Prostate Cancer

8. QUALITY OF LIFE OUTCOMES IN PROSTATE CANCER

This chapter is presented in two parts. The first (Section 8.2) will summarise long-term consequences (≥ twelve months) of therapies for PCa. Based on two SRs, the second (Section 8.3) provides evidence-based recommendations for supporting patients when selecting primary treatment options for localised disease and also supportive interventions aimed at improving disease-specific QoL across all stages of disease.

8.1. Introduction

Quality of life and personalised care go hand in hand. Treating PCa can affect an individual both physically and mentally, as well as close relations and work or vocation. These multifaceted issues all have a bearing on an individual‘s perception of QoL [1342,1343]. Approaching care from a holistic point of view requires the intervention of a multi-disciplinary team including urologists, medical oncologists, radiation oncologists, oncology nurses, behavioural practitioners and many others including fellow patients. Attention to the psychosocial concerns of people with PCa is integral to quality clinical care, and this can include the needs of carers and partners [1344]. Prostate cancer care should not be reduced to focusing on the organ in isolation: side effects or late adverse effects of treatment can manifest systemically and have a major influence on the patient’s QoL. Psychological distress can be caused by the cancer diagnosis itself, cancer symptoms and/or treatment side effects [1345]. Taking QoL into consideration relies on understanding the patient’s values and preferences so that optimal treatment proposals can be formulated and discussed. Cross-sectional patient reported outcomes studies in general PCa populations show the impact of treatment on global and disease specific QoL is greater than that described in clinical trial populations who often have less co-morbidity and belong to higher socio-economic groups. Individuals undergoing two or more treatments have more symptoms and greater impact on QoL [1346,1347]. Subgroups of people including those with poor general health, being unmarried, older age and/or pre-existing depressive symptoms are more at risk of long-term mental health issues following treatment for PCa [1348].

8.2. Adverse effects of PCa therapies

8.2.1. Active surveillance

In a SR [1349] on the long-term (> five year) health-related QoL in patients on active surveillance, it was observed that there were differences in specific functional outcomes between patients on AS and surgery or radiotherapy, ≥ five year after treatment. In patients on AS, the overall HRQoL and psychological well-being outcomes were good. All studies comparing AS with active treatment found no substantial or consistent difference in general HRQoL PROMs between groups. In preservation of continence there is a clear advantage for AS over, active treatment, particularly to RP. Results suggest that even after extended periods, continence is still considerably superior in AS to that in RP. Obstructive voiding symptoms were more common in patients on AS than in post-operative patients. In the domain of sexual function, it is seen that AS group has better than or comparable sexual function to that in the active treatment group. Studies comparing AS with that of PCa-free patients had mixed results with papers observing no statistically significant difference and others reporting that sexual function was, at least numerically, worse in patients on AS than in PCa-free patients. All patients on AS report good quality of life, similar to that in individuals without prostate cancer [1350]. Regarding anxiety it was seen in a registry on active surveillance in the USA that men undergoing active surveillance, had a moderate risk of cancer-specific anxiety that significantly decreases over time. Patients considering active surveillance can be informed that, although it is common experience some anxiety initially, most men rapidly adjust and report low levels of anxiety within two years [1350].

8.2.2. Surgery

A lack of clear consensus in reporting surgical complications following RP, specifically urinary incontinence and stricture rates, and the introduction of different techniques has resulted in a wide variation in the types of complications reported, as well as variation in the overall incidence of complications [1351-1354]. The most common post-operative complication is ED but other related issues to consider include dry ejaculation, which occurs with removal of the prostate, change in the quality of orgasm and occasional pain on orgasm. Men also complain of loss of penile length (3.73%, 19/510 men) [1355]. The second most commonly occurring complication is long-term incontinence [1351-1354] but voiding difficulties may also occur associated with bladder neck contracture (e.g., 1.1% after RALP) [1356].

A key consideration is whether long-term consequences of surgery are reduced by using newer techniques such as RALP. Systematic reviews have documented complication rates after RALP [612-616], and can be compared with contemporaneous reports after RRP [617]. From these reports, the mean continence rates at twelve months were 89–100% for patients treated with RALP and 80–97% for patients treated with RRP. A prospective controlled non-randomised trial of patients undergoing RP in fourteen centres using RALP or RRP demonstrated that at twelve months after RALP, 21.3% were incontinent, as were 20.2% after RRP. The unadjusted OR was 1.08 (95% CI: 0.87–1.34). Erectile dysfunction was observed in 70.4% after RALP and 74.7% after RRP. The unadjusted OR was 0.81 (95% CI: 0.66–0.98) [618,1357]. Further follow-up demonstrates similar functional outcomes with both techniques at 24 months [1357,1358]. A single-centre randomised phase III study comparing RALP and RRP (n = 326) also demonstrates similar functional outcomes with both techniques at 24 months [1359]. Prostatectomy was found to increase the risk of complaints from an inguinal hernia, in particular after an open procedure when compared to minimally-invasive approaches [1360,1361]. For those undergoing minimally-invasive procedures port site hernia has been reported in 0.66% after inserting 12 mm bladeless trocar and can occur more rarely with 8 mm and 5 mm trocars [1362]. Another complication after primary treatment is lower limb and genital lymphedema. A SR found a prevalence of (0-14%) lower limb and (0-1%) genital lymphedema after radical prostatectomy with PLND [1363] and between 0-9% and 0-8% in patients after irradiation on the LNs. In the subgroup that underwent pelvic irradiation after staging pelvic LNs dissections the prevalence of lower limb (18-29%) and genital (2-22%) is substantially elevated.

