incidence and mortality
The crude annual incidence of prostate cancer in the European Union is 78.9/100 000 men. It is the most common cancer in men. The mortality in the EU is 30.6/100 000 men/year [II, C]. Though the incidence and survival rates vary widely between different EU States, mortality rates are similar [II, C].
Subclinical prostate cancer is common in men >50 years [II, A]. Population-based screening of healthy men between 55 and 69 years old reduces prostate cancer mortality by an estimated 20 % using prostate-specific antigen (PSA) testing. Screening increases the prostate cancer incidence and leads to diagnosis of asymptomatic cancers that will not emerge during life. The European screening trial suggests an absolute reduction in prostate cancer mortality of 0.71 deaths per 1000 men after a median follow-up of 9 years, but at the cost of 48 additional radical treatments per life saved. There was no reduction in overall mortality. Decisions on population screening await longer follow-up and the results of analyses of cost-effectiveness and quality of life [I, B].
Serum PSA should be measured and digital rectal examination (DRE) performed in appropriately counselled patients in whom there is clinical suspicion of prostate cancer or in those who wish to be screened.
The decision whether or not to have a prostate biopsy should be made in the light of PSA parameters such as free PSA, PSA velocity and PSA density, DRE findings, prostate size, ethnicity, age, comorbidities, patient values and history of previous biopsy [II, B]. Prostate biopsy should be performed under antibiotic cover with transrectal ultrasound (TRUS) guidance, and a minimum of eight cores obtained [III, A]. The extent of involvement of each core and the commonest and the worst Gleason grades should be reported [IV].
staging and risk assessment
General health and co-morbidities should be assessed. Patients who are not considered suitable for treatment with curative intent by virtue of poor general health do not normally require staging investigations [V]. Clinical T stage should be evaluated by DRE, supplemented when clinically relevant by ultrasound/MRI.
Clinically localized prostate cancer should be categorized as low, intermediate or high risk, where low risk equals all of T1–2a, Gleason <7, PSA <10; high risk equals any of T3–4, Gleason >7, PSA >20 and intermediate risk equals the remainder. Other prognostic nomograms may help to inform patient choice [III, A].
Low-risk. Imaging tests are not routinely recommended for men with low-risk disease. Within the low-risk category, higher percentage positive cores, length of involvement of any core, PSA density and lower free/total PSA ratio are associated with the risk of understaging compared with findings after prostatectomy [III, B].
Intermediate-risk. Bone scintigraphy should be considered if bone metastases are suspected clinically, if the Gleason score is ≥4 + 3 or serum PSA is ≥15 mg/l. The role of pelvic imaging with CT or MRI is not well established in intermediate-risk disease [III, B].
High-risk. CT/MRI of the pelvis should be considered and bone scintigraphy should be performed [III, B].
There is no consensus as to what constitutes optimum management. Patients should be informed of the potential benefits and harms of the different options. Given the range of treatment options and their side-effects, men should have the opportunity to consult with both a surgical oncologist and a radiation oncologist. Men should be warned that treatment for prostate cancer may cause sexual dysfunction, infertility and incontinence. External beam radiotherapy should be based on conformal techniques. Cryotherapy, HIFU and focal therapy are not recommended as standard initial treatment, but rather are regarded as options in current development [II, C].
low-risk group. Options include active surveillance, radical prostatectomy, external beam radiotherapy, brachytherapy with permanent implants or high dose rate brachytherapy with temporary implants. Immediate hormone therapy alone is not recommended. Watchful waiting with delayed hormone therapy in the event of symptomatic progression is an option for men who are not suitable for, or unwilling to have, radical treatment. There are no completed randomized controlled trials comparing these options within the context of low-risk disease. Prospective, non-randomized studies have described the morbidity associated with each treatment option, and may be used as a guide to decision making. Ten-year prostate cancer specific survival approaches 100% for each management option, including active surveillance for selected patient groups [III, A].
intermediate-risk group. Options include radical prostatectomy, external beam radiotherapy and brachytherapy with permanent implants. Immediate hormone therapy alone is not recommended. Watchful waiting with delayed hormone therapy is an option for men who are not suitable for, or unwilling to have, radical treatment [III, A].
The Scandinavian Prostate Cancer Group (SPCG) Study 4 is the only randomized controlled trial comparing radical prostatectomy versus watchful waiting. Eligible patients were <75 years, had newly diagnosed clinically localized prostate cancer, with a negative bone scan, a PSA of <50 ng/ml and a life expectancy of ≥10 years. They were recruited in Scandinavia during the early 1990s, at a time when PSA testing was not routinely performed, and the results may not be applicable to screen-detected cancers. Many of the 695 patients had high-risk disease, with 18% having a PSA of >20 ng/ml and 13% a Gleason score of 8–10. With 11 years median follow-up, 137 men in the surgery group and 156 in the watchful waiting group had died (P = 0.09). The actuarial risk of death from prostate cancer at 12 years was 12.5% for surgery compared with 17.9% for watchful waiting (P = 0.03). Put another way, the number needed to treat (NNT) to avoid one death from prostate cancer was 18.5. This beneficial impact of surgery on prostate cancer mortality was restricted to men aged ≤65 years. Radical prostatectomy increased the rate of erectile dysfunction by 35% (80% versus 45%), and urinary leakage by 28% (49% versus 21%), in comparison with watchful waiting, but these toxicity rates may not be generalizable to high-volume surgical centres and did not appear to lead to a worse overall quality of life compared with the watchful waiting group.
