Impact on Quality of Life 3 Years After Diagnosis of Prostate Cancer Patients: An Observational Case-Control Study

Background Prostate cancer patients are known to suffer from poor sexual and urinary long-term side-effects following treatment, potentially impacting quality of life. The purpose of our study was to compare health-related quality of life at 3 years between prostate cancer patients and healthy controls according to key life-style characteristics. Secondary objectives were to compare urological dysfunction, sexual function, anxiety and depression. Methods Multicentric, case-control, observational prospective, open, follow-up study including 819 prostate cancer patients < 75 years old from the EPICAP cohort newly diagnosed from 1 December 2011 to 31 March 2014 and 879 healthy controls. Participants were excluded if they experienced a relapse. Controls from the same geographical region were age-matched and were excluded if they were diagnosed with prostate cancer. Patients received one of the following treatments: active surveillance (AS), radical prostatectomy (RP), external beam radiotherapy (EBRT), High-intensity Focused Ultrasound (HIFU), chemotherapy (CT), or androgen deprivation therapy (ADT) as appropriate. The primary outcome was the quality of life as evaluated by the QLQ-C30 questionnaire. Scores were analyzed by multivariate analysis to adjust for predefined socio-demographic confounding effects.

Trial registration: clinicaltrials.gov, NCT02854982. Registered 4 August 2016 -retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT02854982 Introduction Prostate cancer (PCa) diagnosis and treatment impact patient short-term quality of life (QoL) and functional symptoms (1), but longer-term effects need to be considered to choose the most adapted treatment and anticipate rehabilitation difficulties. Studies examining QoL following treatment have shown worsening of sexual and urinary troubles over time (2)(3)(4). A large study showed that half of patients included 2 years after diagnosis experienced negative consequences of PCa and treatment, with a negative impact on QoL (5). A French study found that 20% of treated patients had erectile dysfunction and over 10% were treated for acute urinary retention; both dysfunctions occurred at higher frequency in patients treated with prostatectomy alone (6).
A recent review showed that QoL of newly diagnosed PCa patients was independent on the type of treatment, but that surgery had a negative impact on urinary continence and sexual function, external beam radiotherapy (EBRT) on bowel function, active surveillance (AS) having the lowest impact on disease-specific QoL (7). These studies focused on treatment-related clinical symptoms, but did not consider the natural aging process; yet age-related comorbidities may interact with the adverse effects of different treatment modalities.
Our study investigated QoL following PCa in the EPICAP cohort (8) to evaluate its potential deterioration and the occurrence of long term sexual or urinary dysfunctions that could arise from natural aging of the population.

