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Erectile, urinary and bowel dysfunction are typical adverse effects (AEs) after local treatment for prostate cancer (PCa), in the form of radical prostatectomy (RP) and radiotherapy (RAD), although the published estimates vary considerably [1-8]. Missing information about additional androgen deprivation therapy (ADT) and relapse make interpretation of these findings challenging. The prevalence of AEs depends on treatment method, baseline characteristics, time elapsed since treatment and assessment methodology, which eventually should separate function from bother . After RP, most AEs develop immediately after treatment, with gradual improvement during the first year, whereas AEs after RAD develop more slowly. Maximum recovery is usually achieved during the first 2 post-treatment years . Simultaneous use of adjuvant ADT decreases sexual function and leads to increasing fatigue . Further, some of the symptoms described as treatment-related AEs may be experienced by patients with PCa who never had treatment, such as erectile dysfunction (ED) and urinary urgency and frequency . In Europe, reports on typical AEs are usually based on mono-institutional experience or multicentre studies, performed at high-volume university-affiliated hospitals. Estimates published on AEs include patients with recurrence and additional treatment. It is debatable to what extent such studies can serve as a basis for counselling regarding typical AEs in unselected patients.
Global quality of life (QoL) describes physical and mental health status as reported by the patient, separate from typical AEs. Although AEs are reported as bothersome to patients, they are not always associated with reduced global QoL when other factors such as comorbidity and age are taken into account . Further, results from cross-cultural studies indicate that cultural and national differences influence such associations [12, 13]. In Norwegian patients with PCa, for example, sexual function was not significantly associated with global QoL after radiotherapy , contrary to the findings in a US study . More information is therefore needed regarding the relationship between global QoL and typical AEs in patients in different cultures, preferably derived from population-based studies.
Lastly, neuroticism is a personality trait that is closely linked to health perception  and should be accounted for in this context. Of the personality traits presented in the five-factor model of Costa and McCrae , neuroticism has proven to be robustly correlated to several mental and physical health outcomes . An individual's degree of neuroticism develops from early childhood and remains relatively stable after young adulthood. Elderly men facing the physical and mental health challenges from a PCa diagnosis do so with their established degree of neuroticism. In previous studies from our research group, neuroticism has proven to be a relevant variable when assessing symptoms (e.g. sexual bother) and global QoL [18, 19].
Erectile dysfunction is one of the most frequently reported AEs after treatment for PCa. Treatment for ED is available such as the use of phosphodiesterase type 5 (PDE5) inhibitors. In a US study, about half of patients with PCa treated for localized disease tried/received treatment for ED once or more during a 5-year follow-up period . Differences in the use of PDE5 inhibitors may exist between different cultures , and may be related to reimbursement possibilities for these expensive drugs. In Norway, medication for ED (EDmed) has to be paid for by the patients themselves. Use of PDE5 inhibitors has been shown to improve functional and psychosocial aspects of sexual life and may therefore be important for global QoL . Thus, the question is open as to what proportions of patients with PCa in a population-based sample use these agents and whether EDmed use is related to global QoL.
With this background our population-based study of patients with non-metastatic PCa who had completed their planned intervention (no treatment, RP, RAD without ADT or RAD with ADT) had two aims: (i) to estimate the prevalence of typical AEs and low global QoL in relation to treatment. Based on the available literature, we hypothesized, at a median period of 23 months after local treatment, that fewer patients in the RAD group than in the RP without ADT group would experience sexual and urinary AEs, but that more of them would report bowel AEs. Further, we expected adjuvant ADT to increase the prevalence of ED, without significant impact on bowel or urinary AEs; (ii) to explore, independently of treatment group, the association between typical AEs and low global QoL. In a sub-analysis we investigated the use of EDmed and the relationship between such use and global QoL.
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- Conflict of Interest
Our population-based study documents that cure from PCa has its price, but that ‘no treatment’ is also associated with symptoms similar to typical AEs. Two types of urinary AEs emerged with different patterns in the treatment groups. While the prevalence of UI was highest after RP (24%) irritative–obstructive symptoms were most often recorded by patients in the RAD or in the NoTreat group (35–50%). Intestinal AEs were more common after RAD compared with RP or no treatment. More than half of the patients in all groups reported poor sexual drive, though it was significantly less often reported by patients in the NoTreat group. Poor erectile function was reported by >75% of men in all treatment groups, most often after RP. Despite having typical AEs, the global QoL of men with discontinued curative treatment was good for 75%. In adjusted analyses irritative–obstructive urinary symptoms and poor sexual drive each approximately doubled the risk of low global QoL, whereas UI, intestinal symptoms and poor erectile function were not significantly associated with low global QoL. EDmed was most often used by patients who had undergone RP. Such use was not significantly associated with global QoL.
The present results should be interpreted with consideration to the background of the treatment policies valid in Norway around 2004. Firstly, today's surveillance strategy was not implemented as a national recommendation. We suspect that high age and chronic pre-treatment comorbidity allocated many men to our NoTreat group. Secondly, the RADNoHT group consisted mainly of patients with intraprostatic tumours whose comorbidity probably did not allow a major surgical procedure, which would have been the treatment of choice in Norway at that time. These policies explain our high rates of post-treatment comorbidity and high proportion of men with PCS ≤ 40 in the NoTreat and RADNoHT groups. The high proportion of PCS ≤ 40 (23%) in the RADHT group, not different from estimates in the NoTreat and RADNoHT groups, is probably attributable to ADT's negative impact on physical health, persisting for several months after discontinuation of ADT.
