Psychological Distress in Patients Treated for Renal Cell Carcinoma: A Systematic Literature Review

(1) Background: The incidence of psychological distress and its impact on renal cell carcinoma (RCC) patients is unclear. Our aim was to analyze the literature regarding the prevalence of psychological distress and its impact on patients with non-metastatic or metastatic RCC; (2) Methods: A systematic search of five databases was performed. Studies were considered eligible if they included patients with RCC, had a prospective or retrospective design, and assessed anxiety, depression, or psychological distress at any time during treatment or follow-up. Exclusion criteria: no treatment for RCC, or not providing data for RCC patients; (3) Results: A total of 15 studies were included. Reported psychological distress was up to 77% and the prevalence of depressive and anxiety symptoms were up to 77.6% and 68.3% in patients with non-metastatic RCC. There was no association of depression with overall survival (OS) in patients with non-metastatic RCC treated by radical nephrectomy; on the contrary, in patients with metastatic disease, depression had an impact on OS. Limitations are related to the quality of the included studies; (4) Conclusions: Patients with RCC reported a high level of psychological distress like other cancer patients. It seems that for patients with localized disease, psychological distress does not impact OS, while it does in those with metastatic disease.


Introduction
Renal cell carcinoma (RCC) represents almost half of the newly diagnosed urinary tract cancers and has an estimated incidence in the US alone of 79,000 in 2022 [1] and a worldwide reported incidence of more than 431,288 [2]. Treatment of RCC may vary from active surveillance, ablative therapies, partial or radical nephrectomy for localized disease until cytoreductive nephrectomy and systemic treatment (targeted therapies and/or immunotherapy) for metastatic disease [3].
Psychological distress refers to non-specific symptoms that include stress, anxiety and depression; increased levels of psychological distress may indicate the beginning of serious conditions such as major depressive disorder, anxiety disorder, schizophrenia, somatization disorder, or a variety of other clinical conditions [4]. In practice, it is often seen that many patients deny any symptoms of psychological distress [5,6] and often they self-treat with ethanol [7] and/or social recreational agents [8].
Depression and anxiety incidences were reported to be high in patients with urological cancers: 70% in patients with bladder cancer [10], 17% in prostate cancer [11] and 20% in testicle cancer [12]. Both overall and disease-specific mortality outcomes have been shown to be lower in bladder and prostate cancer patients affected by psychological distress [13]. Nevertheless, there is a scarcity of research regarding systematic data related to the impact of psychological distress, depression and/or anxiety on oncological outcomes among RCC patients.
To fill this void, we performed a systematic review to analyze the existing literature regarding the incidence of psychological distress, depression and/or anxiety and their impact on oncological outcomes in patients with non-metastatic and metastatic RCC separately.

Materials and Methods
A systematic search of Web of Science, PubMed, Embase, Clinicaltrials.gov, and American Psychological Association (APA) PsycNet was performed on 1 April 2022, using any combination of the terms: anxiety (EXP) OR depression (EXP) OR psychological distress (EXP) AND nephrectomy (EXP) OR renal carcinoma (EXP) OR kidney cancer (EXP). All original articles that fulfilled the inclusion criteria were included. Additional crosschecking of reference lists and hand search to find additional studies was also performed in Google Scholar ( Figure 1). somatization disorder, or a variety of other clinical conditions [4]. In practice, it is often seen that many patients deny any symptoms of psychological distress [5,6] and often they self-treat with ethanol [7] and/or social recreational agents [8].
Depression and anxiety incidences were reported to be high in patients with urological cancers: 70% in patients with bladder cancer [10], 17% in prostate cancer [11] and 20% in testicle cancer [12]. Both overall and disease-specific mortality outcomes have been shown to be lower in bladder and prostate cancer patients affected by psychological distress [13]. Nevertheless, there is a scarcity of research regarding systematic data related to the impact of psychological distress, depression and/or anxiety on oncological outcomes among RCC patients.
To fill this void, we performed a systematic review to analyze the existing literature regarding the incidence of psychological distress, depression and/or anxiety and their impact on oncological outcomes in patients with non-metastatic and metastatic RCC separately.

Materials and Methods
A systematic search of Web of Science, PubMed, Embase, Clinicaltrials.gov, and American Psychological Association (APA) PsycNet was performed on 1 April 2022, using any combination of the terms: anxiety (EXP) OR depression (EXP) OR psychological distress (EXP) AND nephrectomy (EXP) OR renal carcinoma (EXP) OR kidney cancer (EXP). All original articles that fulfilled the inclusion criteria were included. Additional crosschecking of reference lists and hand search to find additional studies was also performed in Google Scholar ( Figure 1).

