key: cord-0992707-gucnce1f
authors: Juanjuan, Li; Santa-Maria, Cesar Augusto; Hongfang, Feng; Lingcheng, Wang; Pengcheng, Zhang; Yuangbing, Xu; Yuyan, Tan; Zhongchun, Liu; Bo, Du; Meng, Lan; Qingfeng, Yang; Feng, Yao; Yi, Tu; Shengrong, Sun; Xingrui, Li; Chuang, Chen
title: Patient reported outcomes of breast cancer patients during the COVID-19 outbreak in the epicenter of China: A cross sectional survey study
date: 2020-06-07
journal: Clin Breast Cancer
DOI: 10.1016/j.clbc.2020.06.003
sha: f5f708504ffa1d6fe3a9b20502858dbbde5be339
doc_id: 992707
cord_uid: gucnce1f

PURPOSE: We aimed to analyze the psychological status in breast cancer (BC) patients in the epicenter of the COVID-19 pandemic. PATIENTS AND METHODS: A total of 658 individuals were recruited from multiple breast cancer centers in Hubei Province. Online questionnaires were conducted, and included demographic information, clinical features, and four Patient Reported Outcomes (PROs) scales (GAP-7, PHQ-9, ISI, and IES-R). Multivariable logistic regression analysis was designed to identify potential factors on mental health outcomes. RESULTS: Questionnaires were collected from February 16 to 19, 2020, the peak time point of COVID-19 outbreak in China. 46.2% BC patients had to modify planned necessary anti-cancer treatment during the outbreak. 8.9% and 9.3% patients reported severe anxiety and severe depression, respectively. 20.8% and 4.0% patients showed severe distress and insomnia, respectively. Multivariable logistic regression analysis demonstrated poor general condition, shorter duration after BC diagnosis, aggressive BC molecular subtypes and close contact with COVID-19 patients as independent factors associated with anxiety. Poor general condition and CVC (central venous catheter) flushing delay were independently association factors depression. In terms of insomnia, poor generation condition was the only associated independent factor. Poor physical condition and treatment discontinuation were underlying risk factors for distress based on multivariable analysis. CONCLUSION: High rates of anxiety, depression, distress, and insomnia were observed in patients with breast cancer during the COVID-19 outbreak. Special attention should be paid to psychological status of breast cancer patients especially those with poor general condition, treatment discontinuation, aggressive molecular subtypes and metastatic breast cancer.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was initially identified in patients in Wuhan, Hubei Province, in December 2019 [1] . The pandemic disease caused by this virus was named by the World Health Organization (WHO) as coronavirus disease 2019 (COVID- 19) [2] . In late January of 2020, Chinese authorities placed a lockdown on Hubei Province to contain this disease [1, 3] . In addition, nearly all the medical resources were organized and more than 40,000 healthcare workers from other cities were dispatched to work together in Wuhan and other cities of Hubei [4] . These measures and sacrifices have resulted in decreased rates of transmission and better outcomes in China [5] .

Studies from China have demonstrated that cancer patients are significantly more likely to experience worse outcomes to COVID-19 infection [6, 7] , which has led to reevaluation of the risk/benefit balance in cancer therapies [8, 9] . Indeed, almost all the cancer patients in Wuhan, the epicenter of COVID-19 in China, had to discontinue or delay their normal anticancer therapy due to lockdown policies, limited medical resources, and the predicted increased risk of infection at the initial of the outbreak. After the outbreak was under control, modified therapeutic regimens were recommended and online prescription were available for cancer patients since nearly all the cancer clinics were still not active. These changes can lead to significant increases in psychological burden of cancer patients, especially for breast cancer (BC) patients.

BC is the most common cancer among women worldwide. The mean age of breast cancer patients in China is 45-55 years, which is considerably younger than for western women according to the epidemiologic data from China [10] . A diagnosis of breast cancer can result in long-lasting mental health effects on women [11] such as physical hardship, traumatic events during treatment, fear of recurrence, etc. Furthermore, mental illness can further exacerbate quality of life of BC patients, resulting in worse BC outcomes [12] . During the COVID-19 crisis, BC patients in Hubei Province were exposed to a very high risk of COVID-19 infection, and interruptions of standard medical care. Therefore, it is crucial to understand quality of life factors so they may be addressed during this outbreak and hopefully result in less stress for BC patients. In this study, we conducted a survey to measure the psychological status of BC patients and survivors and to identify potential affecting factors in the epicenter of COVID-19 in China at the peak time-point of the crisis.

