Introduction
The most common symptom experienced by oncology patients is fatigue, referred to as Cancer-related fatigue (CRF), it is currently defined as a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity, does not improve with rest and interferes with usual functioning [
1,
2]. The estimates of CRF prevalence an overall pooled is 52% [
3], variable throughout all the cancer trajectory from diagnosis to the end of life [
4], and one-third of survivors report CRF as persistent fatigue for several years after treatment [
5]. In Spain, 75% of unsuccessful return to work in cancer patients is related to CRF [
6]. Also, patients undergoing active therapy are more likely to report more severe symptoms and an incidence of CRF up to 90%, since it can be considered one of the main side effects of some antitumor therapies [
7].
Despite the epidemiology, there is not a complete understanding of CRF pathophysiology, beside the relation with treatments, psychosocial, behavioral, and biological factors. In the last group, a variety of tumor mechanisms have been investigated, including proinflammatory cytokine release, neuroendocrine dysregulation, prolonged alterations in the cellular immune system and disruption in muscle energy metabolism [
8,
9]. Other potential contributing factors are involved, such as anemia, depression, sleep disorders, malnutrition, cardiopulmonary diseases, and hypothyroidism [
10,
11]. Therefore, CRF is a common cause of impaired physical function and autonomy to perform activities of daily living (ADL) [
4,
12]. Additionally, preserved physical function is a good predictor of the life expectancy of cancer patients [
13,
14], and evidence indicates that the functional capacity for ADLs is of extreme importance for the preservation of health-related quality of life (HRQoL) and should be optimized during treatment and palliative care interventions [
15,
16].
In order to this, there is accordance among guidelines that all cancer patients should be screened for the presence of fatigue symptoms and establish an opportune intervention. As a subjective experience, CRF is measured most efficiently via self-report; unidimensional scales, such as VAS (visual analog scale) or the Brief Fatigue Inventory (BFI), are the best screening tools in the clinical context [
2]. The multidimensional scales are complex but cover more fatigue aspects and meet accepted standards of validity. The most widely used are the European Organization for Research and Treatment of Cancer quality of life questionnaire fatigue subscale (EORTC QLQ C30), Multidimensional Fatigue Inventory (MFI-20), and Functional Assessment of Chronic Illness Therapy - Fatigue Scale (FACT-F) [
17].
Nowadays, the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) focuses health services on vulnerable populations, such as cancer patients, who have an increased risk of infection and develop severe complications or even death [
18], especially those with advanced tumor stage or low performance status [
19]. Cancer patients also suffer indirect complications in response to the detrimental impact of COVID-19 on cancer care centers worldwide, where some centers estimated that up to 80% of their patients were exposed to harm due to reduced services as part of a preemptive strategy (55.34%), overwhelmed system (19.94%), staff shortage (17.98%), restricted access to medications (9.83%) [
20], and reduced outpatient visits and social issues [
21].
In Spain, there is no official epidemiological report on COVID-19 in the oncology population; nevertheless, there are studies that offer data on the impact of COVID-19 on Spanish cancer patients during the pandemic, for instance, there has been a 20.8% decrease in newly diagnosed cases [
22]. Previous investigations into the post-COVID-19 period have predominantly focused on the general population, with a notable emphasis on the prevalent and frequently reported symptom of fatigue [
23]. Furthermore, post-COVID-19 manifestations are expected to have a negative impact on long-term quality of life, especially in young adults [
24]. Due to this, post-COVID syndrome is now defined, also known as long COVID, characterized by residual signs and symptoms that persist or develop 4 to 12 weeks after the onset of the acute illness. These symptoms cannot be explained by an alternative diagnosis, and as of now, the pathophysiology remains unclear [
25].
This work was initiated owing of the lack of data regarding the impact of COVID-19 on CRF, also, studies inolving oncological populations are needed as a health strategy to address this global situation promptly. For this reason, the main objective of this study was to assess CRF symptoms and their implications on functional capacity for ADLs and HRQoL in cancer patients during the COVID-19 pandemic, as well as to evaluate whether patients who had a previous infection perceived more impairment in HRQoL.
Discussion
Patients with cancer were considered a vulnerable population during the course of the SARS-CoV-2 pandemic. As a principal finding in this population, our study shows a significant difference in the FACIT-F score between the COVID + group and COVID– group (25 ± 10,40 vs. 34,81 ± 9,50 [p = 0,009], respectively), which means that cancer patients with a history of coronavirus infection have a major impairment on physical function during their usual daily activities due to CRF compared to cancer patients without coronavirus infection.
