Coping strategies as mediators of uncertainty and psychological distress in patients with advanced cancer

Uncertainty in the context of advanced cancer diagnosis often incurs significant psychological distress. The aims were to evaluate the incidence of psychological distress upon diagnosis of advanced cancer and to analyze whether the relationship between illness uncertainty and psychological distress can be mediated by coping strategies.

Patients with unresectable or metastatic cancer often face uncertainty due to lack of information, ambiguous outcomes, and an unpredictable future. 1,24][5] To assess the relationship between these factors, Mishel developed a model in 1988 which analyzed how positive or negative appraisals of uncertainty impact coping strategies, 6 and indirectly affect psychological distress, tolerance of treatment, quality of life, and survival. 7ping involves cognitive and behavioral strategies to manage emotional distress. 8In stressful or life-threatening situation, individuals draw on different strategies to manage demands, potentially aiding in disease adaptation.These strategies may change over the disease course and their efficacy may vary depending on the disease stage. 9Among the different coping strategies, subjects who maintain a positive attitude and fighting spirit have been reported to suffer less psychological distress, while just the opposite is true among those using cognitive avoidance. 10[14] Several studies have explored the relationship between uncertainty, coping strategies, and psychological well-being among cancer patients, but results are inconsistent, possibly due to heterogeneity in the studied populations.These studies suggest a positive correlation between uncertainty and avoidance strategies, which might have detrimental impacts on mental well-being in some cases.More research is needed to understand these relationships, especially at the time of diagnosis of advanced disease.The influence of high levels of uncertainty leading to avoidance strategies and the potential of avoidance to mediate the association between intolerance of uncertainty and psychological distress also needs further exploration.
In light of the above, the aims were to evaluate the incidence of psychological distress in subjects with advanced cancer starting systemic treatment, and to analyze whether the relationship between illness uncertainty and psychological distress can be mediated by coping strategies (Figure 1). 6We hypothesize that uncertainty and maladaptive coping strategies may exacerbate psychological distress.

| Design and procedures
The study protocol complied with the provisions of the Declaration of Helsinki and was approved by the ethics committees of each hospital and by the Spanish Agency of Medicines and Medical Devices (AEMPS).A multi-institutional, prospective, observational study was conducted, involving 15 medical oncology departments in Spain, where medical oncologists manage patients eligible for palliativeintent systemic anticancer treatment.This work is part of the NEOetic cancer patient research program funded by the Bioethics Group of the Spanish Society of Medical Oncology (SEOM).All eligible cases were identified and included consecutively by oncologists.Subjects were informed that their participation was voluntary, anonymous, and confidential.Informed written consent was obtained from all prior to data collection.Inclusion criteria required participants to be over 18 years of age and to have a histologically confirmed diagnosis of locally advanced, unresectable, or metastatic cancer qualifying for systemic treatment with palliative intent.Individuals with any serious mental illness that would prevent them from comprehending the survey were excluded.Data collection procedures were consistent across all hospitals and data were collected and updated by the medical oncologist, through a webbased platform (www.neoetic.es).

| Measures
Sociodemographic characteristics were gathered using a standardized self-report form.Information concerning cancer and treatment was obtained by the attending oncologist through an interview and by patients' medical records.During the consultation discussing systemic cancer treatment benefits, oncologists provided patients with the questionnaires.Patients were then instructed to complete these at home before initiating treatment and return them to study assistants during their next visit.The forms clearly stated that the participation was voluntary and anonymous.
Uncertainty of Illness was gauged using the 5-item, Michel Uncertainty of Illness Scale (MUIS) validated for the Spanish population. 6This questionnaire appraises reactions to uncertainty, ambiguity, and the future.Items are scored on a 5-point Likert scale, yielding total scores of 5-25; higher scores correspond to greater uncertainty.Based on cutoff values from Rodríguez-González et al., scores of ≥16 were regarded as experiencing "uncertainty". 15Cronbach's alpha was 0.83. 6ping strategies were measured using the Mini Mental Adjustment to Cancer scale (M-MAC) which comprises 29 items, classifying four coping strategies: anxious preoccupation, helplessness, positive attitude, and cognitive avoidance 16 ; the version adapted for Spanish cancer patients was used. 17 4-point Likert scale.The higher the score on a given subscale, the more frequently that particular coping strategy is employed.The omega coefficients for the Spanish version of the score range from 0.76 to 0.90. 17 Psychological distress over the past week was determined using the Spanish version of the 18-item Brief Symptom Inventory (BSI-18). 18Raw scores were converted to gender-normative T-scores.
Using Derogatis recommended cut-off values, 18 T-scores ≥63 were judged as at risk for psychological distress. 19

