Quality of Life and Anxiety in Patients with First Diagnosed Non-Muscle Invasive Bladder Cancer Who Receive Adjuvant Bladder Therapy

Inclusion criteria

The present study is a prospective analysis of all patients who underwent surgery for NMIBC in our tertiary center, between 2018–2020 and were planned to receive adjuvant intravesical therapy (Fig. 1). As such, all adult patients (age: 18–80 years) with histopathologically confirmed NMIBC (pTis, pTa, pT1) entered our study. An institutional ethics approval was received (Approval number: 4212/27-07-2018). All eligible patients provided a written informed consent. The study adhered to the Helsinki Declaration [13] and was reported on the basis of the STROBE guidelines [14].

Fig. 1

Study flow-chart.

Exclusion criteria

Patients with severe comorbidities (ASA > III), muscular invasive bladder cancer, previous malignancy, recurrent bladder cancer, refusal to participate, and patients that were, either, not fluent Greek speakers, or who did not adhere to the follow up schedule were excluded.

Study protocol

All patients underwent endoscopic resection of the bladder tumor under spinal anesthesia. Three weeks postoperatively they initiated adjuvant intravesical therapy of either BCG or Epirubicin instillations on an outpatient basis, as described elsewhere [15].

Demographics (age, gender, educational level, marital status, residence and employment status) and habitual data (smoking, alcohol) were recorded for all eligible patients. The SF-36 questionnaire was introduced for the QoL assessment. This tool has been previously validated in the Greek population [16] and its efficacy in the overall QoL evaluation has been extensively confirmed in various settings [17]. All eight subscales of the questionnaire are sub-grouped in two major components, the Physical (Physical Functioning -PF, Role Physical-RP, Bodily Pain-BP and General Health-GH) and Mental (Vitality-VT, Mental Health-MH, Role Emotional-RE and Social Functioning-SF) health aspect. State anxiety echoes the psychological and physiological temporary way of reacting in a specific moment. On the other hand, the trait anxiety refers to a more stable pattern of behavior, reflecting someone’s personality. Results range from 0 to 100, with the latter being the optimal outcome. Consistently, anxiety levels were estimated by the validated State-Trait Anxiety Inventory (STAI-Y) questionnaire [18]. The two subscales of this tool address the state (STAI-Y1) and trait anxiety (STAI-Y2) of the subject. Scores ranging from 29–39 were considered as low, whereas values greater that 60 were translated as increased anxiety. Patient evaluation was performed 2 weeks preoperatively and during the scheduled postoperative follow up (3, 6 and 12 months after surgery) examination. All data was secured in an encrypted electronic repository.

The primary endpoint of our study was the assessment of the SF-36 Physical health aspect variations during the follow up period. Secondary endpoints were the evaluation of the time fluctuations of SF-36 Mental, STAI-Y1 and STAI-Y2. Moreover, an association analysis of patient characteristics with the preoperative and postoperative QoL and anxiety measurements was performed. Based on the reliability of the questionnaires, the minimum required number of sampling observations (power: 80%, effect size: 0.3, type I error: 5%) was estimated at the level of 90 cases.

All data underwent a Shapiro-Wilk test for normality. Independent samples t test was used for continuous variables. Given an incompetence to confirm normality, the evaluation of a possible relationship between distinct patient characteristics and the preoperative QoL and anxiety levels was based on the Mann-Whitney U and the Kruskal-Wallis H test. In order to examine the time-related variations of the questionnaire measurements, a repeated measures ANOVA model (RM-ANOVA) was introduced. Violation of the sphericity assumption was assessed by the Mauchly’s test of sphericity. If a violation was confirmed, then a Greenhouse-Geisser correction was applied. Post hoc comparisons and interactions of time endpoints and patient characteristics were calculated. The effect of distinct characteristics on the measured variables was estimated by the F test. Cronbach’s Alpha was, also, calculated for the evaluation of the internal consistency of the questionnaires in each time endpoint.