As mentioned, in Spain, there is no precise data on the prevalence of COVID-19 infection in the oncology population. However, during the time this study was conducted, 6,128,902 cases were reported in the general population, which corresponds to approximately 13% of the Spanish population. This percentage of COVID + patients aligns with our findings [
30].
Nowadays, there is a lack of research evaluating the direct impact of the COVID-19 pandemic on CRF. There are observational studies to describe fatigue following SARS-CoV-2 infection as one of the principal symptoms of post-COVID-19 syndrome with reported values ranging from 52.3 to 72.8% or more [
24,
31]. A systematic review and meta-analysis which includes 211 studies on 13 368 074 individual and provides valuable information about the prevalence and risk factors, when comparing COVID-19 patients with non-COVID-19 individuals, were fatigue is one of the most frequently reported persistent symptoms after infection, and factors frequently associated with a higher prevalence of persistent symptoms as female gender, advanced age, comorbidities, an extended duration of hospital stay [
32]. However, it is important to note that the individuals analyzed in these studies are part of the general population. By other hand, in most cases the fatigue it was defined as a neurological symptom [
33], unlike CRF which is multidimensional.
Specifically in the oncological population, studies such as one involving 2795 patients with cancer who survived COVID-19 documented a 15% range of sequelae, with fatigue (41.0%) and respiratory symptoms (49.6%) being the most common [
34]. According to post-COVID-19 syndrome, in our patient group, at least three months had passed between the SARS-CoV-2 infection and the interview. Although, by definition, the presence of cancer would rule out the diagnosis of this syndrome, the high values of fatigue, leads us to reflect on whether SARS-CoV-2 infection in the oncological population could be a risk factor for exacerbation of CRF or a concomitant diagnostic of post-COVID syndrome. However, it is not possible to make this distinction with our data or with the current literature data in the oncological population.
In our study, 93.3% of all cancer patients reported some level of fatigue and according to the VAS of CRF, the CRF in the COVID + group was severe (mean = 7), while in the COVID – group, it was moderate (mean = 5). The VAS values of fatigue were even higher in COVID + cancer patients who did not perceive a complete recovery after coronavirus; It is important to note that the perception of recovery after COVID-19 infection is subjective for each participant, of a dichotomous nature in our questionnaire. Therefore, attributing an incomplete recovery solely to CRF is not possible; other factors, such as the patient’s mood or the presence of other symptoms, may play a role in this observation. Regarding the perception of recovery after coronavirus infection, a descriptive study conducted through an online survey to assess multiple relevant symptoms approximately 3 months after the onset of SARS-CoV-2 infection in 2113 participants revealed that about 80% reported a moderate or poor health status and persistent symptoms, including fatigue and dyspnea, were most prevalent [
35], again, in nononcologic patients.
Otherwise, the HRQoL of cancer patients during the pandemic was significantly lower compared with general population [
36,
37], as shown in our results. In addition, a European study in cancer patients undergoing chemotherapy found a deteriorated HRQoL due to fatigue and insomnia symptoms [
38]. However, none of these results are directly related to viral infection, which means that most studies have evaluated the impact on quality of life as an indirect consequence of COVID-19.
Certainly, the negative impact of CRF on daily function and HRQoL assessment using the FACIT-F scale has been supported in other studies [
39‐
41]. Our participants, according to FACIT-F scores, had an average of 33,5 ± 10,11 (a score ≤ 30 means severe CRF and worst HRQoL); moreover, there were some groups with a major impairment of HRQoL, such as cancer patients with metastatic disease (30,85 ± 11,17), and participants in treatment with immunotherapy had a score of 27,10 ± 10,08, the last group is in keeping with previous studies where CRF has been associated with toxicity and side effects of immunotherapy [
42,
43]. Also, cancer patients with a history of depression in our findings had a 24 ± 5,65 FACIT-F score, other research about the impact of the pandemic on cancer people shows deteriorated emotional wellbeing [
44,
45] and a significant prevalence of anxiety and loss of energy [
46]; additionally a published study with 187 cancer patients reported a high rate of symptoms due to the lockdown, where 55.9% had fatigue at the end of the day, 91.5% cognitive alterations and 78% insomnia [
47], which may explain that cognitive or emotional dimensions of CRF were the most affected.