Breast cancer patients and survivors from the epicenter of COVID-19 in China, Hubei Province, were enrolled for this survey study. The study was sponsored by the breast cancer center in Renmin Hospital of Wuhan University and was supported by several breast cancer centers in Hubei province. All the enrolled patients signed digital informed consent before accessing to the questionnaire online, consisting of a series of questions including demographic characteristics, clinical features of breast cancer, current treatment and patient reported outcomes using four validated psychological assessment scales. The four scales included Generalized Anxiety Disorder Questionnaire (GAD-7), Patient Health Questionnaire (PHQ-9), Insomnia Severity Index (ISI), and Impact of Events Scale-Revised (IES-R). Breast cancer patients were asked to answer 7 all the questions anonymously through Wechat software, a popular social media platform in China. The local Wechat communication groups were set up originally for BC patients to connect with their doctors for daily medical consultant and support. The questionnaires were issued to each local BC patients WeChat group from February 16 to 19, 2020. Data were collected from 660 BC patients automatically after the questionnaires were returned. 2 participants who completed the entire questionnaire less than 2 minutes or more than 20 minutes were excluded. Therefore, after the evaluation of questionnaires for eligibility, 658 participants were enrolled for analysis. The flowchart of the patients selection was shown in Figure 1 . This study protocol was approved by the Institutional Ethics Committee in Renmin Hospital of Wuhan University.

PROs of BC patients in epicenter of COVID-19 outbreak in China were evaluated using four Chinese versions of validated questionnaires [13] [14] [15] [16] . GAD-7, a 7-item selfreport scale, was used to briefly measure anxiety disorders of the patients. Evaluation scores of 0, 1, 2, and 3 for seven items represent the response categories of 'not at all', 'several days', 'more than half the days', and 'nearly every day', respectively. The cutoff point of the sum score for mild is a score of 5, for moderate is 10 and for severe is 15.

Depression was measured by PHQ-9, a 9-question instrument, to screen for the presence and severity of depression. Responses of each question range from "0" (not at all) to "3" (nearly every day). Depression severity was classified into none (0-4), mild (5-9), moderate (10) (11) (12) (13) (14) , and severe (＞15) according to DSM-IV criteria. ISI is a selfassessment tool measuring the patient's perception of both nocturnal and diurnal symptoms of insomnia. It has seven questions. A 5-point Likert scale is used to rate each item (e.g., 0=none, 4=very severe), yielding a total score ranging from 0 to 28. The total score is interpreted as follows: absent of insomnia (0-7); sub-threshold insomnia (8) (9) (10) (11) (12) (13) (14) ; moderate insomnia (15) (16) (17) (18) (19) (20) (21) ; and severe insomnia (22) (23) (24) (25) (26) (27) (28) . The IES-R, also a self-report questionnaire, yields a total score (ranging from 0 to 88). It was used to measure distress symptoms caused by COVID-19 outbreak. The IES-R and subscale scores can also be calculated for the intrusion, avoidance, and hyperarousal status. These PROs tools have established sensitivity, specificity, reliability, and factorial and procedural validity.

All statistical analysis were carried out with R software (version 3.5.1). Based on non-normal distribution, the nonparametric Wilcoxon signed-rank test and Kruskal-Wallis test were used to compare the severity of each symptom among two or more groups. The univariable and multivariable logistic regression models were used to identify potential risk factors affecting psychological status for BC patients. The association between risk factors and PROs are presented as odds radios (OR) and 95% confidence interval (CI). The statistical significance level was set at P<0.05, and all tests were 2-tailed.

After excluding 2 patients who completed the entire questionnaire less than 2 minutes or more than 20 minutes, a total of 658 BC patients were enrolled in this analysis, including 247 cases (37.5%) from Wuhan (the epicenter of the outbreak in China), and 411 cases (62.5%) from cities outside Wuhan in Hubei Province. The baseline characteristics of BC patients were shown in Table 1 

The mean scores were 6.01±5.35 and 5.80±5.66 for the GAD-7 and PHQ-9, respectively( Table 2 ). There were 34.0%, 13.3%, and 8.9% patients categorized into the mild, moderate and severe anxiety. There were 25.2%, 12.8%, and 9.3% patients presented mild, moderate and severe depression. The mean scores were 8.66±6.29 and 28.17±18.23 for the ISI and IES-R, respectively (Table 2 ). There were 36.2%, 12.9%, and 4.0% patients reported mild, moderate and severe insomnia. There were 30.7%, 31 .5%, and 20.8% patients showed mild, moderate and severe distress symptoms. Subscale scores of IES-R were calculated to evaluate the intrusion, avoidance, and hyperarousal status ( Table 2) .

Patients with Wuhan exposure, poor general condition by self-identification, treatment discontinuation, and had metastatic breast cancer were more likely to report experiencing severe symptoms of anxiety, depression, insomnia and distress (Table 3, 

Univariable logistic regression analysis showed that patients with Wuhan exposure (P=0.014), poor general condition by self-identification (P=0.008), less than 4 months after BC diagnosis (P=0.003), aggressive BC molecular subtypes (P=0.014), treatment discontinuation (P=0.003), CVC flushing delay exceeding 4 weeks (P=0.032), and close contact with COVID-19 patient (P=0.006) were more likely to report moderate and severe anxiety symptoms (Supplementary Figure 2A Figure 3B ). In terms of moderate or severe insomnia, poor generation condition (P=0.008) was the only independent affecting factor ( Figure 2C ). Poor physical condition (P=0.028) and treatment discontinuation (P=0.046) were independent risk markers for distress based on the multivariate analysis ( Figure 2D ).