The duration of adjuvant ADT is a matter of ongoing debate. As ADT often leads to physical and mental AEs, such treatment should be as short-lasting as possible without reduction of its beneficial effect on survival. In practice, planned long-lasting hormone treatment is often prematurely discontinued in a patient with severe ADT-related AEs, possibly explaining the varying duration of adjuvant ADT in our RADHT group.
The present study adds to the growing evidence that irritative–obstructive urinary symptoms represent late AEs, which affect the global QoL of a patient with PCa. Published studies have emphasized the impact of irritative–obstructive urinary symptoms on satisfaction with treatment outcome and global QoL [6, 8]. In the present study men in the NoTreat and RADNoHT groups were more likely to experience these AEs than men who had undergone RP. Similar results were found in the prospective study by Pardo et al.  where irritative–obstructive symptoms were reduced in about half of the patients 3 years after RP. The prevalence of moderate/severe irritative–obstructive urinary symptoms was highest in our NoTreat group, probably related to the growth of the prostate gland, although not significantly different from the RADNoHT group.
Urinary incontinence has been the main focus of many studies and, as expected, it was most common after RP, but only 10% of patients in the present study, who had undergone RP, described their UI as ‘more than just dribbling’. Prevalence of UI found in the Prostate Cancer Outcomes Study  after 24 months of follow-up was 4.7, 3.3 and 21.5% for watchful waiting, RAD and RP, respectively. Steineck et al.  found that 18% of men randomized to RP and 2% of men randomized to watchful waiting reported a moderate-to-severe degree of urinary leakage after a mean follow-up of 4 years. Our high prevalence of UI in the NoTreat group (13%) and severe leakage (8%) must be viewed on the basis of this group's heterogeneity.
In addition to irritative–obstructive urinary symptoms, poor sexual drive was significantly associated with a doubled risk of having low global QoL. Interestingly, and contrary to Penson et al.'s study , the association between poor erectile function and low QoL did not reach statistical significance. This may be related to cultural differences in patients' view concerning sexual functioning with increasing age. A response shift must also be considered as a possible explanation [35, 36]. Response shift reflects the gradual acceptance of treatment-related AEs and change of expectations as to global QoL. Based on our results we speculate that response shift related to low global QoL develops less easily with regard to irritative–obstructive urinary symptoms and poor sexual drive. This is probably because these AEs are more disturbing and interfere with the general perception of health.
Age, education, comorbidity and neuroticism were identified as confounding factors which moderated the observed association between AEs and low global QoL. Even though the confounding effect of neuroticism was moderate, level of neuroticism consequently had the strongest association with low global QoL (data not shown) which gives further strength to its importance in QoL research. A person's presence of a moderate or high level of neuroticism was more important for reporting low global QoL than erectile or intestinal dysfunction or UI. This result also implies that personality should be taken into account when informing patients about functional AEs, as nervous men might experience more symptoms concurrent with a low QoL, than less neurotic ones.
Even though treatment for ED is available, only about half of our patients had used such medication after PCa treatment, most men in the RP group (84%) and fewest in the NoTreat group (19%). We cannot decide whether these differences are primarily attributable to varying patients' demands or if they reflect prescription patterns differing between urologists and oncologists. Both explanations are probably relevant. With today's knowledge of the importance of early activation of nervous pathways responsible for erectile function , early and more frequent post-treatment management of ED is challenging, also after RAD. About half of ‘ever-users’ report that they had not used EDmed within the 4 weeks before the survey which may indicate that today's EDmed is not effective for many of these patients. Of special interest, and admittedly based on small figures, is the fact that almost two thirds of patients from the RADNoHT group were ‘still users’ as compared with less than half in the other groups. This may indicate that these drugs are particularly effective after RAD as monotherapy. While erectile function was similar in ‘ever-users’ and ‘never-users’, poor sexual drive was significantly more prevalent in the latter group, probably reflecting their lack of motivation to try EDmed. Low global QoL was not significantly associated with EDmed use and the small proportion of ‘still users’ with low QoL is explained by their younger age and fewer comorbid conditions.
Several limitations concerning our cross-sectional study should be mentioned, such as the lack of pre-treatment data. Not recognized intergroup variability in pre-treatment dysfunctions and low global QoL could have introduced a systematic bias. Our choice to select single domains from different instruments for the survey questionnaire instead of one complete validated questionnaire is today questionable. Our solution has to be viewed as a compromise between interests of oncologists and urologists for whom self-report of AEs was a new methodology in 2004. Further, there is uncertainty as to whether or not the questions about ED have been answered disregarding the use of EDmed. Since 85% of ‘still users’ report poor erectile function similarly to ‘never users’ and ‘discontinued users’, the majority have probably reported their function in absence of sexual aids. We propose that future questionnaires should clearly separate the patient's report on erectile function related to the use of EDmed.
The major strengths of the present study are the population-based design and the comparison of three of today's major treatment methods in addition to a ‘no treatment’ group. Further, the described typical AEs are those emerging after completion of planned initial treatment alone, without the use of adjuvant or salvage treatment. Finally, the reported prevalences of typical AEs and low global QoL are probably persistent ones, as several studies have shown that PCa-related QoL stabilizes 6–12 months after treatment [4, 38, 39].
In conclusion, PCa survivors after curative treatment, but also patients without any therapy, report considerable rates of sexual, urinary and intestinal AEs. Irritative–obstructive urinary symptoms and poor sexual drive each approximately double the risk of low global QoL. Use of EDmed was most common among men in the RP group, and was not associated with global QoL.