Anxiety and depression mediate the association between chemotherapy‐induced peripheral neuropathy and fatigue: Results from the population‐based PROFILES registry

Abstract Objective Chemotherapy‐induced sensory peripheral neuropathy (CIPN) is common among colorectal cancer (CRC) survivors. The aim of this study was to examine whether CIPN is associated with both psychological distress (ie, anxiety and depression) and fatigue and whether the relationship between CIPN and fatigue can (partly) be explained by psychological distress. Methods All CRC survivors diagnosed between 2000 and 2009 as registered by the population‐based Netherlands Cancer Registry (Eindhoven region) were eligible for participation. Chemotherapy‐treated survivors completed questions on CIPN (EORTC QLQ‐CIPN20), psychological distress (HADS), and fatigue (FAS) on average 5.6 years after diagnosis. Simple and multiple mediation analyses were performed to examine anxiety and depression as possible mediators in the association between CIPN and fatigue. Results Survivors with high (ie, upper 30% of scores) CIPN (n = 172) reported more anxiety and depressive symptoms and more fatigue compared with those with low CIPN (n = 299). Furthermore, among survivors with high CIPN, those who were anxious, depressed, or both reported more fatigue compared with those without psychological distress. These differences were clinically relevant. Finally, mediation analyses showed that while CIPN was directly associated with fatigue, the relationship between CIPN and fatigue was also significantly mediated by both anxiety and depression. Conclusions CRC survivors with high CIPN report more fatigue, especially those who are also anxious and/or depressed. More research is needed on the direction of the relationship between CIPN, psychological distress, and fatigue. For now, the treatment of fatigue should also focus on addressing psychological distress, as treating fatigue alone might not be sufficient.


| BACKGROUND
Colorectal cancer (CRC) is the third most common cancer among men and women, and the prevalence is still increasing. 1 Due to the increasing prevalence, more patients are living with the side effects of this condition and its treatment. Chemotherapy-induced peripheral neuropathy (CIPN), a side effect of chemotherapy, is common among CRC patients 2 and has been found to severely impact HRQoL. 3 Symptoms of CIPN are predominantly sensory and present as tingling, numbness, and aching or burning pain in the fingers, hands, toes, and feet. 4 While CIPN symptoms reverse or improve in the majority of patients after chemotherapy treatment, a significant proportion of patients experience chronic CIPN. 2 Moreover, symptoms can develop years after treatment has ended. 5 Due to the high prevalence of CRC in combination with the lack of a well-accepted treatment or prevention strategy against CIPN, 6 more CRC survivors could be affected by CIPN.
Besides CIPN, fatigue is also a highly prevalent problem among cancer survivors, with prevalence rates up to 90%. 7 Fatigue is one of the most debilitating symptom among cancer patients and has been related to a worse HRQoL, 8,9 a higher cancer recurrence, 10 and a poorer survival. 10 CIPN has been related to fatigue in previous research, 3,5,11 but the mechanisms underlying this relationship are not well understood.
Psychological distress, that is depression and anxiety, has been found to be strongly correlated with fatigue. 7,12,13 Also, while the studies on the relationship between CIPN and psychological distress are rather scarce, the majority did find that those with CIPN symptoms report more depression and anxiety. [14][15][16][17] Therefore, it is reasonable to argue that psychological distress could be a possible mechanism underlying the relationship between CIPN and fatigue. However, to our knowledge, this has not been examined before.
As interventions are not always successful in treating fatigue among individuals with cancer 18 and since there is no prevention or treatment available for CIPN, knowledge on the mechanisms underlying the relationship between CIPN and fatigue is crucial for developing efficacious interventions for fatigue. Therefore, in this secondary analysis, we examined whether CIPN is associated with both psychological distress and fatigue and whether the relationship between CIPN and fatigue can (partly) be explained by psychological distress. We hypothesize that CIPN will be associated with more anxiety, depression, and fatigue and that the relationship between CIPN and fatigue will be mediated by both anxiety and depression.