Categorical variables were provided as N (Percentage), whereas continuous data were reported as Mean (Standard Deviation). For all analyses, mean±2SE was displayed through all time endpoints. Statistical significance was considered at the level of p < 0.05. All analyses were completed in SPSS version 23 software (SPSS Inc. Chicago, IL, USA).

Summary of evidence

QoL corresponds to the gratification level of an individual’s physical, mental, and social needs and therefore is accomplished through the interaction of various components. The inherent difficulty in differentiating between the subjective and objective components renders QoL assessment a challenging task [19]. Taking into consideration the variability of the available techniques, valid QoL evaluation is based on the suitability of the applied methods. Although the design of most of these tools address samples with heterogeneous base characteristics, the QoL assessment in specific patient categories require the introduction of specified questionnaires. Overall, QoL assessment tools are assigned in two subgroups. General indicators study generic aspects of physical and psycho-social functionality, whether specific assessment tools emphasize on the individual’s perception regarding health and HRQoL [20].

NMIBC has a significant impact on a patient’s QoL. The initial cancer diagnosis, the frequent cystoscopies and the adverse events related to the intravesical therapy affect the physical function, the mental health, the reported fatigue and the role function [6]. The detrimental effect of a BC diagnosis on QoL was reported by Singer et al. [21]. Even though no differences between non-muscle invasive and muscle-invasive bladder cancer patients were found, both groups had decreased physical and emotional functioning compared to the general population. Interestingly, QoL increased with time in all patient groups (p < 0.001).

Similarly, Fung et al. confirmed a significant post-diagnosis reduction of the physical and mental scores between the prediagnosis and post-diagnosis groups (–2.7, 95%CI –3.8, –1.7 vs –1.4, 95%CI –2.6, –0.3). In patients with non-muscle invasive bladder cancer the physical and mental score differences were –1.9 (p < 0.01) and –1.4 (p = 0.01), respectively. In those with muscle invasive bladder cancer there was a statistically and clinically significant difference in the physical but not the mental score (–5.3, p < 0.01 vs –2.7, p = 0.07). The effect on the physical domain had a duration of 10 years [22].

In a prospective analysis by Schmidt et al., it was estimated that the impact of NMIBC on mental health was detectable during the 6-month follow-up period [23]. Mental health was significantly worse than SF-36 scores at diagnosis (mean of 49.7 vs. 53.3, 95%CI: 52.5–54.2). Urinary domain improved significantly from diagnosis (85.2, 95%CI: 82.9–87.4) to 12-month evaluation (90.2, 95%CI: 87.7–92.8), whereas sexual domain decreased from 56.4 (95%CI: 52.8–59.9) to 53.7 (95%CI: 50.0–57.4). However, in case of multiple TURBs, it was found that the initial impairment on mental health, gradually ameliorated. In terms of emotional role and physical and social functioning, a reduction on the estimated scores was confirmed at the 2nd or 3rd reoperation [17].

In our study, SF-36 physical health scores reached nadir at 6 months postoperatively, whereas the mental component was minimized at 3 months. A gradual improvement that reached higher values compared to the preoperative scores over the remaining follow-up period was identified in both tools. These findings are in contrast with the existing literature. In the BOXIT trial, patients with no NMIBC progression or recurrence reached a minimal EQ-5D score at 2 months postoperatively, with no further improvement [24]. Cases of grade III recurrence and progression were associated with statistically significant HRQoL decrease (–0.08; 95%confidence interval [CI], –0.13 to –0.03; and –0.10; 95%CI, –0.17 to –0.03, respectively).