| Data analysis
Data analysis was conducted using descriptive statistics and ANOVAs to examine psychological distress variances related to demographic and clinical variables.Eta squared (η 2 ) were applied to assess effect size 20 and bivariate correlations to evaluate the association between uncertainty in illness (MUIS), coping strategies (M-MAC), and psychological distress (BSI-18).Data was checked for normality, outliers, multicollinearity and homoscedasticity. 21Structural Equation Modeling (SEM) was to identify the relationship between uncertainly and psychological scales. 22We calculated standardized direct, indirect, and total effects using bootstrapping methods and tested model fit using multiple indices. 22,23Bilateral statistical significance was set at p < 0.05 for all tests.Analyses were performed using IBM-SPSS 23.0 and AMOS 23.0 software package.

| Demographics and clinical characteristics
A total of 841 patients were enrolled from February 2020 to April 2022.73 patients were deemed ineligible for various reasons: 56 did not attend a recent oncology appointment for treatment decisionmaking, 7 declined participation, 6 were excluded due to health conditions or age as per the treating oncologist's judgment, and 4 were excluded due to circumstances assessed by the oncologist that could inhibit their participation.

| Psychological variables
A total of 71.7% of the participants scored 63 or higher on the BSI-18 scale, denoting clinically significant psychological distress.In the univariate analyses, the following groups were found to suffer less psychological distress: men (F = 13.477,p = 13.477;eta partial = 0.016), married (F = 4.162, p = 0.042; eta partial = 0.006), and subjects with better ECOG performance status (F = 6.066, p = 0.014; eta partial = 0.007); no statistically significant differences were detected in the other groups (Table 1).The predominate coping strategies were positive attitude (M = 79.2,SD = 17.2) and cognitive avoidance (M = 64.0,SD = 26.1).Illness uncertainty positively correlated with anxious preoccupation, helplessness, cognitive avoidance and psychological distress (all p < 0.05); no relationship was detected with positive attitude (Table 2).Positive attitude was negatively associated with psychological distress (p < 0.001).

| DISCUSSION
To our knowledge, this is the largest study to date in patients with newly diagnosed advanced cancer to assess the relationship between uncertainty and psychological distress and how the relationship between the two may be mediated by coping strategies.Moreover, in contrast to other studies conducted so far, this one was conducted in the era of immunotherapy and biologic drugs from which almost half of the sample benefited.