8.2.3. Radiotherapy

8.2.3.1. Side effects of external beam radiotherapy

Analysis of the toxicity outcomes of the ProtecT trial shows that patients treated with EBRT and six months of ADT report bowel toxicity including persistent diarrhoea, bowel urgency and/or incontinence and rectal bleeding (described in detail in Section 8.3.1.1 below) [1364]. Participants in the ProtecT study were treated with 3D-CRT and studies using IMRT demonstrate less bowel toxicity than noted previously with 3D-CRT [1365].

A SR and meta-analysis of observational studies comparing patients exposed or unexposed to RT in the course of treatment for PCa demonstrates an increased risk of developing second cancers for bladder (OR: 1.39), colorectal (OR: 1.68) and rectum (OR: 1.62) with similar risks over lag times of five and ten years. Absolute excess risks over ten years are small (1–4%) but should be discussed with younger patients in particular [1366].

Patient-reported outcomes suggest a temporary drop in the EPIC hormonal and sexual domains when six months af ADT was added to radiotherapy, with a disappearance of any clinical relevant difference at one year [1147,1367].

8.2.3.2. Side effects from brachytherapy

Some patients experience significant urinary complications following implantation such as urinary retention (1.5-22%), with post-implantation TURP reported as being required in up to 8.7% of cases, and incontinence (0–19%) [1368]. Chronic urinary morbidity is more common with combined EBRT and BT and can occur in up to 20% of patients, depending on the severity of the symptoms before BT. Urethral strictures account for at least 50% of urinary complications and can be resolved with dilation in the majority [719,726]. Prevention of morbidity depends on careful patient selection and IPSS score, backed up by urodynamic studies.

8.2.4. Local primary whole-gland treatments other than surgery or radiotherapy

8.2.4.1. Cryosurgery

In a SR and meta-analysis there was evidence that the rate of urinary incontinence at one year was lower for cryotherapy than for RP, but the size of the difference decreased with longer follow-up [738]. There was no significant difference between cryotherapy vs. EBRT in terms of urinary incontinence at one year (< 1%); cryotherapy had a similar ED rate (range 0–40%) to RP at one year. There were insufficient data to compare cryotherapy vs. EBRT in terms of ED.

8.2.4.2. High-intensity focused ultrasound

In terms of toxicity there are insufficient data on urinary incontinence, ED, or bowel dysfunction to draw any conclusions, although at one-year HIFU had lower incontinence rates than RP (OR: 0.06, 95% CI: 0.01–0.48) [738].

8.2.5. Androgen deprivaton therapy

A summary of psychological impacts due to the use of ADT such as sexual function, mood, depression, cognitive function, and impact on partners can be found in two clinical reviews [1369,1370].

A small RCT evaluated the QoL at one-year follow-up in patients with PSA only relapse after primary therapy without evidence of metastasis, between various ADT regimens, or no treatment. Patients treated by ADT reported a significant decline in spatial reasoning, spatial abilities and working memory as well as increased depression, tension, anxiety, fatigue, and irritability during treatment [1371]. Conversely, a prospective observational study with follow-up out to three years failed to demonstrate any association with cognitive decline in men on ADT when compared to men with PCa not treated with ADT and healthy controls [1372]. A prospective observational study of locally advanced PCA or BCR after local therapy found that immediate ADT was associated with a lower overall QoL compared to deferred treatment [1373]. Another retrospective non-randomised study suggested that men receiving LHRH agonists reported more worry and physical discomfort and poorer overall health and were less likely to believe themselves free of cancer than patients undergoing orchiectomy. The stage at diagnosis had no effect on health outcomes [1374].

8.2.5.1. Sexual function

Cessation of sexual activity is very common in people undergoing ADT, affecting up to 93% [1375]. Androgen deprivation therapy reduces both libido and the ability to gain and maintain erections. The management of acquired ED is mostly non-specific [1376].

Using a specific non-validated questionnaire, bicalutamide monotherapy showed a significant advantage over castration in the domains of physical capacity and sexual interest (not sexual function) at twelve months [1377]. A post-hoc analysis, including only patients with sexual interest suggested that bicalutamide was associated with better sexual preservation, including maintained sexual interest, feeling sexually attractive [1378], preserved libido and erectile function [1379].

8.2.5.2. Hot flushes

Hot flushes are a common side effect of ADT (prevalence estimated between 44–80% of men on ADT) [1375]. They appear three months after starting ADT, usually persist long-term and have a significant impact on QoL.