Our data, also, suggested a significant association of age and alcohol with the Physical and Mental health, respectively. Similarly, in a study of 1160 BCs, Yu et al., reported an improved physical component in young and healthy, single males, that did not smoke and were diagnosed with a NMIBC. Moreover, gender, age, tumor stage and comorbidity status, also, affected preoperative mental health. The biggest effect was found in the Physical Functioning domain, where a 10-year increase in age would decrease the score by 4 points. [3]. Although various patient characteristics interacted with time QoL measurements, none of them was an independent QoL affecting factor. Evidence from recent studies, though, suggest that postoperative HRQoL is significantly associated with modifiable behaviors such as physical activity, dietary habits and smoking. Sufficient physical activity, healthy diet, and non-smoking were significantly associated with HRQoL (p < 0.001) [7].

Likewise, anxiety levels are an important determinant of the treatment efficiency. Anxiety is defined as the unpleasant sense of fear in an unknown and ill-defined threat, followed by a variety of emotional and hemodynamic manifestations. Assessment of anxiety is based on the evaluation of both state and trait anxiety levels [18]. Preoperative anxiety is a well-documented entity with almost 80%incidence [25]. The physical and emotional distress symptoms have a wide severity range and can present several weeks preoperatively [26]. Furthermore, increased perioperative anxiety is related to suboptimal patient recovery, impaired immunologic function and increased morbidity and mortality. Despite initial diagnosis, socioeconomic factors, such as educational and marital status were predictive factors of preoperative anxiety. Preoperative distress, combined with postoperative pain and smoking are considered as independent postoperative anxiety risk predictors [27].

Regardless of a curative or a palliative approach, anxiety and depression rates in cancer patients are estimated at the level of 10%and 20%, respectively [28]. The significant association of BC diagnosis and management with anxiety is supported by the reported depression and anxiety rate. In a recent meta-analysis, pooled postoperative depression and anxiety rates ranged at the levels of 4.7–78%and 12.5–71.3%, respectively [29]. The long term duration of NMIBC treatment results to the development of post-traumatic stress disorder (PTSD) syndrome [30]. In this cohort, it was confirmed that uncertainty and PTSD symptoms were inversely related to QoL as it was quantified by the EORTC QLQ-30 and QLQ-NMIBC24. Although post-resection anxiety and depression status lessens gradually, tumor and operative characteristics, catheterization time and morbidity rates significantly affect overall distress levels. Our analyses showed a significant decrease of state anxiety, in contrast to the trait component, which remained stable. This could be attributed to the fact that since the patients were familiar to the follow-up process, they could more easily manage their reactions. These reactions though could not possibly alter their character and personal behavior in general. Both preoperative and postoperative STAI-Y scores were not associated to the study characteristics.

Another interesting fact in our study is that QoL and anxiety scores showed no statistically difference in terms of the preferred adjuvant therapy. Major concern for both epirubicin and BCG patients seemed to be the procedure itself (i.e, waiting, urethral catheterization, instillation, LUTS, etc) and not the recurrence or disease progress. There were no withdrawals due to LUTS or technical issues. Since they tolerated therapy well, all patients improved their scores over time.

Study limitations are the prospective methodology and non-randomization. Furthermore, there was no risk stratification of NMIBC patients (grade and staging) and no pre-cancer data on anxiety was collected. Additionally, no data on impact of financial/logistical constraints on QoL and anxiety were collected, even though this was not our aim. Although the statistical power of our findings was adequate, our sample size is relatively small. Finally, a longer follow up postoperatively period is needed to draw further conclusions regarding anxiety and QoL in patients with NMIBC.

In conclusion, an improvement in the Physical and Mental health aspect was identified during the follow-up period in patients receiving adjuvant bladder therapy for NMIBC. Furthermore, in contrast to Trait anxiety, State stress levels displayed a gradual declining trend. Preoperative Physical health was inversely correlated with age, while absence of alcohol was associated with lower Mental health. Overall, patient characteristics, habits and the administered treatment did not affect the postoperative QoL and anxiety. Due to several study limitations, larger scale studies with an extended follow up period are required for safe conclusions.