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- We have found that people facing a scenario of uncertainty, such as advanced cancer, present high levels of psychological distress, albeit the latter is mitigated by the coping strategies used.Subjects who respond with anxious preoccupation suffer increased helplessness and psychological distress, while those who respond with cognitive avoidance, exhibit a more positive attitude, and experience less psychological distress.Psychological distress is one of the most usual problems in advanced cancer, affecting up to 70%, with physical and psychological factors accounting for much of the variation. 24The high incidence of psychological distress observed in our study may be attributed to the specific selection of our sample, which consists of patients with incurable advanced cancer with no options for radical treatment.Thus, participants with worse functional status (ECOG≥1) and those with physical disease-related symptoms, such as pain, show greater psychological distress. 25 -1697 negatively affects quality of life, in that it contributes to deterioration of the individual's functional status as a resulted of poor treatment adherence, worse tolerance to the therapies with increased complications, and worse survival outcomes. 27Moreover, psychological distress grows with uncertainty, anxiety about the likelihood of imminent death, demoralization, and the perception of being unable to cope effectively with their new life situation. 28veral studies have assessed the relationship between psychological distress and clinical and socio-demographic variables.In our study, the groups with the lowest psychological distress are male, married, and have a good performance status (ECOG = 0).This is in line with the literature that reports that women with cancer are more vulnerable to psychological distress than men, as they face a probable change of roles and responsibilities in both their family and professional lives, as well as a changed perspective on the future in the face of approaching death.0][31] Research has been conducted, especially in breast cancer, to examine the relationship between marital status and psychological distress and the results are similar to ours, that is, subjects who were unmarried or unpartnered had higher levels of distress and therefore required more psychological care. 32One study of 346 patients with gastrointestinal or metastatic lung cancer published by Ellis J. 33  In another study of 236 hospitalized palliative cancer patients, a questionnaire was administered exploring psychological distress caused by the uncertainty they faced that evinced that more than half of the sample had psychological distress. 5All these results are consistent with those of our study.
As for the association between coping strategies and uncertainty, the latter has been positively related to cognitive avoidance and this, in turn, has a positive relationship with positive attitude, which is in line with the published studies as outlined above.Faced with a stressful, uncertain situation, such as the diagnosis of advanced cancer, one of the most widely used coping mechanisms initially is avoidance, which enables the individual to be temporarily less stressed.Survival with incurable cancers is currently growing, thanks to the emergence of treatments such as immunotherapy; hence, in the scenario of great, prolonged uncertainty, cognitive avoidance may be a healthier strategy, helping to prevent the exhaustion and unproductive focus that constant worry can cause.
Avoidance might make it possible for the person to concentrate on and control the little things, instead of the "elephant in the room" that is not in their hands to solve.This explains the positive relationship between coping strategies based on cognitive avoidance and positive attitude found in this series. 36Nevertheless, longitudinal studies in individuals with advanced cancer are needed to evaluate how coping evolves and the factors that may influence it, such as prognosis or disease control.
On the other hand, subjects who respond with high levels of anxious preoccupation in a scenario of uncertainty, exhibit more helplessness and greater psychological distress.This is consistent with Gibbons' finding 37 that high levels of anxious preoccupation correlated with psychological distress in women newly diagnosed with breast cancer.Another study of 102 cases of localized breast cancer found that anxious preoccupation and helplessness were positively related to psychological distress, while fighting spirit and social support were protective.Furthermore, anxious preoccupation and helplessness predicted 75% of the cases of psychological distress. 38Meanwhile, helplessness appears when the person feels that there is no effective way to control their disease; in our study, it was negatively related to positive attitude and to cognitive avoidance.Helplessness can be defined as a system of negative expectations or a pessimistic attitude of anticipation of an undesirable situation in the future, which is beyond one's control and which entails a higher risk of developing depressive symptoms. 39In this series, participants with high levels of anxious preoccupation had increased negative expectations for the future, which lessened their positive attitude regarding their disease.Longitudinal studies that scrutinize the evolution of this strategy throughout the phases of the cancer would be compelling.

| Study limitations
This study must be pondered together with its limitations.First, given its cross-sectional nature, the directionality of the observed relationships cannot be determined.The findings ought to be confirmed in longitudinal cohort studies.Second, we used self-report instruments, which can give rise to response biases, such as social desirability, recall errors, etc.Finally, our results cannot be extrapolated to subjects with resectable or rare cancer subtypes that were less represented than breast, lung, and digestive tumors in our sample.

| Clinical implications
This study presents results with significant clinical implications for our cancer patients.Individuals newly diagnosed with advanced cancer, who have not yet started any systemic treatment, displayed high levels of psychological distress when confronted with this scenario of uncertainty.In our series, those who face uncertainty by avoiding overthinking have a more positive attitude and lower levels of psychological distress.In contrast, those who excessively worry about their situation suffer greater psychological distress and have less favorable expectations for the future.In the context of advanced cancer at the beginning of treatment, one recommendation would be to encourage patients to set attainable goals and focus on those facets of their lives that they can control, such as physical exercise, diet, and healthy lifestyle habits, to better manage the time in treatment that lies ahead.

