INTRODUCTION
Depression is a prevalent medical condition affecting approximately 280 million people worldwide [1]. An estimated 10%-15% of older adults have clinically significant depressive symptoms [2]. Furthermore, major depressive disorder is prevalent at a rate of roughly 3.8% in the general population, and 5.7% of adults 60 years or older [1]. Unfortunately, the prevalence of depression is even higher in cancer patients. Up to 24% of cancer patients may be diagnosed with depression [3]. Increasingly more attention has been directed to the importance of mental health in the context of cancer and survivorship. For example, the American Society of Clinical Oncology has recommended a palliative care consultation as standard of care for advanced cancer. This consultation has been shown to positively impact quality of life, symptom management, anxiety and depression, caregiver distress, and end-of-life care [4,5]. While this does aid in management of cancer and survivorship, there remains limited proactive intervention.
In patients with bladder cancer, literature demonstrates the risk of suicide is 5-fold higher than the general population with an incidence of 48/100,000 [6]. During survivorship, bladder cancer patients report unmet needs related to psychological support particularly depression, anxiety, poor body image, and sexual dysfunction [7]. Furthermore, It is estimated that bladder cancer is the most expensive malignancy to treat, on a per patient basis, ranging from $65,000 to $180,000 [8]. Depression affects patients’ ability to cope with the burden of the illness; deleterious effects can include diminished acceptance of treatment, extension of hospitalization, reduction of quality of life, and increased suicide rates [9]. Ultimately, bladder cancer survivors experience major depressive disorder at a rate of 8.8% [10]. There may be an even higher proportion with clinically significant depressive symptoms. While there are some effective treatment modalities for depression, preventative measures may provide even greater benefit if more was understood about the relationship of bladder cancer and depression.
At the time of bladder cancer diagnosis, the physician will discuss potential treatment options with the patients. Yet, little is known about how the patient’s treatment discussion will affect their long-term mental health. We intend to explore how these treatment decisions effect the rates of depression in bladder cancer patients. For example, does neoadjuvant chemotherapy (NCT) prior to cystectomy (CYS) lead to higher rates of depression? This information can then be used to advise patients more holistically in their treatment decisions for bladder cancer.
Institutional Review Board approval and informed consent were waived according to our institutional rule.
MATERIALS AND METHODS
This is a retrospective cohort study utilizing a formulated dataset from the TriNetX Research Network Database. TriNetx serves as a widely accessible web-based tool incorporating research population cohorts and feasibility queries. Data is garnered from many academic medical centers as well and health care organizations that is uploaded into the TriNetx database. A search query was performed and designed in consultation with the TriNetX analysts, across dozens of participating health care organization within the TriNetX Research Network. Utilization of International Statistical Classification of Diseases, 10th revision (ICD-10) codes related to bladder cancer and depression diagnoses were employed to identify patients of interest. The search query was further specified to created cohorts pertaining to specific treatments of interest.
The query was formulated to categorize patients with muscle invasive bladder who underwent CYS without NCT compared to the same patient population but who had received NCT. The patient population was limited to patients with T2 muscle invasive bladder cancer. NCT was defined as reception of this treatment within 90 days prior to CYS, as referenced in other similar literature [11].
Diagnosis of depression was concluded using the ICD-10 code F32 which corresponds to an episode of major depression. A psychiatrist was involved in the study for determination of proper terminology and diagnosis selection. A prior diagnosis of depression was excluded, and only new diagnoses were included within 90-day post-CYS in both cohorts. Another exclusion factor was if patients had received chemotherapy for concomitant malignancy.
Demographic including age, sex, race, diabetes mellitus, atherosclerotic heart disease, heart failure, chronic obstructive pulmonary disease, other nonpsychotic mental disorders, and body mass index were controlled for via propensity score matching. The primary endpoint of the analysis was diagnosis of depression within 3 months after CYS. Secondary endpoints of analysis were inpatient hospitalizations, mortality, and suicide attempts within 3 months after CYS. Statistical analyses were then performed with threshold for statistical significance at a p-value of <0.05. STROBE (Strengthening the Reporting of Observational studies in Epidemiology) guidelines were applied when devising the methodology of the study to ensure precision and comprehensiveness.
RESULTS
A total of 3,872 patients were identified with perioperative chemotherapy followed by CYS (cohort 1), and 2,647 patients identified to have undergone CYS without neoadjuvant or adjuvant chemotherapy (cohort 2). Propensity score matching revealed 2,315 patients in each group. Mean age was 69.2 years in the NCT cohort, and 69.3 years in the CYS cohort (p=0.752). There was a higher proportion of males with 78.3% in the NCT group and 76.1% male in the CYS group (p=0.074). No statistical differences were noted in any of the controlled demographics or medical comorbidities and full findings are displayed in Table 1.
