Which One Causes More Anxiety: Pandemic or Cancer?

Introduction : We conducted a survey among cancer patients undergoing active oncology treatment to evaluate their psychological wellbeing during COVID-19 pandemic in comparison to healthy individuals and whether the COVID-19 anxiety affected treatment adherence. Material and Methods 402 participants were included in the study; 193 were cancer patients receiving active treatment while 209 were healthy volunteers. Hospital anxiety and depression scale (HADS) and COVID-19 phobia scale (C19P-S) questionnaires were used. Results Patient group had signicantly lower CP19-S compared to healthy individuals. Patients’ mean HADS-anxiety score was signicantly higher. Mean depression scores were similar between patients and healthy volunteers. There were no treatment deferrals. levels cancer


Introduction
Coronavirus disease  has become an international public health emergency and the World Health Organization declared the pandemic on 11 March 2020 [1]. Since then, the mitigation procedures have imposed stress in the general population. Recent studies reported increased prevalence of psychological disorders due to the COVID-19 pandemic [2]. Oncology patients are expected to have additional anxiety since they are identi ed as a susceptible subgroup for COVID-19 with an increased risk of morbidity and mortality [3]. This information is supported by the studies reported from China and Italy where the case-fatality was higher in patients with cancer than those without (6% vs 2%, respectively) [4,5].
Systemic treatments, especially cytotoxic therapies, are the cornerstone of cancer treatment in both adjuvant and palliative settings [6,7]. It is well documented that the patient adherence to treatment plays an important role in the effectiveness [8]. Oncology patients may experience additional psychological burden in terms of contacting the disease since treatments require frequent hospital visits [2].
Additionally, the fear of experiencing a more severe course of COVID infection secondary to immunosuppressive state may prevent patients from applying to health care. For patients who are not receiving active treatment, the social distancing procedures and restrictions in access to care causing delays in follow-up visits may create additional fear of cancer recurrence [9].
It is important to determine the anxiety levels of oncology patients in order to avoid possible treatment delays due to increased stress levels caused by the pandemic. We conducted a survey among cancer patients undergoing active oncology treatment in order to evaluate their psychological wellbeing during COVID-19 pandemic and compared their anxiety, depression and COVID phobia scores with healthy individuals. We also aimed to see if COVID-19 anxiety affected treatment adherence.

Participants and Study Design
The study consisted of 402 participants of whom 193 were cancer patients undergoing chemotherapy, 199 of the participants were healthy volunteers. Patients receiving active chemotherapy at our oncology center between January and May 2021, during the second wave of pandemic, were included in this study.
Healthy volunteers were the individuals who didn't have a diagnosis of cancer.
Written informed consent was obtained from all participants after full explanation of the purpose and nature of the data collection. The study was approved by an institutional review board and a special permission was obtained from the Ministry of Health.
Participants were asked to complete hospital anxiety and depression scale (HADS) and COVID-19 phobia scale (C19P-S) questionnaires.
The personal information form included questions to address participants' demographic data including age, gender, occupation, education status, current living conditions and source of income. In addition, questions about their co-morbidities and preexisting/existing mental health conditions as well as their families were included. The questionnaire is a 20-item self-report instrument.
C19P-S was developed to assess the severity of COVID-19 phobia. The objects of the scale were created based on a comprehensive review of existing scales on fear, expert opinions, and participant interviews. C19P-S is a 20-item validated self-report instrument. All items in the scale are rated on a 5-point Likertscale from "strongly disagree (1)" to "strongly agree (5)". The higher score indicates a greater phobia.
HADS is a 14-item validated questionnaire developed by Zigmond and Snaith in 1983 [10]. It is used as a screening tool and severity measure for depression and anxiety. Although it was originally developed for patients in hospitals, it is valid in community settings. The validity and reliability study of the scale in Turkey was carried out by Aydemir et al. [12]. It is a 14-item instrument rated on a 4-point Likert-scale. Anxiety and depression were independent measures. The possible scores ranged from 0 to 21 for anxiety and depression. The severity of anxiety/depression symptoms score is assessed as follows: 0-7: none, 7-11: mild, > 11: severe.

