Abstract
Objectives
To evaluate the impact of treatment for localised muscle‐invasive bladder cancer (MIBC) during the first 2 years after diagnosis.
Patients and Methods
A prospective cohort study was conducted including patients diagnosed with non‐metastatic (cM0) MIBC between November 2017 and November 2019 in the Netherlands. Health‐related quality of life (HRQoL) was measured using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ‐C30) as well as the MIBC‐specific QLQ‐BLM30 module. Questionnaires were administered at baseline (pre‐treatment) and at 6, 12 and 24 months after diagnosis. Patients were grouped by treatment: neoadjuvant chemotherapy (NAC) and radical cystectomy (RC), upfront RC, chemoradiation, and radiotherapy. Linear mixed models were used to assess HRQoL changes over time per treatment group.
Results
A total of 518 patients participated in quality of life measurements (46% response rate). After excluding 14 patients who did not complete the EORTC QLQ‐C30 and 114 for baseline completion after start of treatment, a total of 390 patients were included of whom 105 underwent NAC and RC, 148 underwent upfront RC, 58 underwent chemoradiation, and 79 underwent radiotherapy alone. Over time, clinically relevant improvements in emotional functioning and future perspective were observed across all treatment groups. However, a temporary worsening in physical functioning was observed at 6 months. Patients treated with RC (with or without NAC) experienced persistent deteriorations in body image and sexual functioning up to at least 2 years after diagnosis, although urostomy‐related outcomes improved. Patients undergoing chemoradiation showed improvements in urinary symptoms, while those receiving radiotherapy reported significant worsening of dyspnoea over time.
Conclusion
In this largest population‐based study to date on HRQoL in MIBC, HRQoL largely recovered to baseline levels during the first 2 years after diagnosis. However, persistent deteriorations in physical and cognitive functioning, body image, and sexual function were observed, particularly in patients treated with RC (with or without NAC).
Keywords: health‐related quality of life, muscle‐invasive bladder cancer, patient‐reported outcomes, radical cystectomy, neoadjuvant chemotherapy, radiotherapy, chemoradiation, trimodal therapy, EORTC QLQ‐C30, EORTC QLQ‐BLM30
Abbreviations
- CCI
Charlson Comorbidity Index
- ECOG
Eastern Cooperative Oncology Group
- EORTC QLQ‐C30
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire
- FACT‐BL
Functional Assessment of Cancer Therapy‐Bladder
- HRQoL
health‐related quality of life
- MIBC
muscle‐invasive bladder cancer
- NAC
neoadjuvant chemotherapy
- NCR
Netherlands Cancer Registry
- RC
radical cystectomy
Introduction
One in four patients with bladder cancer is diagnosed with muscle‐invasive disease (muscle‐invasive bladder cancer [MIBC]), which typically requires (a combination of) radical surgery, radiotherapy or chemotherapy. Radiotherapy can be offered to patients who are ineligible for radical cystectomy (RC) and chemotherapy [1, 2]. To improve patient counselling and manage expectations, it is important to consider the impact of treatment on different aspects of patients' health‐related quality of life (HRQoL).
There is a lack of population‐based longitudinal data on HRQoL in patients with MIBC, especially in patients treated with chemoradiation or radiotherapy.
Most available HRQoL data are derived from clinical trials focusing on surgical treatments for MIBC and previously performed observational studies had limitations such as being single‐centre, having a cross‐sectional design, and/or having a small sample size [2, 3]. Furthermore, studies often used only generic HRQoL questionnaires and did not include MIBC‐specific domains such as urinary problems, sexual function, urostomy problems, and body image [4].
The objective of the current study was to gain insight into how HRQoL over time is affected in patients with MIBC after different treatments. We performed a nationwide study including patients treated for localised MIBC who were followed for 2 years post‐diagnosis. Insights gained from this study will aid in the counselling of patients with MIBC and contextualise post‐treatment recovery.
Methods
Study Population
The current study was part of the nationwide, prospective BlaZIB study (BlaZIB: BlaaskankerZorg In Beeld; Insight into Bladder Cancer Care) [5]. The aim of the BlaZIB study was to gain insight into and improve the quality of bladder cancer care in the Netherlands. All patients diagnosed with Tis and T1 stage non‐MIBC and non‐metastatic (cM0) MIBC between November 2017 and November 2019 were identified through the Netherlands Cancer Registry (NCR) and recruited for the BlaZIB study. Extensive clinical data on patient, tumour, and treatment characteristics, as well as oncological outcomes, were collected by well‐trained data managers of the NCR who consulted the individual patient files. HRQoL data were collected in 53 out of 78 Dutch hospitals that participated in the HRQoL assessment part of the BlaZIB study. According to the Committee on Research involving Human Subjects (CMO) of Arnhem‐Nijmegen, the BlaZIB study was exempted from approval according to the Medical Research Involving Human Subjects Act (WMO) (case 2017‐3240). The current study was approved by the Privacy Review Board of the NCR (K23.222).
All patients diagnosed with non‐metastatic MIBC who participated in the HRQoL assessment part of BlaZIB were included in the current study. Patients were grouped by treatment: neoadjuvant chemotherapy (NAC) with RC, upfront RC, chemoradiation, or radiotherapy. Patients receiving no treatment other than best supporting care were excluded (n = 1). Disease stage was defined according to the TNM staging system [6]. Performance status was based on Eastern Cooperative Oncology Group (ECOG) performance scores [7]. Comorbidity was classified according to the Charlson Comorbidity Index (CCI) [8]. Socioeconomic status was categorised as low, middle, and high, based on postal code. Smoking status was derived from questionnaires and dichotomised as never or ever smoker.
