was assorted by the surveillance period and is represented in Table 2. There is no statistically significant difference in distribution except variables including hobbies. Regarding variables of hobbies, there are more participants who were categorized as ‘actively participating’ in the third year group.

The answer rate of grade 2 or 3 was highest in the pain/discomfort category, followed by anxiety/depression (Table 3). The grade 2 answer for the pain/discomfort category was significantly higher than expected. With a lapse of time, usual activity (p = 0.038) and pain/discomfort (p < 0.001) categories were improved, but the other categories showed no significant change. The trend that pain/discomfort grade 2 is measured as higher than expected, persisted in all surveillance periods. We summate grades of all 5 categories into total score ranged from 5 to 15, to reflect general QoL. The total score showed significant improvement with lapse of time (p = 0.001).

The EQ-5D VAS showed that pain/discomfort, anxiety/depression, and mobility categories were significantly lower than usual activity and self-care categories. The same trend was observed in all surveillance periods. The categories of pain/discomfort (p < 0.001), self-care (p = 0.012) and usual activity (p = 0.022) were improved with a lapse of time (Fig. 1). We calculated the average scores of 5 categories to indicate general QoL, and the average score was improved with lapse of time (p = 0.001).

We performed multivariate analysis to factors showed to be significant in univariate analysis, and the clinical factors, such as stage of disease, surgery type, chemotherapy, hormone therapy, target therapy, and extent of radiotherapy did not affect EQ-5D-VAS significantly (Table 4). The axillary dissection (axillary dissection Vs. none) deteriorated the self-care, usual activities, pain/discomfort, and the average score of EQ-5D-VAS (p = 0.039, p < 0.001, p = 0.004, and p = 0.004, respectively). With the lapse of time, the categories of pain/discomfort (p < 0.001), self-care (p = 0.034) and the average score (p = 0.004) were improved in multivariate analyses.

For sociodemographic factors, menopausal status (p = 0.003) before surgery, educational status (p = 0.014), household income (p = 0.001), employment change (p = 0.001), activity of hobbies (p < 0.001), physical activity (p < 0.001), and psychotropic medication (p < 0.001) were significant factors influencing the average score of EQ-5D. Psychotropic medication, employment change and activity of hobbies were found to be strongly related to anxiety/depression with p < 0.001. Household income was a strong factor for pain/discomfort and mobility. Physical activity was another strong factor for mobility.

The lowest scored category was sexual activity, followed by sexual enjoyment, future perspective, hair loss, body image, arm symptoms, side effects of systematic therapy, and breast symptoms. There were no significant differences between scores of body image, arm symptoms, and side effects of systematic therapy, while all the other categorical scores were significantly different between each other. These trends were observed in all surveillance periods. The categories of arm symptoms (p < 0.001) and breast symptoms (p < 0.001) were improved with time passage. Other categories showed no statistically significant change with time (Fig. 2.).

For upset by hair loss category, the answer rate was relatively low (55.6%) as compared to other categories, since only the participants who experienced actual hair loss answered the question. There were some missing answers for sexual activity (6.1%), and the answer rate of sexual enjoyment category was only 43.9%, which is suggested to be answered from whom had had sexual activity.

In multivariate analysis, the axillary dissection (axillary dissection Vs. none) and stage of disease were significant clinical factors for the symptomatic area (Table 5). For the functional area, the type of breast surgery influenced body image, chemotherapy affected body image and sexual activity, and the axillary dissection (axillary dissection Vs. none) was the factor which affected sexual enjoyment. Various sociodemographic factors strongly affected each QoL category; household income for side effects of systematic therapy; activity of hobbies for side effects of systematic therapy, arm symptoms, future prospective and sexual activity; medication of psychotropic drug for side effects of systematic therapy and body image; employment change for body image and future prospective were observed with strong significance (p < 0.001).