Serotonin re-uptake inhibitors (e.g., venlafaxine or sertraline) appear to be effective in men but less than hormone therapies based on a prospective RCT comparing venlafaxine, 75 mg daily, with medroxyprogesterone, 20 mg daily, or cyproterone acetate, 100 mg daily [1380]. After six months of LHRH (n = 919), 311 men had significant hot flushes and were randomised to one of the treatments. Based on median daily hot-flush score, venlafaxine was inferior -47.2% (interquartile range -74.3 to -2.5) compared to -94.5% (-100.0 to -74.5) in the cyproterone group, and -83.7% (-98.9 to -64.3) in the medroxyprogesterone group. Another RCT (n = 78) compared oestradiol (transdermal 0,9mg or 0,1% gel) to placebo. After six months oestradiol reduced daily hot flushes frequency (mean adjusted difference MAD -1,6, p=0.04) but the effect on weekly hot flushes was not significant (MAD -19,6 p=0.11) [1381].

With a placebo effect influencing up to 30% of patients [1382] , the efficacy of clonidine, veralipride, gabapentin [1383] and acupuncture [1384] need to be compared in prospective RCTs.

8.2.5.3. Non-metastatic bone fractures

Due to increased bone turnover and decreased BMD in a time-dependent manner, ADT use is linked to an increased risk of fracture (up to 45% RR with long-term ADT) [1385]. Severe fractures in men are associated with a significant risk of death [1386]. A precise evaluation of BMD should be performed by DEXA, ideally before starting long-term ADT. An initial low BMD (T-score < -2.5 or < -1, with other risk factors) indicates a high risk of subsequent non-metastatic fracture and causes should be investigated. Other risk factors include increasing age, BMI of 19 or less, history of previous fracture or parent with fractured hip, current smoking, use of glucocorticoids, rheumatoid arthritis, alcohol consumption > two units per day, history of falls and a number of other chronic medical conditions [1387]. Fracture risk algorithms which combine BMD and clinical risk factors such as FRAX score can be used to guide treatment decisions, but uncertainty exists regarding the optimal intervention threshold, therefore no specific risk algorithm can be recommended for men on ADT for PCa. Obesity (increase in body fat mass by up to 10% and/or BMI > 30) and sarcopenia (decrease in lean tissue mass by up to 3%) as well as weight loss are common and occur during the first year of ADT [1388]. These changes increase the fracture risk [1389]. It is suggested that adding ARTA to ADT will increase this risk. This was also seen in a SR and meta-analysis [1390]. It was found that the use of ARTA was associated with an increase in fractures. Eleven studies were included with a total population of 11,382 men (median [range] age: 72 [43-97] years), with 6,536 in the ARTA group and 4,846 in the control group. Participants in the ARTA group could have received enzalutamide, apalutamide, or darolutamide in combination with androgen deprivation therapy or other enzalutamide combinations; patients in the control group could have received placebo, bicalutamide, or abiraterone. The incidence of fracture was 242 fractures (4%) in the ARTA group and 107 fractures (2%) in the control group. Use of an ARTA was associated with an increased risk of fractures: all-grade fracture (RR, 1.59; 95% CI, 1.35-1.89; p <.001), and likely grade 3 or greater fracture (RR, 1.71; 95% CI, 1.12-2.63; p =.01).

Bicalutamide monotherapy may have less impact on BMD but is limited by its suboptimal efficacy for M1 disease [1391,1392]. The intermittent LHRH-agonist modality might be associated with less bone impact [1393].

8.2.5.4. Metabolic effects

Lipid alterations are common and may occur as early as the first three months of treatment [1388]. Androgen deprivation therapy also decreases insulin sensitivity and increases fasting plasma insulin levels, which is a marker of insulin resistance. In diabetic patients, metformin appears to be an attractive option for protection against metabolic effects based on retrospective analysis [1394], but there is insufficient data to recommend its use in non-diabetic patients.

Metabolic syndrome is an association of independent cardiovascular disease risk factors, often associated with insulin resistance. The definition requires at least three of the following criteria [1395]:

• waist circumference > 102 cm;
• serum triglyceride > 1.7 mmol/L;
• blood pressure > 130/80 mmHg or use of medication for hypertension;
• high-density lipoprotein (HDL) cholesterol < 1 mmol/L;
• glycaemia > 5.6 mmol/L or the use of medication for hyperglycaemia.

The prevalence of a metabolic-like syndrome is higher during ADT compared with men not receiving ADT [1396]. Skeletal muscle mass heavily influences basal metabolic rate and is in turn heavily influenced by endocrine pathways [1397]. Androgen deprivation therapy-induced hypogonadism results in negative effects on skeletal muscle health. A prospective longitudinal study involving 252 men on ADT for a median of 20.4 months reported lean body mass decreases progressively over three years; 1.0% at one year, 2.1% at two years, and 2.4% at three years which appears more pronounced in men at ≥ 70 years of age [1398].