Methods
Study design and setting: EPICAP-QALY is an ancillary study of the EPICAP survey (8). It is a Participants: Participants from the EPICAP cohort completed a screening questionnaire to determine eligibility. Patients who had received hormone therapy within the previous year or who experienced a relapse in the intervening years were excluded, except patients on salvage radiotherapy following prostatectomy for more than 6 months with a PSA level < 1 ng/ml. Age-matched ± 1 year healthy controls were included in a 1:2 ratio. Individuals diagnosed with PCa following inclusion or with a PSA > 10 ng/ml were excluded. Men with PSA > 10 ng/ml were not selected to exclude potential relapse for cases or cancer occurrence for controls.
Outcomes: The primary outcome was QoL 3 years after PCa treatment compared to controls as evaluated by the QLQ-C30 questionnaire (9). Secondary outcome was the comparison of urinary dysfunction between patients and controls using the following questionnaires: IPSS International Prostate Symptom Score (10), ICIQ-MLUTS International Consultation on Incontinence Male Lower Urinary Tract Symptoms (11), IIEF-6 International Index of Erectile Function (12), and HADS Hospital Anxiety and Depression Scale (13).
These questionnaires were used to compare QoL and symptoms according to active surveillance (AS), radical prostatectomy (RP), EBRT, brachytherapy or High-intensity Focused Ultrasound (HIFU), androgen deprivation therapy (ADT) or combined care (CC). A life situation questionnaire complemented with specific questions concerning sexuality was used to test for some potential confounders (14).
Data collection: Age, BMI, PSA level, educational level, housing, living alone, marital status, monthly income, chronic disease and regular medication were collected. Treatment at diagnosis, last treatment received, hormone therapy within previous 12 months, and employment status were also recorded. For controls, urologic consultation for urinary troubles, prostate treatment and PSA testing in the 3 previous year were recorded.
Sample size: By predicting a lower participation rate in cases than controls and a recurrence rate of cases of 10%, we originally planned a cohort of 600 patients and 300 controls paired with a ratio 2:1 on age to highlight a standardized difference in score on the QLQ-C30 of 0.25 ("small" effect according to Cocks et al (9)) with a global bilateral risk alpha of 5% and 90% power. The participation rate was lower than expected and the study included 376 patients to whom we matched 188 patients (among 364 available).
Statistics: The comparability of age was assessed with a Student test. Descriptive statistics are reported as counts and percentages for categorical variables and means and standard deviations for continuous variables with normal distribution and median and quartiles for others. Comparisons of baseline characteristics and putative risk factors between cases and controls were performed with Mann-Whitney, Kruskal-Wallis, Χ2, Student, or Fisher exact test as appropriate.
For each questionnaire, the distribution of scores was analyzed. When extreme values (0 or 100) were over-represented, scores were recoded into classes and described qualitatively with effectives and percentages.
The univariate analysis was performed with a mixed linear model for quantitative scores (QLQ-C30 summary score, VS and IS score of ICIQ-MLUTS). For recoded QLQ-C30 scores analyses were conducted with a mixed logit model. To account for pairing, a random effect on 2: 1 trinoma was considered.
For recoded QLQ-C30 scores, distribution and links with social potential confounders was assessed.
When the symptom or trouble was present in less than 20% of cases or when no apparent link was possible, multivariate analysis was not performed. For other QLQ-C30 scores and for the summary quantitative score, the effects of putative confounders were evaluated. Socio-professional integration items were selected for testing based on their reliability, their clinical pertinence of potential confounding factors and their similarity with items of the QALIPRO study (15). Putative confounders for quantitative scores were analyzed with Spearman correlation test, Kruskal-Wallis or ANOVA as appropriate, and with χ2, Fisher test, Student or Wilcoxon test for qualitative values.
All variables with a P-value lower than 0.20 were considered as potential covariates and adjusted mixed linear general models or logistic models were computed with a random effect on 2:1 trinoma.
All analyses were performed using SAS software (SAS Institute, Cary, NC) version 9.3. P-values < 0.05 were interpreted as statistically significant for 2-sided tests.

Results
Responses to questionnaires were received from 376/704 eligible patients (53.4%) and 364/832 eligible controls (43.8%). The controls were age-matched in a 2:1 ratio with the patients (n = 188) ( Fig. 1). The average patient age was 67.9 years old. Baseline characteristics at inclusion were similar between groups, except for PSA level, which was much lower in the patient group as anticipated due to treatment ( Table 1). The most common treatments for patients were radical prostatectomy (RP) (68.6%) and EBRT (23.9%).  (Table 2). Significant differences were found for social functioning, pain and dyspnea (p < 0.05).  The IPSS score did not significantly differ between medical care (p = 0.0730), even when adjusted for age (p = 0.0919). For the ICIQ-MLUTS questionnaire, VS score and IS score were both significantly different (p = 0.0011 and p < 0.0001, respectively) between treatments and no potential confounder was highlighted. The Bonferonni-post-hoc-analysis (threshold p < 0.0083) showed significant differences between RP and EBRT or brachytherapy or HIFU or ADT for VS score (p = 0.0009) and IS score (p ≤ 0.0001), VS and IS scores being the lowest for patients treated with RP and RT, respectively. IS score was significantly different between AS and RP (p = 0.0013). Finally, frequency of day or night urination did not differ, with respectively p = 0.99 and p = 0.0925. Erectile dysfunction differed between groups, with severe erectile dysfunction for 33.3%, 80.8%, 64.8% and 72.2% respectively for AS, RP, EBRT or brachytherapy or HIFU or ADT and CC. The analysis with the 5 classes of erectile dysfunction could not be tested, but grouping into 3 classes (No dysfunction; Mild, Mild to moderate or Moderate dysfunction; Severe dysfunction), the Fisher test could confirm the difference (p < 0.0001). No HADS scores differed between groups.