Of the studied patients, data conveyed 243 patients (10.5%) with perioperative chemotherapy to have a diagnosis of depression within one year compared to 144 patients (6.2%) without perioperative chemotherapy (95% CI, 0.027-0.059). Odds ratio was 1.768 (95% CI, 1.426-2.192) when comparing cohort 1 to cohort 2. A statistically significant difference was noted in the rate of depression diagnosis between the 2 cohorts with a p-value of <0.001 (Table 2).
Secondary endpoints included mortality, hospitalizations, and suicidal attempts within 3 months from CYS. Mortality rate within 90-day post-CYS for the NCT with CYS group was 124 of 2,315 (5.35%) compared to CYS alone group with mortality rate of 121 of 2,315 (5.22%). There was no statistically significant difference in mortality rate (95% CI, -0.012 to 0.014; p=0.844). Inpatient hospitalization rate within 3 months of CYS was also accounted for. There were 841 individuals hospitalized in the NCT group (36.3%) and 884 in the CYS group (38.1%). Difference in hospitalization rate was nonstatistically significant (95% CI, -0.046 to 0.009; p=0.191). Last, suicidal attempts were collected between both groups with 10 suicidal attempts recorded in the NCT group compared to 0 suicidal attempts recorded in the CYS group. There was a statistically significant difference computed with these findings (95% CI, 0.002-0.007; p=0.002) (Table 3).
DISCUSSION
In this study regarding the impact of bladder cancer, and specifically NCT, on development of depression, there are several pertinent conclusions. Our findings demonstrate a statistically significant increase in the number of depression diagnoses via ICD-10 code F32 within 3 months of therapy in the NCT plus CYS group as opposed to CYS alone. Our findings also note a higher amount of recorded suicide attempts in the NCT group compared to CYS alone. Findings were statistically significant regarding this as well.
There was no statistical or clinically significant difference in mortality or inpatient hospitalizations within 3 months. This facet of the research, along with propensity score matching, elucidate that the cohorts were similar and limit potential confounding factors of demographics or medical comorbidities.
Amongst the literature, there are multiple systematic reviews that establish the connection between bladder cancer diagnosis and increased prevalence of anxiety and depression [12,13]. However, this is the first study to our knowledge to specifically analyze the effects of NCT on depression rates in the setting of bladder cancer. Strong points of this study are the nature of the large patient population with several thousand patients in each group. Cohorts were able to be controlled for with propensity score matching, and a statistically significant difference was noted in depression rates, with a higher incidence at 10.5% in the NCT group (6.1% in CYS alone cohort). The patient population is from healthcare facilities in the Tri-NetX database that is international, attributing to generalizability of the results. The exact rationale to explain why the NCT cohort had a statistically significant higher rate of depression is not fully understood, however, we surmise this is related to the direct morbidity associated with chemotherapy and the possible anxiety related to delay of pending surgery. Prospective studies and further research would help illuminate a more focused causality.
There are several limitations of this study, however. This is a retrospective review, and we are unable to identify and examine certain specific patient factors such as family and social support. This study does only focus on T2 disease to assess patients with the same disease progression. Due to the nature of the database, it was also not possible to identify how many patients completed NCT or how much they received. Additionally, a limitation of the database is our depression definition is denoted solely off ICD-10 codes and is unable to incorporate the use of mental health surveys and antidepression medication usage. Lastly, we were unable to identify what provider in terms of physician specialty diagnosed depression in each patient.
While our findings do suggest a higher rate of depression in patients who received NCT, we do not suggest the removal or exclusion of NCT in treatment plans. NCT remains a part of the standard of care for muscle invasive bladder cancer [14]. What we are suggesting is that bladder cancer remains a very morbid condition and associated treatments are closely intertwined with this. The psychiatric portion of patients’ care can potentially be neglected when focus is directed mainly towards patients’ oncologic care. Increased attention needs to be placed towards psychiatric care as it remains a large component of quality of life. Other factors that may prove advantageous to investigate are effects of adjuvant chemotherapy as well as intravesical chemotherapy for localized bladder cancer and their relation to psychiatric conditions.
Ultimately, our study alludes to the dire need for increased focus on psychiatric care in oncologic patients. The use of standardized mental health questionnaires may be beneficial additions to standard of care for bladder cancer patients. It would be prudent for providers to be aware of local resources for mental health as well as potentially referring patients to providers trained to treat psychiatric conditions.
CONCLUSIONS
Bladder cancer development with or without treatment can induce significant patient morbidity with ensuing depression. Our retrospective cohort study demonstrates NCT correlates to increased incidence of depression. Additional attention needs to be directed towards mental health counseling and treatment for oncologic patients.
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