Phone Consult
All patients had an initial phone consultation with a member of our oncology team prior to their rst treatment session during the initial phase of pandemic. They were given a detailed explanation of the precautions taken in order to ensure their safety.

Patient Treatment Adherence
All patients included in the study were followed-up for the duration of the study and their adherence to the treatment was reported.

Analysis
Data analysis was performed using SPSS (Statistical Package for the Social Sciences) version 25.0 (IBM Corp., Armonk, NY, USA) program. Descriptive statistical methods as well as Shapiro-Wilk and Kolmogorov-Smirnov tests were used to evaluate if the data obtained normal distribution. Normally distributed quantitative data was evaluated with ANOVA (Variance) analysis and multiple comparisons were made with Tukey Test in groups where the difference was signi cant. Quantitative data with abnormal distribution was evaluated with the Kruskal-Wallis Test and the Mann-Whitney U test was used for multiple comparisons in groups with signi cant differences. Chi-Square (Pearson Chi-Square, Continuity Correction, Fisher's Exact Test) tests were used in categorical data analysis. In addition, the level of correlation between two variables was examined with Pearson or Spearman correlation tests. The results were evaluated at the 95% con dence interval and p < 0.05 were considered statistically signi cant.

Demographic and clinical characteristics
Four hundred and two (402) participants completed the questionnaires; 193 (48%) were cancer patients and 209 (52%) were healthy volunteers. The mean age of the participants was 43.80 ± 13.49 years. 67.9% of the participants were female and 32.1% were male. Majority of them (69.7%) were married and living with family (92%). Two-hundred and forty-six (61.2%) participants were university graduates and 57.7% were employed. The detailed demographic patient characteristics are presented in Table 1.

Depression and anxiety
The mean anxiety score of all participants was 6.88 ± 3.95 (range:0-20). Anxiety scores of 250 (62.2%) participants were within normal ranges, 84 (20.9%) were mild and 68 (16.9%) were severe. While there was no difference between two groups in terms of anxiety levels, it was determined that the mean HADanxiety score of the patients was signi cantly higher (7.34 ± 3.82 vs 6.46 ± 4.04, p = 0.027). The mean depression score of all participants was 6.47 ± 3.63 (range:0-20). Depression levels of 248 (61.7%) participants were assessed as mild, while 103 (25.6%) had moderate and 51 (12.7%) had severe depression. The mean depression scores were similar between patients and healthy volunteers (p > 0.05). Statistical analyses revealed that COVID-19 phobia was an independent factor increasing the level of anxiety and depression in both groups. Details of the HADS assessment are presented in Table 2.

Phobia
All participants' CP19-S mean score was 47.90 ± 15.05 (range:20-100); subgroup analysis is given in Patients with chronic disease and a history of a shocking, scary, or dangerous event had signi cantly higher CP19-S levels (p = 0.025 and p = 0.009). The same parameters were found to be independent factors increasing CP19-S score in the multiple linear regression model (p = 0.004) ( Table 3).
Female gender (p = 0.003), having a chronic disease (p = 0.042) or diagnosis of psychiatric illness (p = 0.048) and being exposed to a shocking, scary, or dangerous event (p = 0.005) were statistically related to higher CP19-S levels in the healthy group. Moreover, in the multilinear regression models, age and female gender were found to be independent factors increasing CP19-S (p = 0.014 and p < 0.001). CP19-S evaluation details for both groups are presented in Table 4.
All participants reporting hospital anxiety were found to have signi cantly higher COVID-19 phobia levels (p < 0.05). There was no statistically signi cant correlation between depression levels and hospital anxiety among healthy volunteers (p > 0.05). However, the patients with hospital anxiety had signi cantly higher depression levels when compared to patients not reporting increased anxiety (p < 0.05). This correlation is presented in Table 5.