Assessment of HRQoL
The validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC‐QLQ‐C30) version 3.0 was used to assess cancer‐related HRQoL [9, 10]. The EORTC‐QLQ‐C30 consists of 30 items and includes a global health scale, five functional scales (physical, role, cognitive, emotional, and social) and nine symptom‐related scales/scores (fatigue, pain, nausea/vomiting, dyspnoea, insomnia, appetite loss, constipation, diarrhoea and financial difficulties). Bladder cancer‐specific symptoms were assessed using the validated MIBC‐specific module, the QLQ‐BLM30 [11]. Items of the QLQ‐BLM30 were grouped as proposed by Ripping et al. [12] into the following domains: urostomy problems, urostomy irritation, urostomy embarrassment, urostomy support, single catheter use problems, urinary symptoms, bloating and flatulence, future perspective, body image, sexual functioning, sexual intimacy, sexual enjoyment, male and female sexual problems, and risk of contaminating partner. Both questionnaires were administered at four time points: shortly (±6 weeks) after diagnosis (baseline, before treatment started; T0), and 6 months (T6), 12 months (T12) and 24 months (T24) after diagnosis.
All scores based on the EORTC‐QLQ‐C30 and QLQ‐BLM30 were linearly transformed to a scale of 0–100 [13]. Higher scores on the global health scale and functional scales imply better HRQoL, whereas higher scores on the symptom scales indicate greater symptom burden. The urinary symptom scale only applied to patients without a urostomy. Female sexual problems and single catheter use problems could not be evaluated due to limited data.
Statistical Analysis
Descriptive statistics were used to provide insight into demographic and clinical characteristics per measurement time point and per treatment. Changes in HRQoL outcomes over time were assessed using linear mixed models per treatment group, taking clustering of observations within each patient into account.
All models were adjusted for potential confounders based on the literature to account for their potential influence on within‐group changes over time; age (grand‐mean centred), sex, CCI, body mass index (grand‐mean centred), socioeconomic status, disease stage, and smoking status. All models included a random intercept, and time was used as a categorical variable (baseline, T6, T12 and T24) in all analyses. Model‐derived estimated marginal mean changes were reported. To investigate potential differences in HRQoL changes between men and women [14, 15], we performed an additional linear mixed model that included an interaction term of sex and time. In order to aid the interpretation, the changes in QLQ‐C30 scores were categorised according to clinical relevance, as suggested by Cocks et al. [16], as trivial, small, medium or large improvement/deterioration. Large changes were defined as those with clear and undeniable clinical relevance. Medium changes referred to those likely to be clinically relevant, but to a lesser extent. These suggest moderate impact on the patient's quality of life, considered meaningful in clinical settings. Small changes indicated subtle but still clinically relevant differences. Trivial changes were those unlikely to be clinically relevant or those where no meaningful difference was observed.
As there are no established guidelines for interpreting clinical relevance for the QLQ‐BLM30 questionnaires, more general cut‐off values were used: a change of at least five points was considered to be indicative of a small clinically relevant change, while changes of more than 10 and 20 points were considered to be indicative of medium and large clinically relevant changes, respectively.
All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, North Carolina). A P value < 0.05 was taken to indicate statistical significance.
Results
Study Population
An overview of the included patients and questionnaires is provided in Fig. S1. In total, 518 patients with MIBC participated in the HRQoL part of BlaZIB (initial response rate 46%). Patients who did not complete the baseline questionnaire before start of treatment (n = 128) were excluded. The follow‐up response rates for the HRQoL questionnaires at each time point were: 67% at T6 (245 of 365 invited), 74% at T12 (239 of 323 invited), and 88% at T24 (215 of 243 invited). In total, 160 patients completed all four surveys across the study period. The baseline characteristics of patients at each measurement time point are presented in Table 1. At baseline, the study population consisted mostly of men (77%), the median age was 71 years, and 48% of patients had no comorbidity. In total, 105 patients underwent NAC with RC, 148 underwent upfront RC, 58 underwent chemoradiation, and 79 underwent radiotherapy alone. The number of patients included in each of the treatment groups at each of the time points is shown in Table S1. Baseline characteristics per treatment group are shown in Table S2.
Table 1.
Demographic and clinical characteristics of the total cohort per timepoint.