8.2.5.5. Cardiovascular morbidity

Cardiovascular mortality is a common cause of death in PCa patients [1030,1399,1400]. Several studies showed that ADT after only six months was associated with an increased risk of diabetes mellitus, cardiovascular disease, and myocardial infarction [1401]. The RTOG 92-02 [1402] and 94-08 [1403] trials confirmed an increased cardiovascular risk, unrelated to the duration of ADT and not accompanied by an overall increased cardiovascular mortality. No increase in cardiovascular mortality has been reported in both a secondary analysis of PLCO trial, even among subgroups with pre-existing cardiovascular disease [1404] and a meta-analysis of trials RTOG 8531, 8610, 9202, EORTC 30891 and EORTC 22863 [1405]. However, serious concerns about the conclusions of this meta-analysis have been raised due to poor consideration of bias in the included studies [1406,1407]. A meta-analysis of observational data reports consistent links between ADT and the risk of cardiovascular disease patients treated for PCa, e.g., the associations between LHRH agonists and non-fatal or fatal myocardial infarction or stroke RR: 1.57 (95% CI: 1.26–1.94) and RR: 1.51 (95% CI: 1.24–1.84), respectively [1408]. In an updated meta-analysis on the cardiometabolic effects of ADT, ADT was not associated with metabolic syndrome RR: 1.60 (95% CI: 1.06-2.42), had a lower association with diabetes RR 1.43 (95% CI: 1.28-1.59) as previously reported, and an increased risk of hypertension by 30%, RR 1.30 (95% CI: 1.08-1.55). After adjustment for publication bias ADT was associated with a 25% increased risk for diabetes but was not associated with metabolic syndrome [1409].

An increase in cardiovascular mortality has been reported in patients suffering from previous congestive heart failure or myocardial infarction in a retrospective database analysis [1410] or presenting with a metabolic syndrome [1411]. It has been suggested that antagonists might be associated with less cardiovascular morbidity compared to agonists, but, as yet there is no definite evidence [1320,1412]. In a phase III RCT the use of relugolix, an oral LHRH antagonist, was associated with a reduced risk of major adverse cardiovascular events when compared to leuprolide, an injectable LHRH agonists, at 2.9% vs. 6.2%, respectively, over a follow-up time of 48 weeks (HR 0.46, 95% CI: 0.24–0.88) [1053].

Concerns about LHRH agonists resulted in an FDA warning and consensus paper from the American Heart, Cancer Society and Urological Associations [1029]. Preventive advice includes non-specific measures such as loss of weight, increased exercise, minimising alcohol intake, improved nutrition and smoking cessation [83,1413].

The adverse-effects of different ARTAs (abiraterone, apalutamide, darolutamide, enzalutamide) in the treatment of mCRPC, nmCRPC, and mHSPC were systematically reviewed in a multi-variate network meta-analysis. Here it is suggested that the ARTAs adverse effect profiles do not significantly differ from each other, except that enzalutamide was ranked the most toxic regarding hypertension in mCRPC and nmCRPC, and the most toxic regarding headache across all prostate cancer settings [1414].

8.2.5.6. Fatigue

Fatigue often develops as a side effect of ADT. Regular exercise appears to be the best protective measure. Reporting clinically significant fatigue is associated with severe psychological distress and should prompt screening for anxiety and/or depression [1415]. Anaemia may be a cause of fatigue [1375,1416]. Anaemia requires an aetiological diagnosis (medullar invasion, renal insufficiency, iron deficiency, chronic bleeding) and individualised treatment. Regular blood transfusions may be required in patients with severe anaemia.

8.2.5.7. Neurological side effects

Castration seems also to be associated with an increased risk of stroke [1417], and is suspected to be associated with an increased risk for depression and cognitive decline such as Alzheimer disease [1418].

8.2.5.8. Osteonecrosis during bisphosphonates or denosumab

Bisphosphonates are synthetic pyrophosphate analogs and used in conditions such as malignancy and osteoporosis. Infrequent side effects associated with bisphosphonate use include pyrexia, renal function impairment, hypocalcemia, and avascular osteonecrosis of the jaw. Denosumab is a human monoclonal antibody that is used in the treatment of osteoporosis and bone metastasis [1419,1420]. It acts by inhibiting osteoclast activity, reducing bone resorption, and increasing bone density [1419]. Its highly specific mechanism of action is the inhibition of receptor activator of nuclear factor-kappa B ligand (RANKL). It has been shown to be effective at increasing bone mineral density and decreasing fractures in men with prostate cancer on ADT [1421].

Both drugs are associated with osteonecrosis of the jaw (ONJ) According to the American Society of Bone and Mineral Research, ONJ is described as exposed bone in the maxillofacial region that does not heal within eight weeks of being identified by a healthcare provider in a patient that is currently or has been on bisphosphonates who does not have a history of radiation therapy in the craniofacial region [1422]. The incidence of ONJ is related to the dose and duration of treatment. The risk ranges from greater than 1% at twelve months to 11% after four years of treatment - taking zoledronic acid alone increases the risk of osteonecrosis to 21% after the third year. A SR on denosumab [1423] showed in a total of 8,963 patients with a variety of solid tumours in seven randomised controlled trials (RCTs) that the overall incidence of ONJ in patients with cancer receiving denosumab was 1.7% [95% CI: 0.9–3.1%]. The use of denosumab was associated with a significantly increased risk of ONJ in comparison with bisphosphonates (BPs)/placebo treatment (RR 1.61, 95% CI: 1.05–2.48, P = 0.029). Subgroup analysis based on controlled therapies demonstrated an increased risk of ONJ in denosumab therapy, when compared with BPs (RR 1.48, 95% CI: 0.96–2.29, p = 0.078) or placebo (RR 16.28, 95% CI: 1.68–158.05, p = 0.017). Similar results were observed for prostate cancer (RR 3.358, 95% CI: 1.573–7.166, p = 0.002). Denosumab combined with risk factors such as dental extraction, poor oral hygiene, use of removable apparatus, and chemotherapy may favour the development of ONJ. Therefore, before starting these drugs the patients should undergo a dental examination and maintain good oral hygiene.

