Prostate Cancer

8. QUALITY OF LIFE OUTCOMES IN PROSTATE CANCER

This chapter is presented in two parts. The first part of this chapter (Section 8.2) summarises long-term consequences (≥ twelve months) of therapies for PCa. Based on two SRs. The second part of this chapter (Section 8.3) provides evidence-based recommendations for supporting patients when selecting primary treatment options for localised disease and 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 [1489,1490]. Approaching care from a holistic perspective requires the intervention of a multidisciplinary 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 [1491]. 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 [1492]. 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-morbidities and belong to higher socio-economic groups. Individuals undergoing two or more treatments have more symptoms and greater impact on QoL [1493,1494]. 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 [1495].

8.2. Adverse effects of PCa therapies

8.2.1. Active surveillance

In an SR [1496] on the long-term (> 5 year) health-related QoL in patients on active surveillance, researchers observed that there were differences in specific functional outcomes between patients on AS and surgery or radiotherapy ≥ five years 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 postoperative 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 [1497]. Regarding anxiety, it was observed 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 [1497].

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 [1498-1501]. The most common postoperative 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) [1502]. The second most commonly occurring complication is long-term incontinence [1498-1501], but voiding difficulties may also occur that are associated with bladder neck contracture (e.g. 1.1% after RALP) [1503].

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 [735-739], and can be compared with contemporaneous reports after RRP [740]. Based on 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 nonrandomised 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) [741,1504]. Further follow-up demonstrates similar functional outcomes with both techniques at 24 months [1504,1505]. A single-centre randomised phase III study comparing RALP and RRP (n = 326) also demonstrates similar functional outcomes with both techniques at 24 months [1506]. Prostatectomy was found to increase the risk of complaints from an inguinal hernia, particularly after an open procedure when compared to minimally invasive approaches [1507,1508]. For those undergoing minimally invasive procedures, port-site hernia has been reported in 0.66% after inserting a 12mm bladeless trocar and can occur more rarely with 8mm and 5mm trocars [1509]. Another complication after primary treatment is lower limb and genital lymphedema. An SR found a prevalence of (0-14%) lower limb and (0-1%) genital lymphedema after radical prostatectomy with PLND [533], 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%) lymphedema is substantially elevated.

8.2.3. Radiotherapy

8.2.3.a. 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 (as described in detail in Section 8.3.1.a) [1510]. Participants in the ProtecT study were treated with 3D-CRT and studies using IMRT demonstrate less bowel toxicity than noted previously with 3D-CRT [1511].

An 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 [1512].

Patient-reported outcomes suggest a temporary drop in the EPIC hormonal and sexual domains when six months of ADT was added to radiotherapy, with a disappearance of any clinical relevant difference at one year [1277,1513].

8.2.3.b. 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%) [1514]. 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 [832,839]. 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.a. Whole-gland treatments

An SR and meta-analysis produced evidence that the rate of urinary incontinence at one year was lower for whole-gland cryotherapy than for RP, but the size of the difference decreased with longer follow-up [853]. No significant difference was seen between cryotherapy versus EBRT in terms of urinary incontinence at one year (< 1%); cryotherapy had a similar ED rate (range 0–40%) to RP at one year. Whole-gland HIFU on the other hand showed lower incontinence rates at one year than RP (OR: 0.06, 95% CI: 0.01–0.48) [853].

8.2.4.b. Focal treatments

Over the past decade, prostate cancer has been detected at an earlier stage, with smaller tumours and with more patients potentially suitable for focal therapy [858-860]. Focal therapy is seeking the optimal balance regarding cancer control and functional outcome. A recent SR included data from 5,827 patients across 72 studies covering various energy sources and found evidence that focal therapy has favourable functional outcomes and minimises adverse events [864]. For focal HIFU and cryotherapy, this SR showed pad-free continence rates above 95% and a median decrease of erectile function of only 12%. An SR with only prospective data found that focal ablation showed only 9% reduction in sexual function scores, compared to 43% for whole-gland ablation at one year [865].

8.2.5. Androgen-deprivation therapy

Quality of life
Androgen-deprivation therapy impacts sexual function, mood, depression, cognitive function, as well as the relationship with the patient’s partner [1515,1516]. A meta-analysis of over 7,500 patients confirmed that ADT significantly impairs QoL, particularly emotional, physical, and cognitive functioning, with greater declines seen after six months of treatment [1517].