| HRQoL measurement time points | ||||
|---|---|---|---|---|
| T0 (N = 390) | T6 (N = 245) | T12 (N = 239) | T24 (N = 215) | |
| Sex, n (%) | ||||
| Male | 303 (77.7) | 195 (79.6) | 192 (80.3) | 172 (80.0) |
| Female | 87 (22.3) | 50 (20.4) | 47 (19.7) | 43 (20.0) |
| Age at diagnosis, years, median (IQR) | 71.0 (66.0–77.0) | 72.0 (66.0–77.0) | 72.0 (66.0–77.0) | 71.0 (65.0–76.0) |
| Age at diagnosis, n (%) | ||||
| <60 years | 48 (12.3) | 31 (12.7) | 30 (12.6) | 28 (13.0%) |
| 60–70 years | 108 (27.7) | 59 (24.1) | 61 (25.5) | 60 (27.9 |
| 70–80 years | 168 (43.1) | 109 (44.5) | 108 (45.2) | 99 (46.0) |
| ≥80 years | 66 (16.9) | 46 (18.8) | 40 (16.7) | 28 (13.0) |
| ECOG performance status, n (%) | ||||
| 0 | 167 (42.8) | 105 (42.9) | 110 (46.0) | 106 (49.3) |
| 1 | 84 (21.5) | 57 (23.3) | 55 (23.0) | 46 (21.4) |
| ≥2 | 24 (6.2) | 17 (6.9) | 11 (4.6) | 10 (4.7) |
| Unknown | 115 (29.5) | 66 (26.9) | 63 (26.4) | 53 (24.7) |
| Weighted CCI score, n (%) | ||||
| 0 | 187 (47.9) | 117 (47.8) | 120 (50.2) | 112 (52.1) |
| 1 | 95 (24.4) | 61 (24.9) | 62 (25.9) | 52 (24.2) |
| ≥2 | 88 (22.6) | 54 (22.0) | 48 (20.1) | 39 (18.1) |
| Unknown | 20 (5.1) | 13 (5.3) | 9 (3.8) | 12 (5.6) |
| Body mass index, median (IQR) | 25.9 (23.7–28.7) | 25.9 (23.9–28.8) | 26.0 (23.9–28.7) | 26.0 (23.9–29.0) |
| Body mass index, n (%) | ||||
| Underweight (<20 kg/m2) | 8 (2.1) | 4 (1.6) | 4 (1.7) | 3 (1.4) |
| Normal (20–25 kg/m2) | 145 (37.2) | 95 (38.8) | 88 (36.8) | 84 (39.1) |
| Overweight (25–30 kg/m2) | 160 (41.0) | 103 (42.0) | 109 (45.6) | 95 (44.2) |
| Obese (>30 kg/m2) | 56 (14.4) | 34 (13.9) | 30 (12.6) | 28 (13.0) |
| Unknown | 21 (5.4) | 9 (3.7) | 8 (3.3) | 5 (2.3) |
| Socioeconomic status, n (%) | ||||
| Low | 85 (21.8) | 49 (20.0) | 50 (20.9) | 39 (18.1) |
| Medium | 183 (46.9) | 116 (47.3) | 107 (44.8) | 103 (47.9) |
| High | 122 (31.3) | 80 (32.7) | 82 (34.3) | 73 (34.0) |
| Disease stage (cTNM), n (%) | ||||
| cT2 N0 M0 | 252 (64.6) | 163 (66.5) | 166 (69.5) | 148 (68.8) |
| cT3/4a N0 M0 | 89 (22.8) | 51 (20.8) | 47 (19.7) | 46 (21.4) |
| cT4b or cN+ | 49 (12.6) | 31 (12.7) | 26 (10.9) | 21 (9.8) |
| Focality of the tumour, n (%) | ||||
| Unifocal | 267 (68.5) | 167 (68.2) | 158 (66.1) | 148 (68.8) |
| Multifocal | 112 (28.7) | 69 (28.2) | 71 (29.7) | 60 (27.9) |
| Unknown | 11 (2.8) | 9 (3.7) | 10 (4.2) | 7 (3.3) |
| Treatment, n (%) | ||||
| NAC + RC | 105 (26.9) | 64 (26.1) | 64 (26.8) | 64 (29.8) |
| Upfront RC | 148 (37.9) | 95 (38.8) | 94 (39.3) | 84 (39.1) |
| Chemoradiation | 58 (14.9) | 36 (14.7) | 36 (15.1) | 36 (16.7) |
| Radiotherapy | 79 (20.3) | 50 (20.4) | 45 (18.8) | 31 (14.4) |
| Living situation, n (%) | ||||
| Without partner | 72 (18.5) | 44 (18.0) | 44 (18.4) | 35 (16.3) |
| With partner | 313 (80.3) | 197 (80.4) | 191 (79.9) | 176 (81.9) |
| Unknown | 5 (1.3) | 4 (1.6) | 4 (1.7) | 4 (1.9) |
| Smoking status, n (%) | ||||
| Never Smoked | 55 (14.1) | 35 (14.3) | 33 (13.8) | 28 (13.0) |
| Ever | 331 (84.9) | 207 (84.5) | 202 (84.5) | 183 (85.1) |
| Unknown | 4 (1.0) | 3 (1.2) | 4 (1.7) | 4 (1.9) |
| Alcohol consumption, n (%) | ||||
| None | 54 (13.8) | 28 (11.4) | 26 (10.9) | 26 (12.1) |
| Ever | 332 (85.1) | 214 (87.3) | 209 (87.4) | 185 (86.0) |
| Unknown | 4 (1.0) | 3 (1.2) | 4 (1.7) | 4 (1.9) |
CCI, Charlson Comorbidity Index; ECOG, Eastern Cooperative Oncology Group; HRQoL, health‐related quality of life; IQR, interquartile range; NAC, neoadjuvant chemotherapy; RC, radical cystectomy; T0, baseline (±6 weeks after diagnosis, before start treatment); T6, 6 months after diagnosis; T12, 12 months after diagnosis; T24, 24 months after diagnosis.
Non‐participants in the study were less likely to be male (66% vs 76%) and more likely to have a low socioeconomic status (37% vs 23%) compared to participants (data not shown).
Generic HRQoL Over Time
Global Health and Functional Scales
In the first 2 years after diagnosis, improvements of medium clinical relevance were observed among patients who underwent NAC with RC in global health (mean change +11.3) and role (+12.4), emotional (+11.2), and social functioning (+9.2). In contrast, a temporary deterioration in physical function was observed at T6 (−6.9). For other treatment types, clinically relevant improvements over time were observed only in emotional functioning (+11.5, 4.0 and 8.2 for upfront RC, chemoradiation, and radiotherapy, respectively), which persisted during the 2 years of follow‐up, although results for the chemoradiation group were not statistically significant.
In contrast, in all treatment groups a deterioration of small clinical relevance was observed in physical functioning at T6 (−6.9 after RC with or without NAC, −4.8 after chemoradiation and −7.1 after radiotherapy), which was not statistically significant in the chemoradiation group. During follow‐up, physical functioning was restored to baseline values in patients treated with NAC with RC and radiotherapy, but not in patients treated with upfront RC (−7.2). In patients treated with upfront RC or radiotherapy, a decline in cognitive functioning was observed as well (−5.0 and −6.7, respectively) and this persisted over time (Table 2 and Fig. 1).
Table 2.