8.3. Overall quality of life in men with PCa

Living longer with PCa does not necessarily equate to living well [1342,1344]. There is clear evidence of unmet needs and ongoing support requirements for some individuals and partners after diagnosis and treatment for PCa [1424,1425]. Fear of cancer recurrence and PSA anxiety has a prevalence of 16% and 22%, respectively, across studies [1426]. Combined cognitive- and education-based psychological interventions improve depression, anxiety, and distress [1427]. Cancer impacts on the wider family and cognitive behavioural therapy can help reduce depression, anxiety, and stress in caregivers [1428]. Radical treatment for PCa can negatively impact long-term QoL (e.g., sexual, urinary and bowel dysfunction) as can ADT used in short- or long-term treatment, e.g., sexual problems, fatigue, psychological morbidity, adverse metabolic sequelae and increased cardiovascular and bone fracture risk [1370,1429]. Direct symptoms from advanced or metastatic cancer, e.g., pain, hypercalcaemia, spinal cord compression and pathological fractures, also adversely affect health [1430,1431]. Patients’ QoL including domains such as sexual function, urinary function and bowel function is worse after treatment for PCa compared to non-cancer controls [1432,1433]. A PCa diagnosis commonly results in financial strain both for the individual and their families. This financial toxicity is associated with younger age at diagnosis, black race, low socio-economic status, low educational attainment and living in a rural area. Clinicians should discuss financial strains and signpost to support services so that quality of life and adherence to treatment can be maintained [1434].

As QoL is subjective and can mean different things to different people it can be difficult to measure and compare. Nevertheless, there are some generally common features across virtually all patients. Drawing from these common features, specific tools or PROMs have been developed and validated for men with PCa. These questionnaires assess common issues after PCa diagnosis and treatment and generate scores which reflect the impact on perceptions of HRQoL. During the process of undertaking two dedicated SRs around cancer-specific QoL outcomes in patients with PCa as the foundation for our guideline recommendations, the following validated PROMs were found in our searches (see Table 8.3.1). The tools with the best evidence for psychometric properties and feasibility for use in routine practice and research settings to assess PROMs in patients with localised PCa were EORTC QLQ-C30 and QLQ-PR25. Since EORTC QLQ-C30 is a general module that does not directly assess PCa-specific issues, it should be adopted in conjunction with the QLQ-PR25 module [1435].

Table 8.3.1: PROMs assessing cancer specific quality of life [1435]

8.3.1. Long-term (> twelve months) quality of life outcomes in men with localised disease

8.3.1.1. Men undergoing local treatments

In the updated results of the ProtecT trial [1444] treatment-received analyses revealed different impacts of treatments over six1398042195years. Men remaining on AM experienced gradual declines in sexual and urinary function with age with increases in ED from 35% at baseline to 53% at six1398042195years and nocturia from 20% to 38%. Radical treatment impacts were immediate and continued over six1398042195years. After RP, 95% reported ED persisting for 85% at six1398042195years, after EBRT this was 69% and 74%, respectively (p1398042195<13980421950.001 compared with AM). After RP, 36% reported urinary leakage requiring at least one1398042195pad/day, persisting for 20% at six1398042195years, compared with no change in men receiving EBRT or AM (p1398042195<13980421950.001). Worse bowel function and bother such as bloody stools 6% at six1398042195years and faecal incontinence 10%, was experienced by more men after EBRT than after RP or AM (p1398042195<13980421950.001) with lesser effects after BT. No treatment affected mental or physical QoL. In another paper on the twelve years outcome this trial [1364], it was seen that the generic quality-of-life scores were similar in randomised groups over seven to twelve years, urinary leakage requiring pads occurred in 18-24% of patients In the prostatectomy group over seven to twelve years, compared with 9-11% in the AM group and 3-8% in the radiotherapy group. Erections sufficient for intercourse were reported in 18% at seven years in the prostatectomy group, compared with 30% in the AM and 27% in the radiotherapy groups; all converged to low levels of potency by year twelve. Nocturia (voiding at least twice per night) occurred in 34% in the prostatectomy group compared with 48% in the radiotherapy group and 47% in the AM group at twelve years. Faecal leakage affected 12% in the radiotherapy group compared with 6% in the other groups by year twelve. The AM group experienced gradual age-related declines in sexual and urinary function, avoiding radical treatment effects unless they changed management.