A small RCT evaluated the QoL at one-year follow-up in patients with PSA-only relapse after primary therapy without evidence of metastasis, comparing various ADT regimens with 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 [1518]. A meta-analysis confirmed that ADT significantly increases fatigue, with greater severity in non-metastatic disease and during prolonged treatment [1519]. 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 [1520]. An SR and meta-analysis found no consistent objective cognitive decline with ADT, but did observe a significant worsening in subjective cognition during hormone therapy. Narrative findings also suggested more subjective complaints with enzalutamide than with abiraterone [1519]. 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 [1521].

The side effects induced by ADT are non-negligible and tend to increase over time, prompting attempts to treat metastatic PCa patients while keeping intact the gonadal function, i.e. physiologic testosterone level. A pooled analysis from the MARCAP Consortium showed that testosterone recovery after ADT and radiotherapy is highly variable and influenced by age, baseline testosterone, and duration of treatment. While testosterone recovery was not linearly associated with MFS, a non-linear benefit was seen with six-month ADT, suggesting that the optimal effective castration period (including treatment duration and the time to testosterone recovery) was approximately 10–11 months in this analysis [1522]. This should be interpreted as an observational finding specific to this study, rather than a prescriptive recommendation for ADT duration.

Metastasis-directed therapy (MDT) for men with oligometastatic PCa is a strategy to avoid, or at least postpone, the initiation of ADT. The period of ADT-free survival or eugonadal PFS has been applied as the endpoint for several studies and future reports on its correlation with QoL are awaited. Eugonadal PFS may be prolonged by MDT as compared to intermittent hormone treatment alone in men with oligometastatic PCa either at primary diagnosis or after recurrence [1281]. The EORTC-GUCG 1532 study used eugonadal PFS as end-point as well and showed that it can be achieved with an ARPI with similar PSA response as ADT [1523].

The three-armed Embark study in patients with biochemical recurrence randomised to receive enzalutamide daily plus leuprolide every twelve weeks (combination group), placebo plus leuprolide (leuprolide-alone group), or enzalutamide monotherapy (monotherapy group) demonstrated that treatment with enzalutamide without ADT is not without toxicities and less effective than the combination of ADT and enzalutamide [1524]. The choice between the different treatment options will depend on each patient’s preferences after thorough information by the treating physician.

Different types of ADT
An SR and meta-analysis assessed potential benefits of intermittent versus continuous ADT [1525]. Of note, only a minority of patients with less-aggressive PCa are considered eligible for intermittent ADT. The meta-analysis did not reveal an advantage of continuous over intermittent ADT in PCa-specific mortality and did not show a significant reduction in non-PCa mortality of intermittent versus continuous ADT.

In men with metastatic PCa, ADT must be applied continuously and surgical orchiectomy represents a definitive treatment with similar outcomes as compared to LHRH analogues, as demonstrated in an SR of 15 studies comprising nearly 60,000 men on medical ADT as opposed to close to 5,000 men on surgical ADT [1526]. Surgical ADT is considered cost-effective and might prove beneficial for the patient’s well-being, because a retrospective study suggested less reported worry and physical discomfort, better overall health, and a higher likelihood of considering oneself free of cancer than men receiving LHRH agonists continuously. The stage at diagnosis had no effect on health outcomes [1527].

ADT duration reduced the likelihood of testosterone recovery and prolongs the time to recovery significantly. In 1,230 men with localised PCa randomised to RT without ADT or with ADT for 6, 18 or 36 months of normal testosterone was measured in 87% without ADT, 76% after 6 months, 55% after 18 months, and 43% after 36 months of ADT, respectively. Moreover, time to testosterone recovery increased with ADT duration from 0.3, 1.6, 3 and 5 years for the 0-, 6-, 18- or 36-month schedules, respectively [1071]. In general, testosterone recovered faster in otherwise healthy men with a normal baseline testosterone.

The oral LHRH antagonist relugolix achieved a similar castration resistance-free survival (CRFS) as the LHRH agonist leuprolide, with 48-week CRFS rates of 74.3% and 75.3%, respectively [1528]. After cessation of relugolix and leuprolide testosterone, recovery at 48 weeks was achieved by a greater percentage of men (54% vs. 3.2%), as well as more quickly within median 86 versus 112 days for relugolix and leuprolide, respectively.