Wuhan, a metropolis of 11 million residents in central China's Hubei Province, became the epicenter of COVID-19 in January 2020. Rapidly rising numbers of infected cases put the local health care system under tremendous stress [3] , occupying and affecting the medical needs for patients with non-COVID-19, especially for cancer patients. In addition, cancer patients were exposed at higher risk of infection with COVID-19, and experienced worse outcomes after infection during the COVID-19 epidemic [6, 7] . Under this unique circumstance, cancer patients faced COVID-19 infections and interruption of cancer treatment, resulting in significant mental stress. In this study, we investigated PROs in breast cancer patients in the epicenter at the peak time-point of the COVID-19 outbreak.

We found a wide range of abnormal quality of life metrics BC patients experienced, including stress, anxiety, fear, depression and distress. Approximate 10% BC patients showed severe depression and anxiety. Over one fifth of BC patients presented severe distress symptoms during the COVID-19 outbreak. The scores in our study were significantly higher than BC patients under normal conditions in previous studies which showed about only 3.5% patients reported severe anxiety and depression [17] [18] [19] [20] [21] ,

indicating an additional increase of mental stress on the BC patients by COVID-19 crisis. 10 We identified factors affecting PROs of the BC patients during the COVID-19, which may help to make effective measure to reduce stress for these patients. Based on our results, living in Wuhan, poor general condition by self-identification, shorter duration after BC diagnosis, aggressive breast cancer molecular subtypes, metastatic breast cancer clinical stage, treatment discontinuation, CVC flushing delay, or close contact with COVID-19 patients are associated risk factors for poorer psychological status.

Notably, poor general condition, namely with comorbidities, was the only overlapping independent affecting factor for all four PROs metrics. Several studies have found that breast cancer patients with comorbidities have worse outcome than patients without comorbidities under normal condition [22, 23] . In addition, the death rate among COVID-19 patients with one or more comorbidities was much higher than those without comorbidities [24] [25] [26] [27] . Therefore, breast cancer patients with comorbidities faced more stress which can affect their mental health under this unique circumstance, which we demonstrate. Thus more attention should be paid and some effective measures should be taken to reduce the stress during the COVID-19 crisis among patients with comorbidities.

During the outbreak, changes to usual clinical practice for breast cancer patients were necessary [28] [29] [30] [31] [32] . Notably, the efficacy of compromised anti-cancer therapeutic regimen (519/966, 53.7%) was the main concern among these BC patients, followed by the fear about infection of COVID-19(191/966, 19.8%). A number of modifications to standard treatment paradigms were implemented. For example, during the outbreak, capecitabine was preferentially prescribed for triple negative breast cancer patients.

Pyrotinib, an oral pan-HER receptor tyrosine kinase inhibitor which was approved in China was recommended for HER2 positive breast cancer patients. Several months of neoadjuvant endocrine therapy and delay in surgery was recommended for hormone receptor-positive early breast cancer patients. In terms of CVC maintenance delay, we opened a special clinic to care for CVC weekly. In addition, we rapidly established and expanded telemedicine efforts through social medial, offering outpatient service and prescription or medical consulting. Optimization of physician-to-patient communication was critical for shared decision-making of therapeutic changes.

There are several limitations of our study. There was a possible selection bias for the patients enrolled in this study. Those patients without smartphones or not in the local Wechat groups may not be involved in our survey. In addition, this is a cross-sectional observational study, we need a control cohort to compare the differences of psychological status under different situations and to confirm the effect of COVID-19 in breast cancer patients. Furthermore, our population was diverse and heterogeneous in terms of disease states, which limits the power to each relevant clinical subgroup.

In summary, our study indicates that the psychological status of BC patients deserves more attention during COVID-19 pandemic. BC patients are likely to experience adverse mental well-being. Effective measures should be taken to minimize mental health issues and to provide psychological support. Percentages are weighted to account for the total responder size(n=510); c Percentages are weighted to size of the patients recommended for anti-cancer therapy (n=474). d Percentages are weighted to account for the total responder size(n=966). Abbreviation: BC, breast cancer; N/A, Not provided or not available; TNBC, triple negative breast cancer; HER2, human epidermal growth factor receptor 2; GAD-7, Generalized Anxiety Disorder Questionnaire; PHQ-9, Patient Health Questionnaire; ISI, Insomnia Severity Index; IES-R, Impact of Events Scale-Revised. P value was calculated using the nonparametric Wilcoxon signed-rank test and Kruskal-Wallis test. 

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Supplementary Figure 2. Forest Plots to identify independent affecting factors for anxiety (A), depression (B), insomnia (C) and distress (D) symptoms among BC patients in the center of COVID-19 in China using univariable logistic regression analysis. Abbreviation: BC, breast cancer; CVC, Central venous catheter

Education: High school or more vs Middle school or less

Marital status: Single(including widowed/divorced)vs married; General condition by self-identification: Poor vs

Metastatic vs Early; BC subtype: TNBC/HER2 vs Luminal; BC surgery history: Yes vs No

Close contact: close contact with COVID-19 patient vs No close contact with COVID-19 patient

This research was supported by the grants from the Fundamental Research Funds for the Central Universities (2042019kf0229), the Science and Technology Major Project