The impact of chemotherapy on cognitive function of breast cancer patient

Fang-Fang Li, Ling-Mi Hou, Jin-Shui Li, Shi-Shan Deng, Yun-Hui Huang, Yao Liu, Wen Hu, Wei Rong, Li Fan, Hong-Wei Yang＊,Mao-Shan Chen＊

1Department of Operating Room, Suining Central Hospital, Suining 629000, China.2Department of Breast and Thyroid Surgery,Hepatobiliary and pancreatic institution, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China.3Department of Breast Surgery,Suining Central Hospital,Suining 629000,China.

Abstract

Keywords:Breast cancer;Cognitive function;Quality of life;Chemotherapy

Background

Globally, breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in women [1].The number of cancer survivors continues to increase [2].Chemotherapy as part of the systemic treatments was performed in a significant portion of patients in newly diagnosed early breast cancer [2, 3].Side effects induced by chemical drugs,such as bone marrow suppression, nausea, and cardiotoxicity,usually are well managed [4].However,the neurotoxicity of chemotherapy usually is ignored by physicians and patients, especially the neuropsychological damage[5,6].

Chemotherapy-related cognitive impairment is also a so-called chemo-brain, which defined as the cognitive decline during or after chemotherapy in cancer patients without primary or metastatic tumors of the brain [7, 8].The rate of cognitive impairment induced by chemical agents varied from 35% to 70%,and the duration of cognitive damage can last for over 20 years [7, 9, 10].At present, chemotherapeutic regimens of anthracyclines with or without paclitaxel are the most commonly used regimens for the treatment in breast cancer patients [3].Kesler SR and colleagues have found that regimens with anthracyclines have greater negative effects on cognitive domains than non-anthracycline regimens[11].A series of studies have produced the results that the degree and duration of different chemotherapy-induced cognitive impairment were quite different [6, 12, 13].However, there are also studies showing no significant cognitive changes before and after chemotherapy [14 - 17].These inconsistencies may be due to differences of the participants, treatment regimens, and assessment tools used to measure cognitive function.Deficits in cognitive function vary in social performance, such as memory loss, slow executive function, and impaired expression [8].These symptoms are particularly a burden to patients as they are associated with occupational and social functioning difficulties,as well as decreased daily activities[8,18].

After the treatment, women with breast cancer usually return to their occupational, scholastic, or familial activities, which rely on the cognitive function[19].In the modern biological-psychological-social medical model, the life quality was paid more attention[20, 21].There are so many factors that can affect a patient's quality of life (QoL), including the disease, economic level, educational level, and psychosocial aspects,and so on[19,22].

The relationship between changes in cognitivefunction and QoL is of great concern.Unfortunately,the study on chemotherapy and cognitive function and quality of life in Chinese patients are not well-established.Therefore, the purpose of this study was to delineate the relationship between the changes in cognitive function and its impact on QoL in women with early-stage breast cancer active treatment trough a 1-year survivorship.

Figure 1 Flow chart of patient selection

Methods

Participants

Women with newly diagnosed primary breast cancer have prospectively recruited from the Suining Central Hospital in China, between March 9, 2017, and May 31, 2018.Inclusion criteria were as follows: (1) aging from 20 to 80 years old; (2) histological confirmed invasive breast cancer; (3) stage I to IIIC with a scheduled visit to receive surgery and chemotherapy;(4) breast cancer was the only primary cancer; (5)participating in study willingly and informed consent was signed; (6) Eastern Cooperative Oncology Group(ECOG) performance was 0 or 1.Exclusion criteria were as follows: (1) with history of anti-cancer treatment;(2)accompanied with mental,psychological,or intellectual illness; (3) unable to cooperate in the investigation.A total of 241 patients were ascertained and screened for eligibility.Thirty-five patients did not meet the criteria were excluded.Twenty-three patients were excluded for rejection,less than 2-time point data,or invalid questionnaire.The screening flow chart is shown in Figure 1.This study was approved by the ethical committee of Suining Central Hospital, China(Number: 2017-17).Written informed consent was obtained from all participants.

Demographic and oncological variables

Demographic and disease profile information were collected by participant interviews and electronic medical record review.Demographic variables included age, marital status, and educational level.Cancer-related variables included breast cancer stage,histology, grade, cancer subtype.Treatment-related variables included the type of surgery, chemotherapy regimens, radiotherapy, hormone treatment, and target therapy.