Balancing risks and benefits
To appropriately balance the risks of PCa and non-PCa mortality, both the PCa tumour aggressiveness and comorbidities of individual patients must be taken into account. The omega score, which is a quantitative measure of the relative risk for cancer-related versus competing mortality events, might assist in assessing these risks when, for example, deciding whether the addition of ADT to RT provides a greater benefit regarding PCa mortality than a threat regarding non-PCa mortality [1529].

In men with metastatic PCa, balancing the intensity of continuous ADT combined with either an ARPI, docetaxel or both is no less challenging. An SR and meta-analysis on the impact of performance status (PS) on oncologic outcomes showed that combination systemic therapies significantly improved OS in patients with worse PS, as well as in those with good PS, while the MFS benefit from ARPI in the nmCRPC setting was more pronounced in patients with good PS than in those with worse PS [1530]. However, because most RCTs are limited to men with PS of either 0 or 1, these findings might not apply to men with PS of ≥ 2.

8.2.5.a. Sexual function

Cessation of sexual activity is very common in people undergoing ADT, affecting up to 93% [1531]. Androgen-deprivation therapy reduces both libido and the ability to gain and maintain erections. The management of acquired ED is mostly non-specific [1532].

Using a specific nonvalidated questionnaire, bicalutamide monotherapy showed a significant advantage over castration in the domains of physical capacity and sexual interest (but not sexual function) at twelve months [1533]. 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 [1534], preserved libido and erectile function [1535].

8.2.5.b. Hot flushes

Hot flushes are a common side effect of ADT (prevalence estimated between 44–80% of men on ADT) [1531]. 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 less effective in reducing hot flushes than hormonal therapies based on a prospective RCT comparing venlafaxine, 75 mg daily, with medroxyprogesterone, 20 mg daily, or cyproterone acetate, 100 mg daily [1536]. 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) [1537].

Considering placebo response rates in up to 30% of patients [1538], prospective RCTs are required to document the efficacy of clonidine, veralipride, gabapentin [1539] and acupuncture [1540].

8.2.5.c. ADT induced bone fractures

ADT leads to increased bone turnover and decreased bone mineral density (BMD) over time, which significantly elevates the risk of fractures. The relative risk of fractures increases by up to 45% with long-term ADT [1541]. Severe fractures in men are associated with increased mortality [1542], underscoring the importance of early identification of high-risk patients and timely preventive measures. A precise evaluation of BMD should be performed by DEXA, ideally before starting long-term ADT. A low baseline BMD (T-score < -2.5 or < -1, with other risk factors) indicates a high risk of t 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 [1543]. Several fracture risk algorithms such as FRAX (Fracture Risk Assessment Tool), OST (osteoporosis self-assessment Tool), ORAI (Osteoporosis Risk Assessment Instrument), OSIRIS (osteoporosis Index of Risk), and SCORE (Osteoporosis Risk Estimation) incorporate BMD and clinical parameters to guide decision-making. However, these tools are not specifically validated in the context of ADT for PCa, and no preferred tool can currently be recommended. Nonetheless, they may still offer indicative value for decision making (see also section 8.3.2.2) [1348,1469,1470]. Obesity (defined as > 10% increase in body fat and/or BMI > 30) and sarcopenia up to 3% reduction in lean tissue mass and weight loss are common during the first year of ADT and contribute to an increased fracture risk [1544-1546].

An SR and meta-analysis of 11 studies involving 11,382 men of which 6,536 received enzalutamide, apalutamide, or darolutamide in combination with ADT (or other enzalutamide-based combinations) and 4,846 controls (placebo, bicalutamide, or abiraterone) showed that adding an ARPI to ADT significantly increases the risk of fractures [1547]. The incidence of non-metastatic fractures was 242 (4%) in the enzalutamide/apalutamide/darolutamide group and 107 (2%) in the control group. The use of enzalutamide, apalutamide or darolutamide was associated with an increased risk of fractures: all-grade fracture (RR, 1.59; 95% CI, 1.35-1.89; p < 0.001), and likely grade 3 fracture or greater (RR, 1.71; 95% CI, 1.12-2.63; p = 0.01).

Bicalutamide monotherapy may have a less pronounced effect on BMD; however, its limited oncological efficacy in M1 disease makes it a poor option in this setting [1548,1549]. The intermittent LHRH agonist modality might be associated with less bone impact [1550].