Other observational studies [668,1243,1354,1445-1448] also report findings regarding RP and RT. The Prostate Cancer Outcomes Study (PCOS) studied a cohort of 1,655 men, of whom 1,164 had undergone RP and 491 RT [1354]. The study reported that at five years of follow-up, men who underwent RP had a higher prevalence of urinary incontinence and ED, while men treated with RT had a higher prevalence of bowel dysfunction. However, despite these differences detected at five years, there were no significant differences in the adjusted odds of urinary incontinence, bowel dysfunction or ED between RP and RT at fifteen years. Investigators have reported that although EBRT was associated with a negative effect in bowel function, the difference in bowel domain score was below the threshold for clinical significance twelve months after treatment [1365]. As 81% of patients in the EBRT arm of the study received IMRT, these data suggest that the risk of side effects is reduced with IMRT compared to older 3D-CRT techniques. This is supported by five-year prospective, population-based cohort study where PROMs were compared in men with favourable- and unfavourable-risk localised disease [1447]. In the 1,386 men with favourable risk, comparison between AS and nerve-sparing prostatectomy, EBRT or LDR BT demonstrates that surgery is associated with worse urinary incontinence at five years and sexual dysfunction at three years when compared to AS. External beam RT is associated with changes not clinically different from AS, and LDR BT is associated with worse irritative urinary-, bowel- and sexual symptoms at one year. In 619 men with high-risk localised disease, comparison between non-nerve sparing RP and EBRT with ADT demonstrates that surgery is associated with worse urinary incontinence and sexual function through five years. A SR demonstrates that the risk of post-radiotherapy ED has reduced to a median of 25% at two years with utilisation of IMRT and is now similar to that noted after LDR BT [1449].

A few prospective studies have reported specific long-term urinary functional outcomes after RP and RT even if the studies are not comparative between the two treatment modalities. Considering incontinence and ED after RP the prospective randomised PIVOT trial, comparing RP to observation, reported that 40% of men wore pads, of which 20% wore more than > one pad/day, and an increased rate of ED in the RP group as compared to observation from 70% to approximately 87%, after a median follow-up of 12.7 years [1243]. The corresponding figures from the prospective non-randomised LAPPRO-trial, comparing open- to robot-assisted RP, were 27–29% of the patients reporting urinary incontinence of some degree after eight years and 66–70% reporting ED [1448]. Data on urinary, sexual and bowel function after RT has been reported from the HYPO-RT-PC-trial, a prospective randomised non-inferiority trial comparing ultra-HFX to conventional fractionation RT. In this trial 52–55% of the patients reported urinary problems (RTOG toxicity grade ≥ 1) at five years, of which 4.2–4.7% reported a RTOG grade ≥ 3 urinary morbidity and 7–8% reported moderate-to-severe incontinence at six years. Bowel toxicity of any level (RTOG toxicity grade ≥ 1) was reported in 53–54% of the patients at five years, of which 1.5–1.9% reported a RTOG grade ≥ 3 bowel morbidity, and 66–71% reported to have little or no erection without aids after six years follow-up [668,1446].

8.3.1.2. Guidelines for quality of life in men undergoing local treatments

8.3.2. Improving quality of life in men who have been diagnosed with PCa

8.3.2.1. Men undergoing local treatments

In men with localised disease, nurse-led multi-disciplinary rehabilitation (addressing sexual functioning, cancer worry, relationship issues, depression, managing bowel and urinary function problems) provided positive short-term effects (four months) on sexual function (effect size 0.45) and long-term (twelve months) positive effects on sexual limitation (effect size 0.5) and cancer worry (effect size 0.51) [1450].

Exercise programs during RT combined with ADT result in consistent benefits for cardiovascular fitness (standardised mean difference [SMD], 0.83; 95% CI: 0.31–1.36; p < 0.01) and muscle function (SMD, 1.30; 95% CI: 0.53–2.07; p < 0.01) with a reduction in urinary toxicity (SMD, -0.71; 95% CI: -1.25 to -0.18; p < 0.01) [1451]. In men undergoing AS, twelve weeks of high-intensity interval training may improve cardiovascular fitness and suppress PSA progression [1452].

In men with post-surgical urinary incontinence, conservative management options include pelvic floor muscle training with or without biofeedback, electrical stimulation, extra-corporeal magnetic innervation (ExMI), compression devices (penile clamps), lifestyle changes, or a combination of methods. Uncertainty around the effectiveness and value of these conservative interventions remains [1453]. Surgical interventions including sling and artificial urinary sphincter (AUS) significantly decrease the number of pads used per day and increase the QoL compared with before intervention. The overall cure rate is around 60% and results in improvement in incontinence by about 25% [1454]. Other alternatives, such as the Adjustable Transobturator Male System (ATOMS) and the Adjustable Continence Therapy (proACT) may be an option but seems less efficacious than AUS [1455]. For a more detailed overview of management of urinary incontinence in these men see Chapter 5.6 in the EAU Guidelines for Management of Non-neurogenic Male LUTS [1456].

The use of PDE5 inhibitors in penile rehabilitation has been subject to some debate. A single-centre, double-blind RCT of 100 men undergoing nerve-sparing surgery reported no benefit of nightly sildenafil (50 mg) compared to on-demand use [1457]. However, a multi-centre double-blind RCT (n = 423) in men aged < 68 years, with normal pre-treatment erectile function undergoing either open, conventional or robot-assisted laparoscopic nerve-sparing RP, tadalafil (5 mg) once per day improved participants EPIC sexual domain-scores (least squares mean difference +9.6, 95% CI: 3.1–16.0) when compared to 20 mg ‘on demand’ or placebo at nine months of follow-up, even though the difference vanished after the end of study [1458]. Therefore, based on discordant results, no clear recommendation is possible, even if a trend exists for early use of PDE5 inhibitors after RP for penile rehabilitation [1459]. A detailed discussion can be found in the EAU Sexual and Reproductive Health Guidelines [1460].