| Settings and participants
Details of the data collection have previously been described. 3 However, as the Netherlands Cancer Registry (NCR) is updated continuously, additional details of clinical characteristics were available for analysis in this study. In brief, this prospective, populationbased survey was set up in December 2010 by using data from the NCR, which compiles data of all individuals newly diagnosed with cancer. 19 Everyone diagnosed with CRC between 2000 and 2009 as registered in the Eindhoven region of the NCR was eligible for participation. Those with unverifiable addresses, with cognitive impairment, who died prior to the start of the study or were terminally ill, and those with carcinoma in situ or already included in another study were excluded. One year later, the second data wave took place, which included a questionnaire on CIPN. Therefore, the data presented in this cross-sectional study are based on the second data wave.

| Data collection
Data collection was performed within PROFILES (www.profilesregistry. nl), which is a registry for the study of the physical and psychosocial impact of cancer and its treatment. PROFILES contains a large webbased component and is linked directly to clinical data from the NCR.
Details of the PROFILES data collection have previously been described. 20 CRC survivors were informed of the study via a letter from their specialist if they still had follow-up care visits in the hospital; those who did no longer have any follow-up care received the letter from their former specialist. Nonrespondents were sent a reminder letter and paper-and-pencil questionnaire within 2 months.

| Sociodemographic and clinical characteristics
Survivor's sociodemographic (ie, age, sex) and clinical information were available from the NCR. Comorbidity at time of the study was assessed with the adapted Self-Administered Comorbidity Questionnaire (SCQ). 21 Depression was excluded as a comorbidity since depression is one of the possible mediators in this study. Questions on marital status and educational level were added to the questionnaire.

| Chemotherapy-induced peripheral neuropathy
As a previous study among the same sample of CRC survivors 3 only found a difference in sensory peripheral neuropathy symptoms between those who received chemotherapy and those who did not, we will only focus on the sensory symptoms of CIPN in this study.
Chemotherapy-induced sensory peripheral neuropathy was assessed with the EORTC QLQ Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20). 22 Respondents are asked how often they had experienced the specific sensory neuropathy symptom in the past week. Items are answered on a Likert scale ranging from (1) not at all to (4) very much. Scores were linearly transformed to a 0 to 100 scale, with higher scores indicating more complaints.

| Psychological distress
The Hospital Anxiety and Depression Scale (HADS) was used to assess anxiety (HADS-A) and depressive symptoms (HADS-D). 23 It consists of 14 items, answered on a 4-point Likert scale. Total scores range from 0 to 21, with higher scores indicating more anxiety or depression.
A cutoff value of 8 for each subscale was used to identify a clinically relevant level of anxiety or depression. 24 The HADS is a valid and reliable questionnaire, with mean Cronbach alpha of 0.83 (HADS-A) and 0.82 (HADS-D), and a sensitivity and specificity score of ≈0.80 for both subscales. 25 In the current study, Cronbach alpha was 0.82 for both subscales.

| Fatigue
Fatigue was assessed with the Fatigue Assessment Scale (FAS), 26 which consists of 10 items answered on a Likert scale ranging from (1) never to (5) always. Total scores range from 10 to 50, with higher scores reflecting more fatigue. The FAS has good psychometric qualities. 26 In this study, Cronbach alpha was 0.85.

| Anxiety and depression as mediators between CIPN and fatigue
First, among those with high CIPN, fatigue scores were compared according to their anxiety and depression level (Figure 1). Compared with survivors with high CIPN only, those who were also anxious, depressed, or both reported more fatigue. Moreover, survivors who were both anxious and depressed reported more fatigue compared with those with high CIPN who were only anxious or depressed. All differences were clinically relevant.
Second, simple mediation analyses showed that a high CIPN level was directly associated with more anxiety and fatigue ( In the multiple mediation model, in which the two possible media-

| CONCLUSIONS
In this secondary analysis of a large population-based study among long-term chemotherapy-treated CRC survivors, we first demonstrated that survivors with high CIPN reported more fatigue. In addition, those with high CIPN reported more anxiety and depression, which in turn increased their fatigue levels even more. Finally, both anxiety and depression were significant mediators in the relationship between CIPN and fatigue.

| Association between CIPN, psychological distress, and fatigue
Our first aim was to examine whether CIPN was associated with both psychological distress and fatigue. Regarding psychological distress, survivors with a high CIPN level reported more anxiety and depressive symptoms compared with those with a low CIPN level. The results are in line with several prior studies, in which a positive association between CIPN and either anxiety [14][15][16] or depression 14,15,17 was also found. While we cannot determine causality due to the cross-sectional nature of our study, previous studies have indicated that the association between CIPN and psychological distress may be bidirectional.