Estimated marginal means and change scores with 95% CIs of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ‐C30) functional scale outcomes assessed at baseline (T0), 6 months (T6), 12 months (T12) and 24 months (T24) after diagnosis.
| T0 | T0–T6 | T0–T12 | T0–T24 | |||||
|---|---|---|---|---|---|---|---|---|
| EMM | 95% CI | Mean change | 95% CI | Mean change | 95% CI | Mean change | 95% CI | |
| NAC + RC | ||||||||
| Global health | 66.7 | 61.4; 72.0 | 3.5 | −1.1; 8.1 | 5.7* | 1.2; 10.3 | 11.3 † | 6.6; 15.9 |
| Physical functioning | 84.5 | 79.6; 89.3 | −6.9* | −11.2; −2.7 | −3.6 | −7.8; 0.6 | 0.0 | −4.3; 4.2 |
| Role functioning | 71.6 | 63.8; 79.4 | −4.2 | −10.8; 2.4 | 6.4 | −0.1; 12.9 | 12.4 † | 5.9; 19 |
| Emotional functioning | 82.8 | 77.5; 88.1 | 6.0* | 2.6; 9.4 | 6.7* | 3.4; 10.1 | 11.2 † | 7.8; 14.7 |
| Cognitive functioning | 89.2 | 83.3; 95.0 | −1.1 | −4.7; 2.5 | −1.3 | −4.8; 2.2 | −1.1 | −4.7; 2.5 |
| Social functioning | 78.9 | 71.9; 85.8 | −1.8 | −7.3; 3.7 | 7.0* | 1.6; 12.4 | 9.2 † | 3.8; 14.7 |
| RC | ||||||||
| Global health | 73.8 | 68.4; 79.3 | 1.1 | −2.1; 4.2 | 2.4 | −0.7; 5.6 | 2.8 | −0.4; 6.1 |
| Physical functioning | 81.7 | 76.0; 87.5 | −6.9* | −9.9; −3.9 | −5.3* | −8.3; −2.4 | −7.2* | −10.3; −4.1 |
| Role functioning | 67.4 | 58.8; 76.1 | −8.5* | −13.1; −4 | −4.3 | −8.8; 0.2 | −6.3 | −11; −1.5 |
| Emotional functioning | 88.8 | 83.2; 94.5 | 6.5* | 2.9; 10 | 8.9* | 5.3; 12.4 | 11.5 † | 7.8; 15.1 |
| Cognitive functioning | 88.0 | 81.8; 94.2 | −3.7* | −6.7; −0.7 | −3.6* | −6.6; −0.5 | −5.0* | −8.2; −1.9 |
| Social functioning | 77.1 | 69.5; 84.7 | −3.9 | −8.0; 0.1 | −1.6 | −5.6; 2.4 | −1.3 | −5.5; 2.9 |
| Chemoradiation | ||||||||
| Global health | 75.6 | 63.4; 87.9 | −1.9 | −7.4; 3.7 | 3.2 | −2.4; 8.9 | 2.5 | −3.2; 8.3 |
| Physical functioning | 83.3 | 69.9; 96.7 | −4.8 | −8.5; −1.2 | −0.8 | −4.5; 2.9 | −2.7 | −6.5; 1.0 |
| Role functioning | 78.0 | 69.3; 86.7 | −3.8 | −10.8; 3.3 | 0.4 | −6.7; 7.5 | 3.2 | −4.1; 10.5 |
| Emotional functioning | 89.6 | 83.9; 95.2 | 2.1 | −2.7; 6.9 | 6.5* | 1.7; 11.4 | 4.0 | −1.0; 9.0 |
| Cognitive functioning | 87.9 | 81.6; 94.1 | −3.7 | −7.8; 0.3 | 0.5 | −3.6; 4.7 | −2.5 | −6.7; 1.8 |
| Social functioning | 85.9 | 78.3; 93.5 | −5.0 | −10.0; 0.1 | 2.2 | −3.0; 7.3 | 3.4 | −1.8; 8.7 |
| Radiotherapy | ||||||||
| Global health | 65.4 | 58.0; 72.8 | 0.0 | −6.2; 6.2 | 1.9 | −4.6; 8.4 | 0.5 | −6.9; 8.0 |
| Physical functioning | 68.1 | 60.3; 76.0 | −7.1* | −12.3; −1.9 | −6.8* | −12.3; −1.4 | −5.3 | −11.5; 1.0 |
| Role functioning | 84.0 | 75.3; 92.8 | −6.4 | −13.9; 1.2 | −2.7 | −10.6; 5.3 | −2.3 | −11.2; 6.7 |
| Emotional functioning | 94.1 | 88.3; 99.8 | −0.2 | −5.6; 5.2 | 4.6 | −1.1; 10.2 | 8.2* | 1.8; 14.6 |
| Cognitive functioning | 88.0 | 81.8; 94.3 | −4.9* | −9.5; −0.4 | −6.1* | −10.9; −1.3 | −6.7* | −12.2; −1.3 |
| Social functioning | 88.1 | 80.3; 95.9 | −8.4* | −14.6; −2.2 | −3.7 | −10.2; 2.8 | −2.0 | −9.4; 5.4 |
Linear mixed model is adjusted for age, sex, Charlson Comorbidity Index, body mass index, socioeconomic status, disease stage and smoking status. Green shading = improvement; orange shading = deterioration. Missing scores = model fit not good, not enough variation for linear mixed model, or to few numbers for linear mixed model.
EMM, estimated marginal mean; MIBC, muscle‐invasive bladder cancer; NAC, neoadjuvant chemotherapy; RC, radical cystectomy; T0, baseline (±6 weeks after diagnosis, before start treatment); T6, 6 months after diagnosis; T12, 12 months after diagnosis; T24, 24 months after diagnosis.
Small clinically relevant change.
Medium clinically relevant change.
Fig. 1.