8.2.5.d. Metabolic effects

Lipid alterations are common and may occur as early as the first three months of ADT [1544]. In addition, ADT 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 [1551], 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. It is defined by the presence of at least three of the following criteria [1552]:

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

The prevalence of a metabolic-like syndrome is higher in men receiving ADT compared with men not receiving ADT [1553]. Androgen-deprivation therapy impairs skeletal muscle health and muscular weakness is a common complaint as early as in the initial months of treatment. Skeletal muscle mass has a strong influence on basal metabolic rate and is in turn heavily influenced by endocrine pathways [1554]. A prospective longitudinal study of 252 men on ADT for a median of 20.4 months reported a progressive decline in lean body mass over time: 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 [1555].

An SR on the impact of ADT on body composition found ADT had a relatively stable effect on BMI but increased sarcopenia and subcutaneous adipose tissue [1545]. Sarcopenia at baseline, found in 27% of 110 men with mCRPC, significantly predicted severe toxicity and ER visits in men initiating ARPI treatment. Sarcopenia was also a predictor of radiographic progression and overall mortality regardless of treatment type [1556].

8.2.5.e. Cardiovascular morbidity

Cardiovascular mortality is a common cause of death in PCa patients [1143,1557,1558]. Several studies showed that even short-term ADT (as early as six months) was associated with an increased risk of diabetes mellitus, cardiovascular disease, and myocardial infarction [1559]. The RTOG 92-02 [1560] and 94-08 [1561] trials confirmed an increased cardiovascular risk, unrelated to the duration of ADT and not accompanied by an overall increased cardiovascular mortality. This was confirmed in the 20-year update of the NRG/RTOG 9202 RCT which found no overall increase in CVM with long-term versus short-term ADT, but a significantly higher rate of fatal myocardial infarctions in men with baseline CVD [1562]. No increase in cardiovascular mortality has been reported in either a secondary analysis of PLCO trial, even among subgroups with pre-existing cardiovascular disease [1563], and in a meta-analysis including the trials RTOG 8531, 8610, 9202, EORTC 30891 and EORTC 22863 [1564]. However, methodological concerns have been raised about this meta-analysis, particularly regarding insufficient adjustment for bias in the included studies [1565,1566]. 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 [1567]. In an updated meta-analysis on cardiometabolic effects of ADT, ADT was not significantly 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 found to be associated with metabolic syndrome [1568].

An increase in cardiovascular mortality has been reported in patients suffering from previous congestive heart failure or myocardial infarction in a retrospective database analysis [1569] or presenting with a metabolic syndrome [1570]. It has been suggested that antagonists might be associated with less CMV compared to agonists, but there is as yet no definite evidence [1571,1572]. 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% versus 6.2%, respectively, over a follow-up time of 48 weeks (HR 0.46, 95% CI: 0.24–0.88) [1160]. An SR, including the above RCT, assessing major cardiovascular events in 11 studies comprising approximately 4,200 patients showed a significantly lower risk (HR 0.57 (95% CI: 0.37-0.86) for the antagonist as compared to various agonists, whereas there was no significant difference in all-cause mortality (HR 0.58, 95% CI: 0.32-1.08) [1573].

Concerns about LHRH agonists resulted in an FDA warning and consensus paper from the American Heart Association, American Cancer Society, and American Urological Association [1142]. Preventive advice includes non-specific measures such as loss of Weight, increased exercise, minimising alcohol intake, improved nutrition and smoking cessation [100,1574].

The adverse events of various ARPI (abiraterone, apalutamide, darolutamide, enzalutamide) in the treatment of mCRPC, nmCRPC and mHSPC were systematically reviewed in a multivariate network meta-analysis. Here, it is suggested that the ARPI adverse effect profiles do not significantly differ from each other, except that enzalutamide was ranked the most toxic with regard to hypertension in mCRPC and nmCRPC, and the most toxic with regard to headache across all PCa settings [1575].

An additional SR and network meta-analysis compared the cardiotoxicity profiles of ARPI across disease states [1576]. Enzalutamide and abiraterone (with prednisone) were associated with higher risks of hypertension, vascular events, and arrhythmias compared to darolutamide, which showed a more favourable cardiovascular safety profile. Bayesian modelling suggested that prior treatment exposure may influence toxicity risk, particularly in men with mCRPC. In men with cardiovascular comorbidities, a darolutamide-based regimen may therefore be preferable. A separate RCT-only meta-analysis of over 22,000 patients confirmed that ARPI significantly increase the risk of cardiovascular events, particularly hypertension (RR 1.69), ischemic heart disease (RR 1.84), and arrhythmias (RR 1.38); although this did not translate into increased cardiac mortality [1577].