In a SR of genitourinary cancers with mostly prostate cancers it is evident that sexual well-being concerns for men and their partners are evident from diagnosis and into survivorship. Both (patient and partners) benefited from interventions but many articulated difficulties with initiating the topic due to embarrassment and limited access to interventions in cancer services [1461].

Testosterone

Regarding supplementation of testosterone there seems to be some hesitation by HCP. Although the evidence is limited, men who are managed expectantly for PCa, or who received radical local therapy, do not have worse outcomes when receiving testosterone supplementation [77]. We therefore advise to not hesitate to give testosterone substitution to symptomatic hypogonadal men with prostate cancer where ADT is not the treatment of choice.

8.3.2.2. Men undergoing systemic treatments

Similar to men treated with a radical approach (see above), in men with T1-T3 disease undergoing RT and ADT, a combined nurse-led psychological support and physiotherapist-led multi-disciplinary rehabilitation has reported improvements in QoL. Specifically, this intervention involved action planning around patients’ needs related to lifestyle changes, weight control, toilet habits, sexuality, and psychological problems. This was complemented with pelvic floor muscle therapy. Improvements in urinary (adjusted mean 4.5, 95% CI: 0.6–8.4), irritative (adjusted mean 5.8, 95% CI: 1.4–10.3) and hormonal (adjusted mean 4.8, 95% CI: 0.8–8.8) EPIC domains were found up to 22 weeks of follow-up [1462]. In a three-year follow-up with 92% response rate from the initial study, fewer participants had moderate-severe bowel problems in the intervention (n = 2; 3%) vs. control group (n = 10; 14%) (p = 0.016) but the benefits in terms of urinary function were maintained only in those participants with moderate-severe urinary problems at baseline [1463].

Providing supervised aerobic and resistance exercise training of a moderate intensity improves EORTC QLQ-C30 role (adjusted mean 15.8, 95% CI: 6.6–24.9) and cognitive domain outcomes (adjusted mean 11.4, 95% CI: 3.3–19.6) as well as symptom scales for fatigue (adjusted mean 11.0, 95% CI: 20.2–1.7), nausea (adjusted mean 4.0, 95% CI: 7.4–0.25), and dyspnoea (adjusted mean 12.4, 95% CI: 22.5–2.3) up to three months in men treated with ADT [1464]. Such interventions have also reported clinically relevant improvements in FACT-P (mean difference 8.9, 95% CI: 3.7–14.2) in men on long-term ADT [1465,1466]. These findings are supported by a SR which reported improvements up to twelve weeks in cancer-specific QoL in a meta-analysis of high-quality trials (SMD 0.33, 95%, CI: 0.08–0.58) [1416]. Supervised exercise interventions delivered over twelve months are effective in reducing psychological distress; particularly in those men with highest levels of baseline anxiety and depression [1467]. In untrained older men, SR suggests lower volume exercise programs at moderate-to-high intensity are as effective as higher volume resistance training for enhancing body composition, functional capacity and muscle strength and may reduce barriers to exercise and enhance adherence [1468].

Another SR and meta-analysis of randomised trials shows that exercise interventions for patients on ADT result in higher lean body mass (mean difference: 0.88, 95% CI 0.4 to 1.36, p < 0.01), a lower body fat mass (mean difference: -0.93, 95% CI: -1.10 to -0.10, p < 0.05), and a lower body fat rate (mean difference:-0.93, 95% CI: -1.39 to -0.47, p < 0.01). Greater efficacy was noted for exercise duration of ≥ six months (vs. < six months) and exercise immediately after starting ADT (vs. delayed exercise) [1469]. A SR and meta-analysis in patients with prostate cancer undergoing ADT, on supervised exercise therapy vs. no therapy shows that supervised exercise therapy is probably superior to no exercise therapy in improving ‘disease-specific quality of life’ 0.43 (95%CI: 0.29, 0.58) and ‘walking performance’ −0.41 (95% CI: −0.60, −0.22) with a moderate certainty of evidence [1470]. A SR and meta-analysis on determining the factors that affect adherence to exercise programs, found that exercise had no effects (p < 0.05) on quality of life and fatigue. For aerobic fitness, and upper- and lower-body strength significant effects (all p < 0.05) were observed. Adherence to exercise-based interventions was 80.38%, with improvements observed in aerobic fitness and strength. Subgroup analysis revealed exercise adherence impacted fatigue and strength, with greater improvements observed in programs > twelve weeks [1471].

If dietary intake is not adequate, vitamin D and calcium supplementation should be offered, as there is evidence that vitamin D and calcium have modest effects on bone in men on ADT [1457]. Online tools are available to calculate daily calcium intake for individual patients. For vitamin D deficiency a dose of at least 800 IU/day colecalciferol can be recommended. Use of a 25(OH) assay may be helpful to measure vitamin D levels [1472,1473].