Among the different tumor entities in our study, pancreatic cancer patients had a significantly higher perception of CRF and reported a worse HRQoL (FACIT-F 18,00 ± 3,60; EVA 7,67 [6–9]). Similar results have been obtained in a study examining the prevalence and severity of fatigue in 2244 cancer patients across 15 entities, where CRF levels were significantly higher in pancreatic cancer patient, particularly in the physical dimension [
48]; Importantly, it is crucial to note that the entire group of our pancreatic cancer patients presented with metastatic disease, indicating an advanced stage of illness that could significantly influence the levels of experienced fatigue. Apart from the difference groups according to SARS-CoV-2 exposure, the differences in the FACIT-F results above the other variables were not statistically significant and should be interpreted with caution due to low size in some groups.
All the values of the FACIT-F scale obtained in this study had an inverse correlation compared to the VAS values (Pearson’s
r = – 0,76), which means that the HRQoL level is better meanwhile the perception of asthenia is lower; this concordance between the two scales was also described in other studies [
49]; therefore, we think that each of the tests can be applied to reliably assess this symptom in clinical practice.
In terms of performance status, most of the participants had a mild or no dependence for functional ability (ECOG-PS ≤ 2), which could be a protective factor. According to a cohort study on patients with active or previous malignancy and confirmed SARS-CoV-2 infection, an ECOG-PS of 2 or higher was one of the independent risk factors associated with increased 30-day all-cause mortality and morbidity (2 vs. 0 or 1: 3,89, 2,11 − 7,18) [
50]. Despite the good performance status in our patients, only 28.3% had an active job, which suggests that the function for basic self-care activities is not as limited as the function for advanced activities, but the information is insufficient to statistically define whether this is related to CRF or the pandemic socioeconomic situation.
On the other hand, there is strong evidence of the beneficial effects of physical activity in CRF [
51,
52] and the improvement of cancer health-related outcomes [
53], as well recent studies have been remark the importance of rehabilitation programs because home confinement can put cancer patients at a greater risk of physical deconditioning and immobilization [
54]; related to this, we think that it is important to analyze that 53.3% of our patients reported regular physical activity, and this value is high compared to other works [
55], but it is not possible to know if these percentages can be associated with CRF levels according to the results. While it is true that some effective interventions to enhance adherence to healty lifestyle habits, including exercise, are increasingly employed in people with cancer [
56], it is possible that patients in this sample, who also mostly had a good performance status (ECOG levels 0 and 1), took part in these interventions. This, in turn, may explain their interest in actively participating in medical research studies such as this one.
Strengths and limitations
The current study represents, to the best of our knowledge, the first report in the literature to assess CRF values based on exposure to SARS-CoV-2 infection using validated tools to measure outcomes in terms of HRQoL and performance status (measured by FACIT-F) within the oncology population.
In spite of the methodological efforts to control heterogeneity in the final sample through selection criteria, it is not necessarily considered representative of the overall oncological population; nevertheless, our group of cancer patients is related to the descriptions of the rest of the oncological population in Spain.
Although our work provides new information on the significant impact of COVID-19 and CRF on oncology patients, there are limitations to warrant.
The online application of the questionnaire may be difficult due to the multidimensional aspects of CRF diagnosis, and patients or caretakers may not know their entire clinical history. Also, the participation of people who do not have access to electronic devices and the internet is limited.
Despite the significant impact on social media and the imperative to achieve the calculated sample size, the major limitation arose from the small number of participants, particularly noticeable in certain groups such as the COVID + group. This limitation affected the application of statistical tests for comparing and interpreting some results. Concerning the composition of the patient group, in addition to the presence of metastatic disease, information about the cancer stage was not included in the study, which could also correlate with the levels of fatigue. Similarly, apart from determining the type of oncological treatment the patients were undergoing during data collection, additional details, such immunotherapy medications used, which may influence the clinical course of fatigue were not investigated. Moreover, in our patient sample, to ascertain the diagnostic of depression as a comorbidity that significantly contributes to CRF, it relied on the question of whether there was a history of depression; we recognize that this approach may present a limitation, as values could potentially be higher with the utilization of questionnaires aimed at identifying the actual presence of a depressive disorder.
On the other hand, given that there is a considerable number of asymptomatic SARS-CoV-2 infections, it is possible that some of these patients have been analyzed within the COVID-19 group.
CRF is a neglected and often undiagnosed symptom that warrants further research to highlight its significance, particularly given its high prevalence and substantial impact on both cancer patients and their families. In this regard, we consider the observational results of this study to offer valuable and original insights, shedding light on the heightened fatigue symptoms and diminished physical function experienced during routine daily activities post-COVID-19. Finally, owing to its rigorous methodology, this study is reproducible, its limitations are identifiable for potential enhancement, and it contributes to the augmentation of high-quality evidence in related research endeavors.
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