Protocol
The protocol of this systematic review followed the Cochrane handbook [14] and the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria

Protocol
The protocol of this systematic review followed the Cochrane handbook [14] and the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) criteria (www.prisma-statement.org (accessed on 30 August 2022)) [15]. The present systematic review was registered in the PROSPERO International prospective register of systematic reviews (registration no. CRD42021282104).

Inclusion and Exclusion Criteria
The PICOS (Population, Intervention, Comparator, Outcome and Study design) approach was utilized to define study eligibility. Initial studies were considered eligible if they reported psychological distress (P) before nephrectomy for renal cancer (I) and reported psychological distress after nephrectomy at specific time points during follow-up (C) to determine if there is a change in psychological distress status (O), using validated scales (S). However, only one study met this criteria [16], so we decided to expand the inclusion criteria to studies that included patients with kidney cancer, had a prospective or retrospective design, and assessed anxiety, depression and/or psychological distress at any time during treatment and/or follow-up. Exclusion criteria: studies that included patients undergoing no treatment for RCC, or not providing data on anxiety, depression and/or psychological distress separately for RCC patients.
The primary outcome was the prevalence of anxiety, depression and/or psychological distress among patients with non-metastatic and metastatic RCC separately. The secondary outcome was the impact of anxiety, depression and/or psychological distress on outcomes of patients with non-metastatic and metastatic RCC, separately.
For each selected study, the following items were recorded independently by two investigators (L.V and M.D.V): first author's name, year of publication, country, design, number of patients, treatment option, patients' characteristics, questionnaires used, reported results (primary outcome: prevalence of anxiety, depression and/or psychological distress and secondary outcome: impact on oncologic outcomes) and follow-up. Two investigators (L.V and M.D.V) independently manually conducted a literature search and extracted data from the included full-text articles; disagreements were resolved by consensus.

Study Quality and Risk of Bias Evaluation
Study quality was determined by the Newcastle-Ottawa Scale (NOS) [17] for cohort studies. Thresholds for converting the NOS were established according to the Agency for Health Research and Quality (AHRQ) standards. Five studies had good quality, one study had fair quality and the other nine had poor quality (Supplementary Material Table S1A).
The "risk-of-bias" (RoB) evaluation of each study was assessed according to the Cochrane Handbook for systematic reviews of interventions for including non-randomized studies. RoB was determined by examining the risk of pre-assigned confounders. The main confounding factors were age, gender, marital status, socioeconomic status, and occupation. The presence of confounders was determined by consensus (Supplementary  Material Table S1B).

Results
A total of 6873 abstracts and titles were initially identified in all five databases. After removal of reviews, meeting abstracts, books, and duplicates, 669 remained. Then, 645 articles were excluded after screening titles and abstracts. We assessed 24 full text articles and, finally, 15 studies were included ( Figure 1).
Ten studies assessed the prevalence of psychological distress, anxiety and/or depression in non-metastatic RCC (Table 1), two the association of psychological distress, anxiety and/or depression in non-metastatic RCC with survivals outcomes ( Table 2) and another two the association of psychological distress, anxiety and/or depression in metastatic RCC with survivals outcomes; one reported changes in anxiety and depression levels at 12 weeks after treatment in metastatic RCC patients (Table 3).  The RoB evaluation showed that two studies had a 'low risk of bias' (in green) and 13 studies had a 'high risk of bias' (in red, see Supplementary Material Table S1B). All included studies reported results considering age and gender as cofounders and five studies reported results considering all main confounding factors.

Psychological Distress, Anxiety and/or Depression in Patients with Non-Metastatic Renal Cell Carcinoma
Ten studies that assessed psychological distress, anxiety and/or depression in nonmetastatic RCC patient were identified [16,[18][19][20][21][22][23][24][25][26]. They included a total of 2188 patients (841 females, 38.4%) from different countries such as Turkey [18], Canada [19], Korea [20], the United States (US) [16,21,24,25] (849 patients, 38.8%), Germany [22], China [23] and Italy [26]. These studies used different validated tools to assess psychological distress, anxiety and/or depression such as the Edmonton Symptom Assessment System-revised (ESAS-r), SF-12 Health Survey, Perceived Stress Scale (PSS), Center for Epidemiologic Studies Depression Scale (CES-D), Zung Self-Rating Anxiety Scale (Zung SAS), Patient Health Questionnaire-9, National Comprehensive Cancer Network (NCCN) Distress Thermometer, Beck Depression Inventory-II (BDI-II), State-Trait Anxiety Inventory (STAI), General Health Questionnaire (GHQ), Hospital Anxiety and Depression Scale (HADS), as well as the Social Problem Questionnaire (SPQ.). Despite the variety of scales used, the psychological distress rate was reported to be as high as 77% [21] and the prevalence of depressive and anxiety symptoms was up to 77.6% and 68.3% [23], respectively. Nevertheless, these studies investigated and reported distress, anxiety and/or depression at different stages of disease such as pre-nephrectomy or during follow-up, with only one study reporting baseline data and at 24 weeks [16]. Time-dependent reporting found no change in depression nor in anxiety scores ( Table 1). The heterogeneity among studies prohibited the performance of a meta-analysis of the available data.