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ‐C30) estimated marginal mean scores for global health and functional scales in patients with muscle‐invasive bladder cancer assessed at baseline (T0), 6 months (T6), 12 months (T12), and 24 months (T24), per treatment group. Results are based on linear mixed models adjusted for age, sex, Charlson Comorbidity Index, body mass index, socioeconomic status, disease stage and smoking status. A lower score indicates a deterioration in functioning. Significant and clinically relevant changes between baseline and T6/T12/T24 are marked with an asterisk (*) in the corresponding colour. NAC, neoadjuvant chemotherapy; RC, radical cystectomy; T0, baseline (±6 weeks after diagnosis, before start treatment); T6, 6 months after diagnosis; T12, 12 months after diagnosis; T24, 24 months after diagnosis.
Symptom Scales
In general, patients treated with NAC with RC showed improvements of small to medium clinical relevance with regard to fatigue (−12.9), nausea and vomiting (−7.6), pain (−10.1), and appetite loss (−13.7) at T24. Patients treated with chemoradiation also reported an improvement in appetite loss (−7.2). Conversely, patients who underwent upfront RC and patients who underwent radiotherapy reported an increased burden of dyspnoea (+7.0 and +9.8, respectively). In addition, upfront RC patients reported a higher burden of diarrhoea at (+4.9) T24 (Table S3, Fig. S2).
Bladder Cancer Treatment‐Specific HRQoL
In patients with RC (with or without NAC), small and medium clinically relevant improvements were observed in urostomy‐related problems between baseline and T24, whereas patients treated with chemoradiation reported improvements in urinary symptoms (−11). All patients, regardless of treatment, reported a medium to large clinically relevant improvement in future perspective (+14.5–27.1). On the other hand, in patients with RC (with or without NAC) small and medium clinically relevant deteriorations were observed concerning body image (+7.8 and +10.9) and large deteriorations regarding male sexual problems (+32 and +25.8), which persisted over time. In addition, patients who received upfront RC reported less sexual enjoyment at T24 compared to baseline (−13.3; Table 3 and Fig. 2).
Table 3.
Estimated marginal means and change scores with 95% CIs for the European Organisation for Research and Treatment of Cancer Quality of Life muscle‐invasive bladder cancer‐specific module (QLQ‐BLM30) outcomes assessed at baseline (T0), 6 months (T6), 12 months (T12) and 24 months (T24) after diagnosis.
| T0 (urostomy scales T6)* | T0–T6 | T0–T12 | T0–T24 | |||||
|---|---|---|---|---|---|---|---|---|
| EMM | 95% CI | Mean change | 95% CI | Mean change | 95% CI | Mean change | 95% CI | |
| NAC + RC | ||||||||
| Urostomy problem | 18.8 | 15.0; 22.6 | NA | NA | −7.3 † | −11.1; −3.4 | −11.6 ‡ | −15.5; −7.8 |
| Urostomy irritation | 27.1 | 18.4; 35.9 | NA | NA | −3.3 | −9.2; 2.7 | −6.3 † | −12.3; −0.4 |
| Urostomy embarrassment | 14.0 | 6.4; 21.5 | NA | NA | −4.4 | −9.0; 0.2 | −8.5 † | −13.1; −3.8 |
| Urostomy support (needed) | 27.8 | 13.9; 41.6 | NA | NA | −13.0 ‡ | −19.1; −6.9 | −14.9 ‡ | −21.0; −8.8 |
| Bloating and flatulence | 24.0 | 17.6; 30.4 | −4.4 | −10.0; 1.2 | −4.6 | −10.1; 1.0 | −9.0 † | −14.6; −3.4 |
| Future perspective (worries) | 49.4 | 41.9; 56.9 | −17.8 ‡ | −23.5; −12.0 | −21.3 § | −27.0; −15.6 | −25.8 § | −31.6; −20.0 |
| Body image (problems) | 16.0 | 9.4; 22.6 | 13.3 ‡ | 8.5; 18.1 | 10.3 ‡ | 5.5; 15.1 | 7.8 † | 3.0; 12.7 |
| Sexual functioning | 19.3 | 12.1; 26.5 | −3.8 | −8.5; 0.9 | 1.3 | −3.5; 6.1 | 3.4 | −1.4; 8.3 |
| Male sexual problems | 21.8 | 5.1; 38.5 | 35.4 § | 18.3; 52.6 | 35.5 § | 19.6; 51.4 | 32.0 § | 16.6; 47.3 |
| Sexual intimacy | 21.3 | 10.8; 31.9 | 6.7 | −4.8; 18.3 | −3.3 | −14.6; 7.9 | −7.9 | −18.8; 2.9 |
| Risk of contaminating partner | 17.8 | 6.8; 28.7 | −3.5 | −14.0; 6.9 | −10.6 ‡ | −20.6; −0.5 | −4.5 | −14.4; 5.4 |