Discussion
Three clinical trials, have shown equivalent OS between EBRT, RP and AS in low-risk prostate cancer subjects (16)(17)(18). The ProtecT trial showed no difference in OS 10 years after diagnosis irrespective of treatment (18). It remained to know what would be the impact of each of these approaches in terms of QoL and long-term side-effects to select the most appropriate therapeutic option.
Our study was particularly adapted to assess the impact of natural aging, diagnosis and treatment on QoL at 3 years after diagnosis. For 376 patients and 188 age-matched controls adjusted for socio-demographic confounding variables, QoL was similar between patients and controls, with a very high QoL and few reported symptoms. Most QoL items were equivalent between groups, except worse social functioning in patients compared to controls, probably linked to side effects. Patients showed an increased prevalence of incontinence compared to controls, though other markers of urinary dysfunction were similar between groups, in particular following RT. Patients had worse incidence of severe erectile dysfunction compared to controls (88.5% vs 55%), especially following surgery.
However, anxiety and depression were not different between patients and controls.
Because QoL is impacted by various socio-demographic factors (19), its evaluation requires a dedicated control cohort to minimize potential biases (20). However, only a few studies evaluating QoL and symptoms of PCa patients were performed using such a control group (16,17). Taylor et al. Previous studies using the QLQ-C30 questionnaire for PCa reported a score of approximately 70 (out of 100) for global QoL in a Finnish and a German population (22) and 80 in a French population (15).
The unexpected high QoL and low symptoms scores observed in EPICAP-QALY could be attributed to the relatively young age and high level of income of our population.
Treatment-related incontinence and erectile dysfunctions appear in the first years of treatment and persist over time with a severity that varies according to treatment (21). There was heterogeneity in patients' characteristics as our study was not randomized. Patients undergoing radiotherapy are usually older, have more co-morbidities and a more aggressive disease (23). When developing individualized prediction models for the outcomes (relapse or death), some patient characteristics are associated with different treatment-related outcomes, for example reduced mortality rate in patients with elevated Gleason score choosing EBRT, whereas patients with perineural invasion fared better following surgery (23). These differences could also impact QoL. Nevertheless, there is a difference in long-term side-effects between the different treatments. In our study, global QoL and physical functioning scores were higher for AS and lower for ADT, with a negative impact on cognitive functions.
In a previous study, long-term change in urinary incontinence was worse for patients treated with RP compared to brachytherapy, while long-term change in urinary irritation/obstruction was worse for patients treated with EBRT or brachytherapy (24). Two other studies with 2 and 3 years of follow-up found that patients experienced worse sexual function and urinary incontinence after RP, worse urinary irritation/obstructive symptoms after RT, and mostly transient declines in bowel function after EBRT (25,26 Proportion of long-term bowel dysfunction as evaluated by the EPIC questionnaire was higher in the EBRT group (1) while no difference between subgroups was observed in our study. In the CAESAR + study (28), patients treated with RP or EBRT reported better QoL than patients receiving combined treatments while two other studies showed that global QoL did not significantly differ in the longterm, irrespective of treatment (26,29).
Our study has several limitations. It is not a prospective study, so urinary and erectile dysfunction and QoL data at baseline are missing. The social-professional questionnaire was developed for testis patients usually younger and in employment, but provided necessary information for use in the statistical models as well as insights into the implication of diagnosis on working prospects (14).
Because the treatment was not randomized, some confounding factors could have an impact on sideeffects between patient subgroups. It is also likely that non-responders had a different opinion on their medical care.

Conclusion
Our study demonstrates that for prostate cancer patients below 75 years old, the diagnosis of prostate cancer has only a marginal impact on the quality of life and on symptoms at 3 years, which is an additional argument in favor of PCa screening. Conversely, our data revealed that the choice of the therapeutic option is critical as it could have a significant impact on social functioning due to the potential occurrence of long-term side effects.

Ethics approval and consent to participate
The EPICAP-QALY study is registered at clinicaltrials.gov (number NCT02854982). It was performed at Nimes University Hospital between August 2015 and October 2017 and was approved by the institutional review board. Written informed consent was obtained from all study participants and was approved by the CNIL (authorization number DR-2011-121).

Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare no competing interest

Funding
This work was supported by the "Ligue Nationale contre le Cancer". The funders had no role in the design of the study, in the collection, in the analysis and in the interpretation of the data, in the writing of the manuscript or in decision to publish.

Authors' contributions
NH and PFP designed the study; NH supervised the study and obtained funding; FM, BT, XR, SK, SB, and NH were involved in the acquisition and the analyses of the data; SK and SB wrote a first draft of the manuscript; SK, SB, FM, XR and NH edited the final manuscript; SB performed the statistical analyses; FM, XR and BT provided administrative and technical support.
All authors have read and approved the manuscript. Figure 1 Flow chart Figure 2 Boxplot of QLQ-C30 summary score between patients and controls