Impact of Anxiety and/or Depression on Oncological Outcomes in Patients with Non-Metastatic Renal Cell Carcinoma
Two studies reported oncological outcomes in relation to anxiety and depression in patients with non-metastatic RCC. One included 1990 patients from the US [27] and one 182 patients from China [28]. When analyzing a retrospective database, Packiam et al. [27] found no association of anxiety or depression with recurrence, distant metastases, overall survival (OS) or death from RCC after 10 years of follow-up. On the contrary, Song et al. [28] found that patients with sustained anxiety according to the Hospital Anxiety and Depression Scale-Anxiety (HADS-A) were more likely to die from any cause with a median follow-up of 43 months. Even in the context of a randomized clinical trial (RCT), other oncological outcomes such as recurrence, metastases or cancer specific survival were not analyzed. Both studies failed to detect an association of depression with OS (Table 2).

Impact of Psychological Distress, Anxiety and/or Depression on Patients with Metastatic Renal Cell Carcinoma
Three studies investigated the impact of psychological distress, anxiety and/or depression, on patients with metastatic RCC. Two studies included 304 patients from the US [29,30] and one included 127 patients from China [31]. Different instruments were used to measure distress, anxiety and/or depression including a touch screen-based instrumenteither HADS or CES-D. A meta-analysis was not performed due to heterogeneity between studies. Cohen et al. [30] found a statistically significant association between clinical depression measured with CES-D (score ≥ 16), and OS with a hazard ratio (HR) of 1.5 (95%CI 1.00-2.23). Similarly, in the study of Bergerot et al. [29], a poorer OS was observed in patients with high distress compared to those with low distress (20 mo. vs. 45.8 mo.), but statistical significance was not reached. In a prospective evaluation of a Chinese cohort, Wang et al. [31] reported that, in patients with metastatic RCC, anxiety and depression increased 3 months after interferon-α treatment (Table 3).

Discussion
A high level of distress, depression, and/or anxiety in patients with non-metastatic RCC was reported. This is in line with other serious urological neoplasia such as bladder cancer [32]. A prevalence of clinical severe depression in up to 12 % of patients was reported [18], which is much higher than the reported World Health Organization (WHO) rate of 5.7% for depression in the elderly [33] or in times of COVID-19 (28% for depression; 26.9% for anxiety; 24.1% for post-traumatic stress symptoms; 36.5% for stress; 50% for psychological distress) in the general population. As a limitation, many studies included within prevalence rate patients with mild, moderate or severe depressive or anxiety symptoms, or did not stratify patients according to symptom severity [34]. Even within the included studies in the present review, there is no clear delimitation regarding the presence of clinically significant symptoms of depression, anxiety, or psychological distress.
However, when analyzing the data regarding the impact of distress, depression, or anxiety on oncological outcomes in patients with non-metastatic RCC, it seems that these conditions have no influence on mid-and long-term outcomes. This may be related to the good overall prognosis of non-metastatic RCC [37] and probably in these settings it would be interesting to evaluate the impact on quality of life (QoL) and further adherence to follow-up.
Conversely, in metastatic disease, we found that a high level of distress and depression is associated with OS; other endpoints were not analyzed, such as recurrence, progression, or cancer-specific survival. This correlation was also shown in both bladder and prostate cancers [13]. It is of the utmost importance to identify the patients at risk and to treat them according to their symptom severity. If these symptoms are severe, then these conditions may influence treatment adherence as was shown in other cancers [38,39]. Moreover, a large multinational survey showed that 50% of RCC patients are 'very often' or 'always' experiencing disease-related anxiety [40].
The present systematic review analyzed the up-to-date data regarding the prevalence and the impact of psychological distress, anxiety and/or depression, on patients with nonmetastatic or metastatic RCC. However, some limitations should be pointed out such as the poor quality of the data, risk of bias, lack of randomized clinical studies and standardization of the reported results that prevailed when performing a meta-analysis.

Conclusions
Patients with RCC reported a high level of psychological distress similar to that of patients with other urological malignancies. It seems that for patients with localized disease, these symptoms had no impact on oncological outcomes. Conversely, in metastatic disease, psychological distress is associated with worse outcomes. The impact of psychological distress on therapy adherence and long-term wellbeing warrants further research. Providers, patients, and families need awareness and targeted interventions to identify and help affected patients in a sensitive and effective manner.