| Sexual enjoyment | 39.1 | 23.4; 54.7 | −15.2 ‡ | −30; −0.4 | −2.1 | −16.7; 12.5 | −2.6 | −16.5; 11.2 |
| RC | ||||||||
| Urostomy problem | 17.3 | 13.6; 20.9 | NA | NA | −5.1 † | −9.0; −1.2 | −4.7 | −8.7; −0.7 |
| Urostomy irritation | 21.7 | 12.1; 31.2 | NA | NA | −4.3 | −10.1; 1.6 | −0.4 | −6.4; 5.6 |
| Urostomy embarrassment | 9.6 | 2.2; 17.0 | NA | NA | −0.6 | −4.2; 3.0 | −4.6 | −8.3; −0.9 |
| Urostomy support (needed) | 27.5 | 14.7; 40.4 | NA | NA | −8.7 † | −13.8; −3.7 | −10.1 ‡ | −15.3; −4.8 |
| Bloating and flatulence | 13.6 | 8.4; 18.8 | 0.2 | −3.5; 4 | 0.1 | −3.7; 3.9 | 0.0 | −3.9; 3.8 |
| Future perspective (worries) | 31.7 | 23.6; 39.7 | −20.9 § | −25.5; −16.4 | −23.7 § | −28.2; −19.1 | −27.1 § | −31.7; −22.4 |
| Body image (problems) | 10.8 | 4.2; 17.3 | 10.5 ‡ | 6.5; 14.6 | 10.1 ‡ | 6.1; 14.2 | 10.9 ‡ | 6.7; 15 |
| Sexual functioning | 16.6 | 8.9; 24.2 | −4.1 † | −7.9; −0.3 | −1.2 | −4.9; 2.5 | −2.0 | −5.8; 1.9 |
| Male sexual problems | 23.5 | 5.3; 41.7 | 25.1 § | 11.3; 38.8 | 27.8 § | 15.3; 40.3 | 25.8 § | 12.3; 39.3 |
| Sexual intimacy | 15.9 | 1.0; 30.8 | 3.3 | −5.8; 12.3 | 2.7 | −5.8; 11.1 | 0.2 | −9.1; 9.5 |
| Risk of contaminating partner | 22.6 | 8.4; 36.8 | 7.1 | −3.1; 17.3 | 3.7 | −5.6; 13.1 | −4.7 | −15.5; 6.1 |
| Sexual enjoyment | 52.2 | 30.2; 74.1 | −32.1 § | −44.1; −20.1 | −18.7 ‡ | −29.6; −7.9 | −13.3 ‡ | −25.5; −1.1 |
| Chemoradiation | ||||||||
| Urinary symptoms | 36.1 | 23.9; 48.4 | −3.5 | −10.4; 3.5 | −11.3 ‡ | −18.3; −4.4 | −11.0 ‡ | −18.1; −3.8 |
| Bloating and flatulence | 10.6 | 0.3; 20.9 | 1.9 | −3.6; 7.4 | −0.8 | −6.4; 4.8 | 1.4 | −4.4; 7.1 |
| Future perspective (worries) | 28.1 | 19.9; 36.4 | −17.4 ‡ | −24.1; −10.8 | −23.8 § | −30.6; −17.1 | −26.8 § | −33.8; −19.8 |
| Body image (problems) | 6.9 | −4.3; 18.2 | 3.9 | −1.0; 8.8 | −2.0 | −7.0; 3.0 | 0.6 | −4.5; 5.7 |
| Sexual functioning | 11.9 | −0.5; 24.2 | −1.7 | −9.8; 6.3 | 6.9 | −1.2; 15 | 7.9 | −1.4; 17.2 |
| Male sexual problems | 29.9 | −12.6; 72.5 | −4.7 | −22.8; 13.4 | 2.2 | −14.6; 18.9 | 7.1 | −10.0; 24.2 |
| Sexual intimacy | 9.7 | −15.3; 34.6 | 1.2 | −11.1; 13.5 | −9.0 | −20.2; 2.2 | −1.2 | −12.5; 10.2 |
| Risk of contaminating partner | 21.3 | −7.8; 50.4 | 5.9 | −8.0; 19.7 | −2.5 | −15.0; 9.9 | −2.3 | −14.8; 10.2 |
| Sexual enjoyment | 25.1 | 0.1; 50.0 | −3.3 | −18.2; 11.6 | 5.4 | −8.6; 19.3 | 5.3 | −8.2; 18.9 |
| Radiotherapy | ||||||||
| Urinary symptoms | 28.4 | 20.0; 36.9 | 4.7 | −2.3; 11.8 | −4.2 | −11.5; 3.1 | 0.8 | −7.9; 9.5 |
| Bloating and flatulence | 19.7 | 12.7; 26.7 | 4.4 | −1.0; 9.8 | 0.9 | −4.8; 6.6 | 4.5 | −2.1; 11.1 |
| Future perspective (worries) | 23.6 | 15.3; 31.9 | −8.6 † | −16.1; −1.2 | −15.1 ‡ | −23.0; −7.1 | −14.5 ‡ | −23.8; −5.2 |
| Body image (problems) | 14.4 | 6.7; 22.2 | −0.5 | −7.3; 6.2 | −1.0 | −8.0; 6.1 | −0.5 | −8.7; 7.6 |
| Sexual functioning | 8.8 | 0.7; 16.9 | −4.3 | −10.5; 1.9 | 1.0 | −5.7; 7.8 | −3.8 | −12.2; 4.7 |
| Male sexual problems | 21.9 | −11.9; 55.8 | 23.8 § | 4.0; 43.6 | 7.2 | −15.7; 30.1 | 1.5 | −24.1; 27.1 |
| Sexual enjoyment | 13.5 | −28.4; 55.5 | −2.1 | −19.8; 15.6 | 14.2 | −7.5; 35.8 | 8.2 | −17.1; 33.5 |
Linear mixed model is adjusted for age, sex, Charlson Comorbidity Index, body mass index, socioeconomic status, disease stage and smoking status. Green shading = improvement; orange shading = deterioration. Missing scores = model fit not good, not enough variation for linear mixed model, or to few numbers for linear mixed model. Orange is for negative clinically relevant changes/ deteriorations Green is for positive clinically relevant changes/ improvements
EMM, estimated marginal mean; MIBC, muscle‐invasive bladder cancer; NAC, neoadjuvant chemotherapy; RC, radical cystectomy; T0, baseline (±6 weeks after diagnosis, before start treatment); T12, 12 months after diagnosis; T24, 24 months after diagnosis; T6, 6 months after diagnosis.
Baseline of urostomy scales is T6 and mean changes are based on T6 instead of T0.
Small clinically relevant change.
Medium clinically relevant change.
Large clinically relevant change.
Fig. 2.