Questionnaire survey

Questionnaires were administered individually.Investigators have received uniform training before beginning investigations.Participants completed questionnaires 4-time points before chemotherapy through 1-year survivorship: in five days'pre-chemotherapy (baseline, T1), in one-month post-chemotherapy(T2),6 months(T3)and 12 months(T4) after the completion of chemotherapy.Patients who had at least two measurement points were included in the final analysis.

The Functional Assessment of Cancer Therapy-Cognitive (FACT-Cog) version 3 scale was used to assess the cognitive function.It consisted of 37 items and each item is rated on a 5-point scale,ranging from 0 (“not at all”)to 4(“very much”).Higher scores represented greater cognitive function.In the previous study, it has been shown that the FACT-Cog scale has strong reliability and validity in breast cancer patients(Cronbach's α =0.707-0.929)[23].

QoL was measured by the Functional Assessment of Cancer Therapy-Breast Cancer (FACT-B) version 4 scale in patients with breast cancer.This instrument consists of 36 items, including 5 subscales: physical,social/family, emotional, functional, and breast cancer.Each item scored from 0 (“not at all”) to 4 (“very much”),and higher score meaning better level of QoL.This questionnaire has good validity and reliability properties in breast cancer patients (Cronbach's α =0.59-0.85)[24].

Statistical analysis

All analyses were conducted by STATA SE13.0 software for Windows.The questionnaires were entered into Epidata software (version 3.1) database in a double-blind method and verified.Descriptive statistics were used in the form of means and ranges for the continuous variables and percentages for the categorical variables.Scores of cognitive functions and QoL were compared with each time point by one-way repeated measures ANOVA test.Patients classified into three groups according to change rate of the total cognitive scores at T1 time point compared the mean scores of T2, T3 and T4 time points: non-obvious group, decreased less than 20%; obvious group,decreased 20%-50%; and serious group, decreased over and equally to 50%.A probability level of 0.05 was considered statistical significance.

Results

Participant characteristics

One hundred and eighty-three patients finally met the study criteria enrolled in the analyses.The participant characteristics are summarized in Table 1.As presented in Table 1, the mean age was 50.2 years (standard deviation = 12.4, range: 26-73 years).Descriptive analysis of tumor stage shown that 16.9% of the patients in stage I, 55.7% in stage II, and 27.3% in stage III.Among the 183 patients, all patients received surgery and chemotherapy, and 67.8% received radiation,80.3%received hormone therapy,and 16.9%received target therapy.The chemotherapy regimens were 3.3% anthracyclines only, 24.6% taxanes only,and 72.1 combined.Surveys of the questionnaire were conducted at baseline (T1) and then on average 4.1 ±1.2 months(T2),9.4±1.5 months(T3),and 14.6±1.7 months(T4)after baseline.The completion rates of the FACT-Cog scale at 4-time points were 100%(183/183)in T1, 97.8% (179/183) in T2, 93.4% (172/183) in T3,and 85.8% (157/183) in T4, respectively.The completion rates of the FACT-B scale at 4-time points were 100% (183/183) in T1, 96.7% (177/183) in T2,97.8% (179/183) in T3, and 81.4% (149/183) in T4,respectively.

Table 1 Characteristics of enrolled participants

Table 2 Scores of cognitive functions and quality of life at different time in breast cancer patients

Table 3 Relationship between cognitive changes and quality of life at different time

Changes of cognitive function

The total mean score of cognitive function tested by FACT-Cog scale was 126.1± 18.4 at baseline, 107.7 ±20.3 at T2, 112.2 ± 21.5 at T3, and 121.3 ± 17.9 at T4,respectively.One-way repeated measures ANOVA test revealed that the total score was significantly different at the four-time points (F= 49.7,P＜0.001)(Table 2).The trends of cognitive scores shown that cognitive impairment was most pronounced after chemotherapy and followed by a slowly turn back after the completion of chemotherapy (Figure 2A).According to the changing degree of the cognitive score, there were 33.3% (61/183) patients in the non-obvious group, 39.9% (73/183) in the obvious group,and 26.8%(49/183)serious group.

Quality of life over time

The total mean QoL scores tested by FACT-B scale were 98.4 ± 19.8 at T1, 61.8 ± 21.4 at T2, 75.6 ± 23.9 at T3, and 82.6 ± 22.4 at T4 time point respectively.There were statistically significant differences in QoL scores at different time points.Also, five aspects of QoL evaluated Pole-vaulted at four time points were significantly different (allP＜0.05) (Table 2, Figure 2B).The QoL score recovered slowly after the completion of chemotherapy, but not back to baseline level at 1-year follow-up(Figure 2A).

