Health-Related quality of life by 31-item Cervantes scale in breast cancer survivors undergoing adjuvant endocrine therapy

HIGHLIGHTS • CS-31 seems to be appropriate for use in oncology and may help to monitoring adverse effects and HRQL.


Introduction
Breast Cancer (BC) is a heterogeneous disease comprised of several subtypes with Hormone Receptor-positive (HR+) BC representing 80% of those diagnosed after menopause [1].
Currently, the adjuvant treatment of postmenopausal early-stage HR + BC with an Aromatase Inhibitor (AI) is considered the standard care [2], being an important ally in increasing disease-free survival [3].However, it often causes adverse effects related to the central nervous system such as fatigue, depression, and vasomotor symptoms (hot flashes and night sweats); musculoskeletal symptoms such as arthralgia and osteoporosis; cardiovascular such as hypercholesterolemia and angina; and vulvovaginal symptoms including dryness and dyspareunia [4].Some of these symptoms are frequent in old age, such as depression [5], or during menopause, particularly vasomotor symptoms [6].Specifically, in relation to AI, the toxicity can be explained, at least in part, to estrogen depletion [7], a hormone that participates in multiple systems and, therefore, has a potential for generalized toxicity in its deprivation [4].
Adverse effects, arising from or exacerbated by AI use, are negatively associated with adherence and persistence to treatment [8] and health-related quality of life (HRQL) [4].In this sense, the 31item Cervantes Scale (CS-31) is a HRQL questionnaire that considers particularities of the perimenopausal and postmenopausal women [9] and may be an appropriate option to assess HRQL in BC survivors during AI use.
The CS-31 is a measurement of patients' perception of their own health status or HRQL, i.e., an instrument capable of measuring patientreported outcomes (PRO) [10].PRO instrument has a higher potential to identify adverse effects of therapy (toxicity monitoring), targets for intervention (symptom control), and allows health professionals to understand how treatment effectiveness can be affected by patient perceptions of toxicity (adherence to treatment) [11].
Thus, the aim of this study was to perform additional validation of the CS-31 for BC survivors during adjuvant endocrine therapy.

Ethics statement, Study design, selection of participants and eligibility criteria
This prospective study was approved by the Human Research Ethics Committee of the Federal University of Uberlandia (n°1.331.949/15,addendum n°2.905.835/18) and complies with the Declaration of Helsinki.All participants signed a free and informed consent.This study follows the STROBE Statement.
The study was carried out from January 2016 to August 2018 with postmenopausal BC survivors undergoing adjuvant endocrine therapy with AI at the Clinical Hospital of the Federal University of Uberlandia, Minas Gerais, Brazil.The follow-up time was 24 months, and the faceto-face assessments were performed at three-time points: T0, initial follow-up period; T1, intermediate follow-up period, 12 months after T0; and T2, final follow-up period, 24 months after T0, with interviews carried out by properly trained researchers.
Clinical and sociodemographic data were obtained through the analysis of medical records or interview.

Sample Size
The sample size of a group of individuals and three measurements was calculated with the G*Power software, version 3.1 (D€ usseldorf, Germany) [12].An F test was conducted using ANOVA repeated measures, based on an effect size f of 0.25, an alpha level of 0.05, and at 80% power, a total of 28 women required at each time.
This study included postmenopausal breast cancer survivors undergoing adjuvant endocrine therapy with Aromatase Inhibitors (AI).Participants were recruited at any stage of AI treatment through nonprobabilistic convenience sampling.Volunteers were consecutively recruited to minimize selection bias.
Initially, 256 patients were selected to participate.After analyzing medical records, 107 patients were excluded, resulting in a final sample size of n = 149.Following the eligibility assessment, 56 patients were further excluded, leaving 93 patients for evaluation.Subsequently, four patients were excluded due to recurrence of breast cancer, incomplete questionnaires, or failure to attend all appointments.In total, 89 patients formed the baseline for the study.Detailed information on survivor recruitment and selection, along with Cervantes' sample recruitment, is provided in Figure 1.