8.2.5.f. Fatigue

Fatigue often develops as a side effect of ADT, for which 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 [1578]. Anaemia may be a cause of fatigue [1531,1579]. If present, anaemia requires further evaluation to identify the cause (medullar invasion, renal insufficiency, iron deficiency, chronic bleeding) and treatment should be individualised. Regular blood transfusions may be required in patients with severe anaemia.

8.2.5.g. Neurological side effects

Castration also appears to be associated with an increased risk of stroke [1580], and is suspected to be associated with an increased risk for depression and cognitive decline such as Alzheimer disease [1581].

8.2.6. Osteonecrosis during bisphosphonates or denosumab

Bisphosphonates are synthetic pyrophosphate analogues used in the treatment of conditions such as bone 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 [1582,1583]. It acts by inhibiting osteoclast activity, reducing bone resorption, and increasing bone density [1582]. The highly specific mechanism of action of denosumab is the inhibition of receptor activator of nuclear factor-kappa B ligand (RANKL). Denosumab has been shown to be effective at increasing bone mineral density and decreasing the risk of fractures in men with prostate cancer on ADT [1584].

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 and who does not have a history of radiation therapy in the craniofacial region [1585]. 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. Using zoledronic acid alone increases the risk of osteonecrosis to 21% after the third year. An SR on denosumab [1586] showed that, in a total of 8,963 patients with a variety of solid tumours in seven randomised controlled trials (RCTs), 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). Concomitant risk factors such as dental extraction, poor oral hygiene, use of removable apparatus, and chemotherapy may further increase the risk of ONJ. Therefore, before starting these drugs, 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 [1489,1491]. There is clear evidence of unmet needs and ongoing support requirements for some individuals and partners after diagnosis and treatment for PCa [1587,1588]. Fear of cancer recurrence and PSA anxiety has a prevalence of 16% and 22%, respectively, across studies [1589]. Combined cognitive- and education-based psychological interventions improve depression, anxiety and distress [1590]. Cancer impacts on the wider family and cognitive behavioural therapy can help reduce depression, anxiety and stress in caregivers [1591]. 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 [1516,1592]. Direct symptoms from advanced or metastatic cancer, e.g. pain, hypercalcaemia, spinal cord compression and pathological fractures, also adversely affect health [1593,1594]. Patients’ QoL including domains such as sexual function, urinary function and bowel function is worse after treatment for PCa compared to non-cancer controls [1595,1596]. 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 socioeconomic 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 [1597].

As QoL is subjective and can mean different things to different people and can be difficult to measure and compare. Nevertheless, there are a number of 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 that reflect the impact on perceptions of HRQoL. During the process of undertaking two dedicated SRs relating to cancer-specific QoL outcomes in patients with PCa as the foundation for our Guideline recommendations, several validated PROMs were identified 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. Because 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 [1598].

Table 8.3.1: PROMs assessing cancer-specific quality of life [1598]

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

8.3.1.a. Men undergoing local treatments

In the updated results of the ProtecT trial [1607], treatment-received analyses revealed different impacts of treatments over six years. 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 six years and nocturia from 20% to 38%. Radical treatment impacts were immediate and continued over six years. After RP, 95% reported ED persisting for 85% at six years, while after EBRT this was 69% and 74%, respectively (p < 0.001 compared with AM). After RP, 36% reported urinary leakage requiring at least one pad/day, persisting for 20% at six years, compared with no change in men receiving EBRT or AM (p < 0.001). Worse bowel function and bother such as bloody stools (6% at six years) and faecal incontinence (10%) was experienced by more men after EBRT than after RP or AM (p < 0.001), with pronounced effects following BT. No treatment affected mental or physical QoL. Another paper on the twelve-year outcome of this trial [1510] showed that the generic quality-of-life scores were similar in randomised groups over seven to twelve years, and 18-24% of patients experienced urinary leakage requiring pads 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. The PACE-A Trial randomised 123 patients over 10 years to prostatectomy or SBRT [1608]. At 24 months, only 32 patients in the surgery group and 46 of the RT group were available for analysis. Each group has one patient with more than one security pad per day. In summary, the authors show an equal urinary bother score, with more imitative symptoms and bowel symptoms for SBRT. The overall sexual function is better in the SBRT group. However, this study showed a differential dropout with only 50% patients of the surgery group in the final readout - an extremely show recruitment and an unmet target size.