| CONCLUSIONS
Our study shows that patients with newly diagnosed advanced cancer present psychological distress in the face of an uncertain scenario that may be mediated by coping strategies such as cognitive avoidance.Psychological assessment from the time of diagnosis is essential to understand the coping strategies of the disease for a better approach and support of the patient to help reduce their psychological distress and improve their quality of life.
Items are rated on a F I G U R E 1 Hypothesized study model adapted from Michel's uncertainty in illness theory.OBISPO ET AL.

Figure 2
Figure 2 portrays illness uncertainty as directly and positively correlated with cognitive avoidance, anxious preoccupation, and psychological distress, as indicated by regression coefficients (β) of 0.16, 0.19, and 0.06 respectively.This suggests that an escalation in illness uncertainty can lead to increased utilization of cognitive avoidance and anxious preoccupation as coping strategies, alongside a rise in psychological distress levels.Cognitive avoidance showed a positive correlation with a positive attitude (β of 0.51), implying that individuals who use this coping strategy often hold a more positive outlook.Meanwhile, anxious preoccupation correlated positively with both helplessness (β of 0.75) and psychological distress (β of 0.55), suggesting it heightens feelings of helplessness and escalates psychological distress.Our study underscores the relationship between illness uncertainty, coping strategies, and psychological distress levels.It also emphasizes the significant role of both cognitive avoidance and anxious preoccupation in managing illness uncertainty.

T A B L E 2
was conducted to determine which factors predicted referral to psychological care units.The authors found that younger and unmarried individuals benefitted most from psychological support.Another study published by Goldweigz34 discovered that unmarried males with digestive tract cancer were at higher risk for psychological distress.Our study unearthed no statistical relationship with age, probably because there were more partici-pants>65 years of age, with neoplasms other than breast cancer.The most used coping strategies at diagnosis of unresectable advanced cancer and prior to commencing systemic treatment were positive attitude and cognitive avoidance.At that time, our participants' main concerns relate to the symptoms of their disease, possible adverse events of therapies, persistent uncertainty surrounding tumor progression and death.Qualitative studies demonstrate that, in the early stages following diagnosis, people use the coping strategies they used prior to the onset of cancer.9Subsequently, these strategies change and develop as the person learns to live with their disease, often influenced by their context and environment.A recently published study involving 367 breast cancer patients sought to analyze the coping strategy most used at diagnosis and changes in strategies during the course of the disease and their relationship with disease-free survival.The authors discovered that the most prevalent strategy was positive attitude, as in our study.35In our study, uncertainty was positively related to psychological distress.Patients with metastatic cancer often grapple with elevated levels of uncertainty due to the severity of the disease, which contributes to increased psychological distress stemming from the complexity of treatment and the limited availability of therapeutic options.This relationship between uncertainty and psychological distress has been reported across different types of tumors and stages of disease.Verduzco7 recently published a study involving 527 Correlations between uncertainty in illness, coping strategies, and psychological distress.0.05; **p < 0.01.F I G U R E 2 Theoretical model predictive of psychological distress among patients with advanced cancer, based on Michel's uncertainty of illness theory.Lines represent significant pathways.*p < 0.05, **p < 0.001.subjects with advanced cancer over the age of 70 years, predominantly gastrointestinal and lung cancer, who were about to start a new line of systemic treatment.This study found that high levels of uncertainty were associated with increased anxiety and depression.
Demographic and medical characteristics of participants and differences in psychological distress.
A study published by McMullen 26 included patients about to initiate outpatient chemotherapy and evaluated possible sociodemographic and clinical factors associated with increased emotional distress.They found that those with a Karnofsky index <80% had moderate to high levels of psychological distress as measured by the DASS-21 scale.Psychological distress T A B L E 1 Abbreviations: η 2 , Eta squared; SD, Standard deviation.OBISPO ET AL.