Anti-resorptive therapy is recommended for men on ADT for > six months with either a BMD T-score of < -2.5 or with an additional risk factor for osteoporosis or annual bone loss confirmed to exceed 5%, or in cases of severe fracture. Referral to a bone specialist should be considered in complex cases with severe fracture and/or multiple risk factors. Alendronate, risedronate, zoledronate and denosumab have all been shown to prevent bone loss in men with hormone-sensitive locally-advanced and metastatic PCa on ADT [1474-1477]. Patients should be warned about the < 5% risk of osteonecrosis of the jaw and/or atypical femoral fractures associated with these drugs. Bisphosphonates increase BMD in the hip and spine by up to 7% in one year [1476,1478]. The optimal regimen for zoledronic acid for men on ADT with hormone-sensitive locally-advanced and metastatic PCa remains unclear: quarterly [1479] or yearly [1480] injections. The question is relevant as the risk of jaw necrosis is both dose- and time-related [1481]. A quarterly regimen should be considered for a BMD ≤ 2.5 as a yearly injection is unlikely to provide sufficient protection [1482,1483]. Care should be taken when discontinuing treatment as rebound increased bone resorption can occur.

In M0 patients, denosumab has been shown to increase the lumbar BMD by 5.6% compared to a 1% decrease in the placebo arm after two years, using 60 mg subcutaneous regimen every six months [1421]. This was associated with a significant decrease in vertebral fracture risk (1.5% vs. 3.9%, p = 0.006). The benefits were similar whatever the age (< or > 70 years), the duration or type of ADT, the initial BMD, the patient’s weight, or the initial BMI. This benefit was not associated with any significant toxicity, e.g., jaw osteonecrosis or delayed healing in vertebral fractures. In M0 patients, with the use of a higher dosage (120 mg every four weeks), a delay in bone metastases of 4.2 months has been shown [1280] without any impact on OS, but with an increase in side effects. Therefore, this later regimen cannot be recommended.

In the SPARTAN phase III study (apalutamide in nmCRPC) [1267], patients receiving apalutamide experienced falls more frequently vs. those receiving placebo (15.6% vs. 9.0%). In the final multivariable model, the baseline patient characteristics of older age, poor ECOG, history of neuropathy, and α-blocker use before study treatment, remained significantly associated with fall. After-baseline clinical characteristics significantly associated with time to fall were development of neuropathy, arthralgia, and weight loss before fall. Preventive interventions should be considered when the identified baseline conditions and post-treatment neuropathy, arthralgia, or weight decrease are present, to reduce risk of fall.

8.3.2.3. Decision regret

Several treatments with curative intent for localised PCa are available all with comparable ten-year OS [489]. They vary in terms of the incidence of major side effects, including urinary symptoms, bowel symptoms and compromised sexual functioning [1364,1365,1484]. For this reason, patients’ treatment preferences, in which they weigh expected benefits against likely side effects, are a central consideration in shared decision-making and in making informed treatment decisions [1485-1487].

It remains challenging, however, to evaluate whether the decision-making process can be viewed as successful; that is, whether the choice of treatment best reflects the patient’s preferences and expectations [1488,1489]. According to Decision Justification Theory (DJT), it is the more specific information on which treatment experiences lead to regret that decision regret needs to be better understood and to minimise it in future patients [1490]. About 25% of men with PCa undergoing either single or combined modality treatments report experiencing worse side effects than expected [1491]. Urinary incontinence most strongly correlates with regret after prostatectomy [1492].

Unmet expectations are comparable among the treatment groups, except for fatigue. Fatigue is less frequently reported as worse than expected by patients who received BT when compared to patients who received RP or EBRT. This could be explained by the less invasive treatment course of BT in comparison to EBRT with or without ADT and RP [1493]. Unmet expectations were more frequently reported by patients with positive surgical margins following surgery; having had a passive role in the decision-making process; and who had higher scores on the decisional conflict scale (i.e., more uncertainty about the treatment decision). Interestingly, positive surgical margins are not directly associated with an increased risk of PC-related mortality [960]. Active participation and support in the process of forming a preference increases the chance of choosing a treatment that is in line with patients’ expectations [1487,1494-1496].

While it may seem desirable to tailor the patients’ role in decision-making to their initial preference, and particularly to a preference for deferring to the advice of the clinician, this does not result in less decisional conflict or regret. Increasing patients’ knowledge regardless of initial preference may actually be preferable [1492].

8.3.2.4. Decision aids in prostate cancer

Shared decision-making can increase patients’ comfort when confronted with management decisions but has been shown to improve health outcome [1497] and more training seems needed for health care professionals guiding patients [1498]. Patient education decreased PSA testing [1499] and increased adherence to AS protocols [1500,1501]. Autonomous active decision-making by patients was associated with less regret after prostatectomy regardless of the method chosen and decision aids reduce decisional conflict [1502]. Still, guidance is needed to optimise patients’ understanding of the options [1503]. Patients prioritised effectiveness and pain control over mode of administration and risk of fatigue when confronted with treatment choice in metastasised PCa [1504]. When implementing decision aids clinical validity and utility should be carefully evaluated and distinguished [1505]. A decision aid should educate as well as promote shared decision-making to optimise efficacy [1506] and pay attention to communicative aspects [1507].

8.3.2.5. Guidelines for quality of life in men undergoing systemic treatments