Other observational studies [785,1448,1501,1609-1612] also report findings regarding RP and RT. The Prostate Cancer Outcomes Study (PCOS) looked at a cohort of 1,655 men, of whom 1,164 had undergone RP and 491 RT [1501]. 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 [1511]. 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 a five-year prospective, population-based cohort study in which PROMs were compared in men with favourable and unfavourable risk localised disease [1611]. 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. An 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 [1613].

A number of 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, 20% of whom 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 [1448]. The corresponding figures from the prospective non-randomised LAPPRO-trial, comparing open to robot-assisted RP, showed 27–29% of the patients reporting urinary incontinence of some degree after eight years and 66–70% reporting ED [1612]. Data on urinary, sexual and bowel function after RT has been reported from the HYPO-RT-PC trial, a prospective randomised noninferiority 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, 1.5–1.9% of whom reported an RTOG grade ≥ 3 bowel morbidity, and 66–71% reported having little or no erection without aids after six-year follow-up [785,1610].

8.3.1.b. Recommendations 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.a. Men undergoing local treatments

In men with localised disease, nurse-led multidisciplinary rehabilitation (addressing sexual functioning, cancer worry, relationship issues, depression, and 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) [1614].

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) [1615]. In men undergoing AS, twelve weeks of high-intensity interval training may improve cardiovascular fitness and suppress PSA progression [1616].

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 relating to the effectiveness and value of these conservative interventions remains [1617]. 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 approximately 60% and results in improvement in incontinence by approximately 25% [1618]. Other alternatives, such as the Adjustable Transobturator Male System (ATOMS) and the Adjustable Continence Therapy (proACT) may be an option, but appear to be less efficacious than AUS [1619]. 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 [1620].

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 [1621]. However, a multicentre double-blind RCT (n = 423) in men aged < 68 years, with normal pretreatment 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) as compared to 20mg ‘on demand’ or placebo at nine months of follow-up, even though the difference vanished after the end of study [1622]. 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 [1623]. A detailed discussion can be found in the EAU Sexual and Reproductive Health Guidelines [1624].

An SR of genitourinary cancers with mostly prostate cancers makes it evident that sexual well-being concerns for men and their partners are evident from diagnosis and into survivorship. Both patients and partners benefited from interventions but many articulated difficulties with initiating the topic due to embarrassment and limited access to interventions in cancer services [1625].

Testosterone supplementation

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 [93]. The panel currently see no contraindication to give testosterone substitution to symptomatic hypogonadal men with prostate cancer where ADT is not the treatment of choice.

8.3.2.b. Men undergoing systemic treatments

Similar to men treated with a radical approach, in men with T1-T3 disease undergoing RT and ADT, a combined nurse-led psychological support and physiotherapist-led multidisciplinary rehabilitation programme has reported improvements in QoL. Specifically, this intervention involved action planning concerning 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 [1626]. In a three-year follow-up with 92% response rate from the initial study, fewer participants had moderate-to-severe bowel problems in the intervention (n = 2; 3%) versus the 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 [1627].

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 [1628]. 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 [1629,1630]. These findings are supported by a SR that 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) [1579]. A meta-analysis including 34 studies and 2,741 men confirmed that supervised exercise significantly improves fatigue (SMD –0.32), cancer-specific QoL (SMD 0.24), and muscular strength, with the greatest effects seen in combined aerobic and resistance training [1631]. No relevant adverse effects were reported, and training adherence was high Supervised exercise interventions delivered over twelve months are effective in reducing psychological distress, particularly in those men with the highest levels of baseline anxiety and depression [1632]. In untrained older men, the SR suggests that 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 [1633].