31-item Cervantes Scale
All participants replied by interview to the CS-31.Figure 2 provides the items contained in this instrument.
The CS-31 was developed in 2004 [9] and a Brazilian Portuguese version validated in 2012 [13], with Cronbach's alpha for the global score of 0.91 and 0.83, respectively.This instrument has been validated in a non-cancer population, but the authors would like to see if it would be useful in a population of BC survivors undergoing adjuvant endocrine therapy.
The CS-31 consists of 31 items rated on a Likert scale from 0 to 5 and divided into four domains, namely Menopause and Health (subdivided into Vasomotor Symptoms, Health, and Aging), Sexuality, Couple Relations, and Psychological.The global score can range from 0 to 155 points, with a higher score representing a worse HRQL.As recommended, the questionnaires were considered invalid if three or more questions were left unanswered.But, if one or two unanswered questions, the score was obtained by multiplying by a correction factor [9].

Psychometric evaluation
All participants replied by interview to the Functional Assessment of Chronic Illness Therapy -Fatigue (FACIT-F) and Hospital Anxiety and Depression Scale (HADS), which are validated instruments and already well-established for BC patients.

Statistical analysis
Internal consistency was studied considering the global score, including all items, and for each domain.The authors use Cronbach's alpha coefficient, considering adequate values between 0.70 and 0.95 [18].
Convergent analyses were assessed by determining the correlation between the CS-31 and a specifically related measure from FACIT-F (global score and domains).The authors hypothesized that the global score between CS-31 and FACIT-F, as they are general measures, as well as constructs indirectly related (Sexuality and Couple Relations of CS-31 with Social/Family Well-Being of FACIT-F) should correlate with r > 0.4.The present hypothesis was correlations with r > 0.6 due to similar constructs, such as the Psychological of CS-31 and the Emotional Well-Being of FACIT-F.Construct validity is given a positive rating if at least 75% of the results are consistent with prior hypotheses [18].The authors defined the strength of the correlation coefficient as weak if r < 0.4; moderate if r is ≥0.4 and ≤0.6; and strong if r > 0.6 [19].
The authors assessed the change in global and domain scores of FACIT-F and CS-31 between the three time points (T0, T1, and T2).Differences were evaluated using the One-way ANOVA test with repeated measures and Sidak post-hoc, or the non-parametric Friedman with multiple comparison tests.
The known-group validation analysis was performed to assess if the instrument would be able to discriminate between subgroups of survivors, using one-way ANOVA with Sidak post-hoc.The CS-31 global scores were compared with non-cases, doubtful cases, and cases of anxiety and depression by HADS.The authors hypothesized that those survivors with higher scores for both anxiety and depression would have a worse HRQL.In BC patients, the HRQL is closely related to these psychological disorders [20].
All statistical analyses were performed using IBM SPSS Statistics (Armonk, NY, USA), software package (SPSS Statistics for Windows, version 21.0), considering statistically significant p-values of less than 0.05.

Internal consistency
The CS-31 presented good global internal consistency (Cronbach's alpha = 0.89), without significant change if a single item was deleted (Table 2).

Construct validity
The authors established five a priori hypotheses of strong and moderate convergent analyses between the CS-31 and FACIT-F (global score and domains).Correlations were performed and there was confirmation for all hypotheses tested (Table 3).

Responsiveness analyses
In Table 4, the authors identified that there was a significant improvement in HRQL by the CS-31 Global score (p = 0.001) as well as by FACIT-F Total Score (p = 0.044), throughout the study.All the significances indicate worse global and domain scores in T0 compared to T1 and T2, either by CS-31 or FACIT-F, indicating that survivors started endocrine therapy with a worse HRQL.The CS-31 Global score, the Menopause and Health score (p = 0.004) and the Psychological score (p = 0.002) were higher in T0 compared to T1 and T2, and did not differ between T1 and T2.The Emotional Well-Being score (p = 0.029), Physical Well-Being score (p = 0.016) and FACIT-F TOI (p = 0.017) differed statistically between T0 and T2, with higher scores at baseline.The Fatigue Subscale had higher scores at T0 when compared to T1 (p = 0.012).The domains Sexuality and Couple Relations, as well as FACT-G, Functional, and Social/Family Well-Being (FACIT-F) did not differ statistically.

Known-group validity
As previously hypothesized, those survivors with higher scores for both anxiety and depression by HADS presented worse HRQL by CS-31 when compared to subgroup non-cases (Table 5).