Relationship between cognitive function and QoL

The declining trend of QoL after chemotherapy was similar to that of cognitive impairment (Figure 2A).Among the patients in the non-obvious group,obvious group,and serious group,the baseline QoL scores had no statistical differences (P=0.792).the QoL scores were significantly different in different time (P＜0.05 for all) (Table 3).The increase of the QoL score was most pronounced in the cognitive changing serious group,and secondly in the obvious group(Figure 2C).In the different cognitive changing group, repeated measures ANOVA test shown that the QoL scores were significantly different among groups at four time points(F=4.17,P=0.012)(Figure 2C).

Figure 2 Trends of cognitive function scores and quality of life before and after chemotherapy in breast cancer patients.

Discussion

The decline in cognitive function after chemotherapy is pronounced in patients with breast cancer.The recovery rate of cognitive function was slowly and did not return to the baseline level at 1-year of follow-up.It indicates that chemical agents have a heavily negative influence on cognition and could persist for a long time.In Chinese patients,the persisted duration of cognitive deficits was not clear.It's reported that cognitive impairment from chemotherapy can last up to 20 years [7].However, this study investigated the long-term effects of the chemotherapeutic regimen of cyclophosphamide, methotrexate, and fluorouracil on cognitive function, which was not appropriate to evaluate patients under modern treatment models.Kesler SR and colleagues have found that regimens with anthracyclines may have greater negative effects on cognitive domains than non-anthracycline regimens[11].So, we can propose that chemotherapy-induced cognitive impairment could persist for a considerable period.

Many methods were used to evaluate the cognitive function,but there is still no unified gold standard[25].The neuropsychological tests have often used to assess the cognitive function in patients, but the limitation of repeated measures induced illusion of improvements in cognitive function has limited its application [26].We used the FACT-Cog scale to assess the cognitive performance before and after chemotherapy and used the changing degree of cognitive score to evaluate the influence of chemical agents.FACT-Cog scale was a subjective assessment scale that could objectively reflect the state of patients [27, 28].In our study, an obvious decline in cognitive occurred in 66.67% of patients, and 26.8% of these patients showed a reduction degree of over 50%.Many factors were associated with cognitive changes, including chemical drugs,cycles,and the educational level,and so on[29].Anthracyclines and paclitaxel drugs are the main chemotherapeutic agents for breast cancer.Both of these drugs could induce cognitive dysfunction in breast cancer patients [6, 12, 13].In these studies, the measurement tools of cognitive function were relatively complex,and hard to repeat which limited its clinical uses. The exact mechanism of chemotherapy-induced cognitive impairment is not yet clear, but it is generally accepted that chemotherapeutic drugs passing through the blood-brain barrier cause changes in brain structure and function in specific regions [9].So, imaging techniques, such as magnetic resonance imaging,positron emission tomography, and electroencephalography, were investigated in the evaluation of cognitive function [30-32].Unfortunately, these methods could check the function changes in the brain quickly, but could not reach accurately.Further studies are needed to identify an applicable technique in assessing cognitive performance quickly and exactly.

Our study demonstrated that there was an obvious correlation between cognitive function and quality of life.The trends of cognitive score and quality of life through the pre-chemotherapy to follow-up were almost parallel, which decreased obviously after the completion of chemotherapy and then turn back slowly at the follow-up.Five aspects of QoL declined after the chemotherapy, and only the social/family return to the baseline level.The social domain had the good scores may be referred to family support and social health care.Patients exposed to chemotherapy had a significantly lower longitudinal cognitive function,which decreased the performance in thinking, memory,and executive [6, 13].Psychosocial problems will reduce the patient's ability to perform and their self-satisfaction,thus reducing the survivor's quality of life [18].In our study, we found similar changes in cognitive function and QoL.Besides, the impact of

cognition on QoL may be less during the follow-up period than that during chemotherapy.this may attribute to the factors and weights that affect the quality of life in breast cancer patients,as these factors may differ at different stages [20].Some studies reported that cognitive training during chemotherapy for breast cancer patients could improve executive performance and quality of life [33, 34].Clinical trials have demonstrated that QoL is associated with changes in clinical variables including survival [19, 35, 36].Therefore, it is necessary to evaluate the cognitive problem and given necessary interventions.Better understanding the cognitive function changes after cancer treatment is important, which is helpful for improving the QoL of breast cancer survivors without interference of chemotherapeutic efficacy.

Conclusion

Chemotherapy is closely associated with cognitive impairment, which further contributes to a significant decrease in QoL of breast cancer patients.We should pay more attention to the cognitive changes brought by chemotherapy and conduct prospective studies to improve the cognitive function and QoL of breast cancer.