Discussion
To our knowledge this is the rst study comparing the HADS and CP19P-S scores of oncology patients with healthy volunteers. Pandemic is a traumatic life event that affected all of the population. Cancer patients and survivors are especially prone to chronic distress and they experience long term psychological problems which are usually neglected. Regardless of cancer stage, whether curative or palliative, 10-20% of patients experience depression and anxiety [13]. Detection and prevention of distress is important since it can affect treatment adherence [14]. Several previously reported studies linked anxiety disorders to postponement of chemotherapy [15,16].
Healthcare systems all around the world have been challenged by the COVID-19 pandemic. Although several precautions and adjustments were taken for the safety of oncology patients, they continued to experience high stress levels due to losses related to COVID-19. The initial studies that reported higher mortality rates for cancer patients added to the preexisting anxiety and depression of our patients, challenging them to make decisions between cancer and COVID [17].
In the current study, cancer patients had higher HADS scores when compared to the control group. However, their Covid-19 anxiety was signi cantly lower, which might have resulted in limited hospital anxiety leading to no treatment deferrals. Cancer remains to be the main life-threatening disease even during a pandemic, as COVID is a probability whereas cancer is a reality for our patient population. We attributed lower CP19-S scores to our telemedicine visits which aimed to address concerns of patients regarding safety measures for COVID-19. Informing our patients appropriately had critical importance in our pandemic strategy. Using telemedicine since the beginning of the pandemic resulted in no treatment postponements among our patients, although their wellbeing is affected more during the second wave of the pandemic. Karacin et al. [18], also used telemedicine as an important tool for the management of pandemic and investigated the effects of pandemic on the chemotherapy adherence. They reported lower chemotherapy deferral rates after this strategy was implemented.
Zhang et al. [19] investigated the psychological effects of chemotherapy interruption due to COVID-19 and they reported that especially patients with advanced refractory tumors had higher anxiety levels.
They suggested phone counselling as a strategy to offer relief while reducing the psychological harm caused by treatment interruption. Although we found telemedicine interactions helpful, we agree that further psycho-social support should be provided for oncology patients in order to help them cope with the uncertainty. However, Rodrigues-Oliveiraet al. [20] investigated the effect of COVID-19 on the anxiety levels of patients receiving RT for head and neck cancer using the HAD scale. His results suggested complying with treatment schedules despite increased COVID 19 anxieties. Although the radiotherapy treatment modality has a potentially more concerning schedule that necessitates a patient's daily presence at the hospital, when compared with chemotherapy, these patients also did not defer the RT even though telemedicine was not used.
Patients and healthy participants that reported increased anxiety for hospital visits, had signi cantly higher HAD anxiety, HAD depression and CP19-S scores. Although there wasn't any signi cant correlation among healthy participants in terms of anxiety and depression scores, cancer patients reporting anxiety were also found to have signi cant levels of depression. We can speculate that a reason for increased depression can be the possibility of treatment interruption which led to fear of cancer recurrence and mortality. It is important to de ne the contributing factors as well as coping strategies. A periodical virtual mood assessment can help us de ne the patients at risk for depression. Although not shown in our study, depression may lead to treatment refusal and deferral. Giese-Davis et al. [21] reported longer survival in metastatic breast cancer patients when their depression is managed.
Several studies showed the link between depression and cancer survival. Survival after a cancer diagnosis is multifactorial and depends on several factors such as treatment adherence, immunity as well as self-care including smoking cessation, exercise and diet. Zimmaro et al. [22] reported shorter survival when head and neck cancer patients were depressed.
Our study has some limitations. Patients included in the present study were heterogeneous in terms of their cancer diagnoses and our control group selection itself might introduce a bias. Although we did not aim to make a case-control study, one can criticize the distinct characteristics of two groups included in this study. Another weakness of our study is that we did not have a baseline pre-pandemic psych evaluation, and neither of our questions addressed their psychological status before COVID.

Conclusion
Cancer patients are already vulnerable for depression and anxiety, the disease itself carries the stigma of a chronic, potentially fatal illness. Although the pandemic increased levels of anxiety, cancer treatment continued to be a priority in our patients' lives and they aimed to continue their ongoing treatments without interruptions. Strategies including phone consults should be developed in order to support cancer patients coping with the pandemic and increase their courage to avoid treatment delays.

Declarations
Funding: The authors have no other relevant a liations or nancial involvement with any organization or entity with a nancial interest in or nancial con ict with the subject matter or materials discussed in the manuscript. No writing assistance was utilized in the production of this manuscript. O Sonmez conceived and designed the study. All contributed to the design, analysis and interpretation of the data. E Tezcanli prepared the rst draft and all contributed to subsequent drafts and the nal paper.