Discussion
The psychometric properties revealed that CS-31 is a valid instrument for assessing HRQL in BC survivors during adjuvant endocrine therapy.The CS presented adequate internal consistency, satisfactory construct validity, and known-group validity, with statistical significance between anxiety and depression and worse HRQL.Furthermore, the authors identified a prospective improvement in HRQL of the baseline for the other time points.
The authors identified higher scores for anxiety and depression in survivors with worse HRQL and improvement in HRQL over the study.Recently, Martino and collaborators [21] identified that after 6-months of treatment with AI, BC patients presented a significantly higher perceived HRQL for both physical and mental components, added to a significant reduction in symptoms of anxiety and depression, possibly due to the decline of the physical and psychological effects of recent diagnosis and previous treatments [21].
Regarding the Sexuality and Couple Relations domains of CS-31, as well as the Social/Family Well-Being of FACIT-F, the latter which also presents items related to sexual life and couple relations, have not changed over time.Often, the adverse effects of treatment, as well as induced menopause, cause sexual dysfunction among BC survivors, with a relevant impact on sexual function [22].The disturbances in sexual life are among the factors that might deteriorate the quality of life in BC survivors [23].The adjuvant endocrine therapy, especially AI, can cause vaginal atrophy [24], dryness and dyspareunia [4], and some urogenital effects, and may be lifelong if untreated [25].Possibly, the treatment has a more lasting impact on sexuality and a longer follow-up would be necessary to investigate changes in these domains.Furthermore, it should be noted that sexuality is considered a biopsychosocial concept, and therefore it is believed to be associated with biological and psychosocial factors [26].The main recommendation for the management of sexual health in BC survivors is that a multidisciplinary team needs to include sexuality as an integral part of treatment, contributing to an improvement of HRQL [22].Even though the CS-31 was not designed for this population, these women have predominantly adverse effects like those of other postmenopausal women, although intensified by the AI use.The authors need to consider that the CS-31's target population is women aged 45 to 64 years [9] and the present sample includes women aged 47 to 79 years.For this purpose, the authors divided survivors into two age groups (47 to 64 and 65 to 79 years) and observed that age had no effect on the CS-31 scores by performing the Generalized Linear Model (GLzM) analysis (data not shown).In addition, the CS-31 is a self-reported questionnaire, however, in this study, all participants replied by interview, which may have inhibited responses to items in the Sexuality and Couple Relations domains.Even so, the standardization for this type of application was a methodological care considering that in the present sample there were illiterate survivors.
As pointed out by others [13], the authors identified that most of the invalid questionnaires were filled out by women who were not married or without a partner, referring to a sexually inactive life.This seems to be a limitation of the CS-31, and adaptations to this instrument are necessary to contemplate all climacteric women, irrespective of their marital status and sexual activity.
Adherence to adjuvant endocrine therapy is suboptimal in BC patients.It is negatively associated with the treatment for adverse events [8] and associated with increased early tumor recurrence and mortality rates [27].Potentially, clinical interventions to manage these adverse effects may improve HRQL and BC outcomes [28].CS-31 is multidimensional allowing in-depth analysis of adverse effects and general

Figure 1 .
Figure 1.Diagram reporting the number of survivors recruited and selected in the study, and the Cervantes' sample.Time point: T0, Initial follow-up period; T1, Intermediate period, corresponding to 12-months after T0; and T2, Final follow-up period, corresponding to 24-months after T0; CS-31, 31-item Cervantes Scale.

Table 1
Demographic and clinical characteristics of the breast cancer survivors during endocrine therapy.

Table 2
Cronbach's α of the 31-item Cervantes Scale (CS-31).No single item significantly modified the internal consistency of the CS-31 global and domains when deleted. a

Table 4
Variation in the domains and global scores of the CS-31 and FACIT-F over time.Initial follow-up period; T1, Intermediate period, corresponding to 12-months after T0; and T2, Final followup period, corresponding to 24 months after T0; CS-31, 31-item Cervantes Scale; FACIT-F, Functional Assessment of Chronic Illness Therapy − Fatigue; FACIT-F Trial Outcome Index (TOI): Physical Well-Being + Functional Well-Being + Fatigue Subscale; FACIT-F Total Score: Emotional Well-Being + Physical Well-Being + Functional Well-Being + Social/Family Well-Being + Fatigue Subscale; FACT-G Total Score: Emotional Well-Being + Physical Well-Being + Functional Well-Being + Social/Family Well-Being.SD, Standard Deviation.One-way ANOVA test with repeated measures and Sidak posthoc, or the non-parametric Friedman with multiple comparison tests.Bold value is statistically significant at p < 0.05.

Table 5
Known-group validation analyses.