(A) European Organisation for Research and Treatment of Cancer Quality of Life muscle‐invasive bladder cancer‐specific module (QLQ‐BLM30) estimated marginal mean scores for sexual health scales assessed at baseline (T0), 6 months (T6), 12 months (T12), and 24 months (T24), per treatment group. (B) QLQ‐BLM30 estimated marginal mean scores for the remaining scales assessed at baseline (T0), 6 months (T6), 12 months (T12), and 24 months (T24), per treatment group. Results are based on linear mixed models adjusted for age, sex, Charlson Comorbidity Index, body mass index, socioeconomic status, disease stage and smoking status. Significant and clinically relevant changes between baseline and T6/T12/T24 are marked with an asterisk (*) in the corresponding colour. NAC, neoadjuvant chemotherapy; RC, radical cystectomy; T0, baseline (±6 weeks after diagnosis, before start treatment); T6, 6 months after diagnosis; T12, 12 months after diagnosis; T24, 24 months after diagnosis.
Results in Men and Women
At baseline women scored worse than men on physical functioning, fatigue, nausea and vomiting, pain, sexual functioning, and future perspective. These differences in scores diminished over time except for pain symptoms. Other observed changes were largely similar in men and women, except that women experienced significantly more loss of appetite than men at 6 months (Figs S3, S4).
Discussion
The aim of this study was to evaluate the impact of treatment for MIBC on generic and bladder cancer (treatment)‐specific HRQoL, up to 2 years after diagnosis. In general, a persistent clinically relevant improvement in emotional functioning and future perspective was observed regardless of type of treatment. This is probably explained by acceptance of the consequences of the disease and its treatment, and the increased clarity about prognosis [17]. By contrast, a general temporary deterioration in physical functioning was observed, which might be related to the fact that most patients were still being treated or were in their recovery period.
In patients who underwent NAC with RC, a significant improvement in social and role functioning was observed. We hypothesised that this might be the result of gradual resumption of ‘normal’ activities. Patients also reported improvements in urostomy‐related outcomes as they became more accustomed to their urinary diversion over time. However, they also reported worsening of body image and male sexual problems that did not recover to baseline. Previous research suggests that body image can still improve up to 8 years after RC [18].
To our knowledge, only one other study has reported HRQoL specifically in patients treated with NAC with RC. Kitamura et al. [19] conducted a randomised controlled trial using the Functional Assessment of Cancer Therapy‐Bladder (FACT‐BL) questionnaire. Similar to our study, they reported a temporary decline in physical well‐being, which returned to baseline after 1 year. Also, a temporary decline in body appearance was found and an improvement in urostomy‐related embarrassment over time. Any possible changes in social well‐being, emotional well‐being or sexual function were not mentioned.
Patients who underwent upfront RC reported improvements in all urostomy‐related outcomes, similarly to patients who received NAC with RC. They also reported worsening in body image, male sexual problems and sexual function. Furthermore, they experienced a deterioration in both physical and cognitive functioning that did not recover over time. This may be attributed to the higher median age and greater comorbidity burden in these patients compared to those who received NAC with RC (71 vs 67 years, and CCI ≥2 in 22.3% vs 8.5%, respectively), which could have impaired their recovery.
Currently, there is a lack of systematic reviews that address changes in HRQoL among patients receiving RC, which include baseline measurements and MIBC‐specific questionnaires. Existing reviews focus predominantly on differences between open RC and robot‐assisted RC or between different urinary diversions [3, 20, 21, 22]. However, three recent single‐centre studies have reported on the change in HRQoL in the first 1–2 years after treatment with RC, using the EORTC QLQ‐C30 [23, 24, 25]. Two of these also included the QLQ‐BLM30 questionnaire [24, 25]. All reported worsening in physical functioning, body image, and (male) sexual problems, and improvements in urostomy‐related problems [24, 25]. In addition, also similar to our findings, improvements in future perspective [24] and emotional functioning [23] were reported. More recently, Rogers et al. [26] conducted a longitudinal study including 51 patients treated with RC or radiotherapy ± systemic treatment evaluating quality of life at 3 (baseline), 6, 9 and 12 months after diagnosis of bladder cancer. They reported similar findings of decreased physical functioning after radical treatment that did not recover 1 year after diagnosis, as well as worsened male sexual function and body image, while future worries decreased.
In our cohort, patients who underwent chemoradiation showed improvements in urinary symptoms and future perspective. No significant changes in other HRQoL domains were found. The literature on HRQoL over time in patients treated with chemoradiation is limited. In a prospective study including seven hospitals, Lagrange et al. [27] investigated the HRQoL of 53 patients up to 36 months after chemoradiation. They reported that 6 months after treatment all functional scales were similar to baseline or had slightly improved, persisting over time [27]. This is consistent with our findings. Although Lagrange et al. did not use the QLQ‐BLM30, they included five additional questions to assess bladder function. Patients reported sustained improvement in bladder function at 24 months, which is similar to our observation [27]. This improvement may be attributable to effective tumour control and/or recovery from irritation caused by the treatment.
Patients who received radiotherapy alone experienced persistent worsening of dyspnoea, cognitive functioning, and physical functioning. The BC2001 trial conducted by Huddart et al. [28] evaluated the HRQoL of patients who received radiotherapy with or without chemotherapy, using the FACT‐BL questionnaire, up to 60 months post‐treatment. In this study, patients treated with radiotherapy without chemotherapy reported a significant improvement in emotional well‐being, persisting over time. This finding is consistent with the improved emotional functioning observed in our cohort 2 years after diagnosis. Furthermore, patients in the BC2001 trial reported a decline in physical well‐being, functional well‐being and the bladder cancer subscale after treatment, but these levels returned to baseline by 6 months and even improved over time. This is only partly in line with our findings as we observed an impaired physical functioning 1 year after diagnosis, and a full recovery was only seen after 2 years. An explanation might be that patients in our population‐based cohort were older (49% vs 21% of patients were ≥80 years, respectively) and had a high burden of comorbidities (35% CCI score ≥2). These factors may have contributed to a slower recovery and could also explain the worsening of dyspnoea and cognitive functioning in our study.