FIGURE 2
Multiple mediation analysis of anxiety and depressive symptoms as mediators in the association between chemotherapyinduced sensory peripheral neuropathy and fatigue.Unstandardized beta's are reported. *P < 0.05, **P < 0.01, ***P < 0.001 On the one hand, CIPN symptoms could induce psychological distress due to the pain associated with CIPN and the limitations in the patient's ability to perform tasks independently. 31 In addition, CIPN might serve as a constant reminder of having (had) cancer, which could also contribute to anxiety and depression. Reversely, people with a high level of anxiety or depressive symptoms may actually be likely to report more CIPN symptoms. 16 One of the possible biological mechanisms that have been suggested to play a role is an increased production of proinflammatory cytokines, which has been related to both anxiety and CIPN. 32,33 Moreover, proinflammatory cytokines that are produced in an anxious condition might interfere with recovery from the nerve injury in CIPN. People with depressive symptoms may also be likely to report more CIPN, as the deficits of serotonin and norepinephrine in their brain might lead to the amplification of minor signals from the body, causing an increased attention to bodily symptoms. 34

| Mediation of psychological distress in the association between CIPN and fatigue
The second aim of our study was to examine whether the relationship between CIPN and fatigue would be mediated by anxiety and depression. Both anxiety and depression were found to be associated with fatigue and to mediate the relationship between CIPN and fatigue.
While prior studies did find anxiety and depression to be predictors of fatigue, 12,13 this is the first study that has examined anxiety and depression as possible mediators in the association between CIPN and fatigue. Both anxiety and depression may affect fatigue in various ways. It could be that patients with CIPN who are depressed experience more fatigue, because they either lack the motivation to exercise 37 or because of the sleep disturbances often associated with depression. 38 Anxious patients with CIPN may be less physically active because of the fall risk among those with neuropathy in the feet 14 or because they may belief that too much activity could worsen CIPN symptoms. Also, the high-stress responses that those with anxiety often experience may increase levels of fatigue. However, as existing research has yet been able to determine the direction of the relationship between psychological distress and fatigue, only tentative inferences can be made.

| Study limitations
This study has some limitations that need to be mentioned. First, we only focused on sensory symptoms of CIPN, as a previous study in the same sample of CRC survivors only found differences in these symptoms between survivors who underwent chemotherapy and those that did not. 3  Despite these limitations, this is the first study that has examined anxiety and depression as possible mediators in the relationship between CIPN and fatigue. Also, we feel that this study provides valuable new insights into the limited available data on the relationship between CIPN and anxiety, depression, and fatigue. In addition, we used the FAS to measure fatigue, which takes more elements of fatigue into account compared with the EORTC QLQ-C30 fatigue subscale, which was mostly used in prior studies. Further, as this was a large population-based study with a high response rate, we feel that our findings can be generalized to the general CRC survivors' population treated with chemotherapy.

| Clinical implications
Given that this was a cross-sectional study, no clear statements can be made regarding the causality in the relationship between CIPN, psychological distress, and fatigue. Further studies are needed that focus on the interrelationship between CIPN, psychological distress, and fatigue. For example, intervention studies aimed at improving psychological distress could be evaluated on its concomitant effect on CIPN and fatigue.
For clinical practice, this study first shows that interventions for CRC survivors with high CIPN are needed, as they report clinically relevant higher fatigue levels. Further, CRC patients with CIPN who report fatigue should be screened for psychological distress, as those with anxiety and/or depression report the most fatigue. Accordingly, in the treatment of fatigue, treatment should also focus on the presence of anxiety and depression, as treating fatigue alone might not be sufficient. Exercise and psychological interventions are recommended, as these interventions have been proven to be effective in reducing not only psychological distress and fatigue, but CIPN as well. 39,40