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 (versus < six months) and exercise immediately after starting ADT (versus delayed exercise) [1634]. An SR and meta-analysis in patients with prostate cancer undergoing ADT, on supervised exercise therapy versus no therapy shows that supervised exercise therapy is likely 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 [1635]. An SR and meta-analysis focussed 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. Significant effects (all p < 0.05) were observed for aerobic fitness and upper- and lower-body strength. 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 > 12 weeks [1636]. In a prospective randomised trial in frail patients with mCRPC or mHSPC (n = 52), starting enzalutamide at 120mg once daily, instead of the standard 160mg, was associated with significantly less fatigue at 24 weeks (mean difference in FACIT-Fatigue: 6.2; 95% CI: 1.4–11.0) and stable self-reported cognitive function and depressive symptoms, without evidence of reduced PSA response, PFS or OS [1637]. These findings suggest that reduced starting doses of ARSIs may help mitigate treatment-related QoL deterioration in frail patients.

If dietary intake is inadequate, vitamin D and calcium supplementation should be offered, because there is evidence that vitamin D and calcium have modest effects on bone in men on ADT [1621]. 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. The use of a 25(OH) assay may be helpful to measure vitamin D levels [1638,1639].

Antiresorptive 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 [1640-1643]. Patients should be warned about the < 5% risk of osteonecrosis of the jaw and/or atypical femoral fractures associated with these drugs. Therefore before starting these drugs the patients should undergo a dental examination and maintain good oral hygiene. Bisphosphonates increase BMD in the hip and spine by up to 7% in one year [1642,1644]. The optimal regimen for zoledronic acid for men on ADT with hormone-sensitive locally advanced and metastatic PCa remains unclear: quarterly [1645] or yearly [1646] injections. The question is relevant as the risk of jaw necrosis is both dose- and time-related [1647]. A quarterly regimen should be considered for a BMD ≤ 2.5 as a yearly injection is unlikely to provide sufficient protection [1648,1649]. Care should be taken when discontinuing treatment because rebound increased bone resorption can occur. A prospective sub-study of the phase III PEACE-1 trial assessed BMD over 24 months in men with de novo mCSPC treated with ADT and docetaxel, with or without abiraterone acetate plus prednisone (AAP) [1650]. Bone loss was observed in both arms, but the addition of AAP did not significantly accelerate BMD decline. Osteoporosis was more frequent in the AAP arm (21% vs. 15%), and all reported fractures (n = 4) occurred in this group, although numbers were small and follow-up limited.

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 60mg subcutaneous regimen every six months [1584]. 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 (120mg every four weeks), a delay in bone metastases of 4.2 months has been shown [1426] without any impact on OS, but with an increase in side effects. Therefore, this higher dose regimen is not recommended.

In the SPARTAN phase III study (apalutamide in nmCRPC) [1651], patients receiving apalutamide experienced falls more frequently versus 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. To reduce risk of fall, preventive interventions should be considered when the identified baseline conditions and post-treatment neuropathy, arthralgia or weight decrease are present.

8.3.2.c. Decision regret

Several treatments with curative intent for localised PCa are available all with comparable ten-year OS [612]. The treatments vary in terms of the incidence of major side effects, including urinary symptoms, bowel symptoms and compromised sexual functioning [1510,1511,1652]. 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 [1653-1655].

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 [1656,1657]. According to Decision Justification Theory (DJT), two main components of decision-related regret exist. One is associated with the (comparative) evaluation of the outcome and the second with the feeling of self-blame for having made a poor choice [1658]. Approximately 25% of men with PCa undergoing either single- or combined-modality treatments report experiencing worse side effects than expected [1659]. Urinary incontinence most strongly correlates with regret after prostatectomy [1660].

With the exception of fatigue, unmet expectations are comparable among the treatment groups. 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 [1661]. 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 [1061]. 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 [1655,1662-1664].

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 in fact be preferable [1660].

8.3.2.d. 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 [1665] and additional training appears to be needed for healthcare professionals guiding patients [1666]. Patient education decreased PSA testing [1667] and increased adherence to AS protocols [1668,1669]. Autonomous active decision-making by patients was associated with less regret after prostatectomy regardless of the method chosen, and decision aids reduce decisional conflict [1670]. Still, guidance is needed to optimise patients’ understanding of the options [1671]. Patients prioritised effectiveness and pain control over mode of administration and risk of fatigue when presented with treatment choice in metastasised PCa [1672]. When implementing decision aids, clinical validity and utility should be carefully evaluated and distinguished [1673]. A decision aid should educate as well as promote shared decision-making to optimise efficacy [1674]. Also bear in mind communicative aspects [1675].

8.3.2.e. Recommendations for quality of life in men undergoing systemic treatments