This study is the largest prospective, population‐based cohort study on (bladder) cancer‐specific HRQoL to date, including pre‐treatment data and multiple measurements of HRQoL over time. In addition to the commonly used EORTC QLQ‐C30 questionnaire, we included the MIBC‐specific QLQ‐BLM30. This questionnaire provided insights into bladder cancer treatment‐specific issues, including body image, sexual function, urostomy problems, and urinary symptoms.
Nonetheless, it is important to acknowledge the limitations of this study. The questionnaire's baseline response rate in the overall BlaZIB‐cohort was 46%. Comparable response rates were reported in other population‐based studies on bladder cancer [29, 30]. Non‐responders did not differ significantly in terms of disease stage or comorbidity burden (CCI); however, they more often had a higher socioeconomic status (23.2% of responders vs 37.1% of non‐responders had low social economic status) and a higher physical functioning (41.1% of responders vs 36.5% of non‐responders had ECOG 0) compared to non‐responders. This suggests that our study population may represent a somewhat healthier and more advantaged subset of the overall invited cohort, potentially leading to an overestimation of HRQoL outcomes. This is consistent with the general considerations of response bias in quality of life research, where those in poorer health or with greater symptom burden may be less likely to complete questionnaires. Attrition over time due to disease progression or mortality may also contribute to an underestimation of the negative impact on HRQoL, particularly at later time points.
In addition, not all hospitals (53 of the 78) participated in the HRQoL component of the BlaZIB study, which may have introduced selection bias. However, the baseline characteristics of patients invited for HRQoL assessments were largely similar to those of the overall BlaZIB cohort. The median (interquartile range) age was identical (73 [66–80] years), and also similar were comorbidity burden (CCI score ≥2 in 24.7% vs 25.7%) socioeconomic status (low socioeconomic status in 29.5% vs 30.2%), and clinical stage distribution (8% vs 8.9% had cT4b or N+ disease).
Furthermore, we had limited data on patients treated with chemoradiation (n = 36) or radiotherapy (n = 28) at T24, therefore, these results are less robust and subtle changes in HRQoL in these patients might have been missed.
Finally, while our study was not designed to directly compare the outcomes of different treatments – due to differences in patient characteristics such as age, comorbidity burden (CCI) and disease stage – we believe this is less of a limitation in clinical practice, where treatment decisions for MIBC are often driven by tumour characteristics and contraindications. Instead, the value of our findings lies in supporting patients with realistic expectations and helping healthcare providers tailor supportive care strategies to individual needs.
In conclusion, this study provides insights into various HRQoL outcomes as experienced by patients treated for MIBC before treatment and until 2 years after diagnosis. Two years post‐diagnosis, patients' scores in most domains had either returned to baseline levels or demonstrated improvement. However, persistent deteriorations in physical and cognitive functioning were found in patients treated with upfront RC. In addition, worse body image and male sexual functioning were found in patients treated with RC, with and without NAC. The findings of this study can be used in guiding the counselling of MIBC patients and providing context for post‐treatment recovery.
Disclosure of Interests
None declared.
Supporting information
Fig. S1. Flowchart describing inclusion of patients in the study cohort.
Fig. S2. EORTC QLQ‐C30 estimated marginal mean (EMM) scores for symptom scales assessed at baseline (T0), 6 months (T6), 12 months (T12), and 24 months (T24), per treatment group.
Fig. S3. EORTC QLQ‐C30 estimated marginal mean (EMM) scores for global health and functional scales in muscle‐invasive bladder cancer patients assessed at baseline (T0), 6 months (T6), 12 months (T12), and 24 months (T24), stratified by sex.
Fig. S4. EORTC‐BLM30 scores Estimated marginal mean (EMM) scores for Urostomy scales (A), Sexual health scales (B), and the remaining scales (C) assessed at baseline (T0), 6 months (T6), 12 months (T12), and 24 months (T24), stratified by sex.
Table S1. Number of patients included at each timepoint.
Table S2. Demographic and clinical characteristics per treatment group.
Table S3. Estimated marginal means (EMM) and change scores with 95% confidence intervals (CI) of the EORTC QLQ‐C30 symptom scales outcomes assessed at baseline (T0), 6 months (T6), 12 months (T12) and 24 months (T24) after diagnosis.
Acknowledgements
None.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Fig. S1. Flowchart describing inclusion of patients in the study cohort.
Fig. S2. EORTC QLQ‐C30 estimated marginal mean (EMM) scores for symptom scales assessed at baseline (T0), 6 months (T6), 12 months (T12), and 24 months (T24), per treatment group.
Fig. S3. EORTC QLQ‐C30 estimated marginal mean (EMM) scores for global health and functional scales in muscle‐invasive bladder cancer patients assessed at baseline (T0), 6 months (T6), 12 months (T12), and 24 months (T24), stratified by sex.
Fig. S4. EORTC‐BLM30 scores Estimated marginal mean (EMM) scores for Urostomy scales (A), Sexual health scales (B), and the remaining scales (C) assessed at baseline (T0), 6 months (T6), 12 months (T12), and 24 months (T24), stratified by sex.
Table S1. Number of patients included at each timepoint.
Table S2. Demographic and clinical characteristics per treatment group.
Table S3. Estimated marginal means (EMM) and change scores with 95% confidence intervals (CI) of the EORTC QLQ‐C30 symptom scales outcomes assessed at baseline (T0), 6 months (T6), 12 months (T12) and 24 months (T24) after diagnosis.