high-risk or locally advanced group. Options include radical prostatectomy or external beam radiotherapy plus (neo)adjuvant treatment. Immediate hormone therapy alone is not recommended. Watchful waiting with delayed hormone therapy is an option for men who are not suitable for, or unwilling to have, radical treatment. The case for local treatment of men with locally advanced disease is based on a single randomized controlled trial, the SPCG-7 trial, in which 875 men (T2–3; PSA<70; N0 M0) received 3 months of combined androgen blockade (CAB) followed by flutamide monotherapy, and were randomized whether or not to receive radical radiotherapy to the prostate. There was a beneficial impact of radical radiotherapy in terms of cause-specific (11.9% compared with 23.9%; P < 0.001), and overall mortality (29.6% versus 39.4%; P = 0.004) [I, B].
neoadjuvant and adjuvant treatment
Neoadjuvant luteinizing hormone-releasing hormone agonist (LHRHa) therapy for 3–6 months is recommended for men receiving radical radiotherapy for high-risk disease, and should be considered for men with intermediate-risk disease [I, A].
In TROG 96-01, 818 men with locally advanced prostate cancer were randomly assigned to radiotherapy alone, radiotherapy plus 3 months neoadjuvant and concurrent CAB or radiotherapy plus 6 months CAB. The 5-year biochemical disease-free survival was 38% (95% CI 32–44) with radiotherapy alone, 52% (95% CI 45–58) with 3 months CAB and 56% (95% CI 50–63) with 6 months CAB. Compared with radiotherapy alone, the use of 6 months hormone therapy significantly improved prostate cancer specific survival [hazard ratio (HR) 0.56; 95% CI 0.32–0.98; P = 0.04] from 91% to 94% at 5 years. In the RTOG trial 86-10, 456 patients with T2–4 disease received CAB for 2 months before and during radiotherapy, or radiotherapy alone. There was a statistically significant improvement in 10-year prostate cancer specific mortality (23% versus 36%; P = 0.01) with the addition of CAB.
Adjuvant hormonal therapy for 2–3 years is recommended for men receiving neoadjuvant hormonal therapy and radical radiotherapy who are at high risk of prostate cancer mortality [I, A].
In RTOG 9202, 1554 patients received 4 months neoadjuvant and concurrent CAB plus radical radiotherapy and were randomized to receive an additional 2 years of adjuvant androgen deprivation or not. In an unplanned subgroup analysis, the addition of adjuvant therapy improved overall survival in those with Gleason score 8–10 (81.0% compared with 70.7%; P = 0.044). The EORTC 22961 trial randomized 970 men between 6 months and 36 months of androgen deprivation in addition to radical radiotherapy. The 5-year overall mortality for short-term and long-term suppression was 19.0% and 15.2%, respectively.
Bicalutamide 150 mg daily is an alternative to LHRHa therapy in men who place a high value on retaining sexual function during treatment. Men starting long-term (>6 months) bicalutamide should consider prophylactic radiotherapy to both breast buds within the first month of treatment (e.g. with a single fraction of 8 Gy using orthovoltage or electron beam radiotherapy) [I, B].
Men starting LHRHa therapy should be informed that regular exercise reduces fatigue and improves quality of life [II, B].
Immediate postoperative radiotherapy after radical prostatectomy is not routinely recommended. Adjuvant hormone therapy after radical prostatectomy is not recommended [I, A].
Three randomized trials have compared postoperative radiotherapy with observation after radical prostatectomy: EORTC 22911, SWOG 8794 and ARO 96-02. Each trial has shown an advantage to postoperative radiotherapy in terms of PSA failure, but long-term outcomes are only available for the SWOG trial, which included 425 men with pT3 disease. Overall survival was improved with adjuvant radiation (HR 0.72; 95% CI 0.55–0.96; P = 0.023). However, of the 211 patients randomized to observation, only 70 (33%) received salvage radiotherapy at any time. So SWOG 8794 was, to a large extent, comparing a curative approach (adjuvant radiotherapy) versus a palliative approach (delayed hormone therapy). It should not be assumed that the survival advantage for adjuvant radiotherapy will also apply to men who would otherwise be monitored using a sensitive PSA assay, with early salvage radiotherapy in the event of a rising PSA.
Radiotherapy to the prostate bed has a risk of adverse effects on urinary, bowel and sexual function. For example, the SWOG 8794 trial reported urethral strictures in 17.8% of men randomized to adjuvant radiotherapy versus 9.5% in those randomized to observation (RR 1.9; 95% CI 1.1–3.1; P = 0.02). Total urinary incontinence was seen in 6.5% versus 2.8% (RR 2.3; 95% CI 0.9–5.9; P = 0.11) and rectal complications in 3.3% versus 0% (P = 0.02).
treatment of relapse after radical therapy
Following radical prostatectomy patients should have their serum PSA level monitored using a sensitive PSA assay, with salvage radiotherapy to the prostate bed recommended in the event of PSA failure [II, B].
There are no randomized trials comparing salvage radiotherapy versus observation in men with PSA failure after radical prostatectomy. A retrospective analysis of men with PSA failure after surgery compared the long-term outcome of those managed by observation (n = 397), with that of those managed by salvage radiotherapy (n = 160). There were 116 deaths from prostate cancer for analysis. Salvage radiotherapy was associated with a significant reduction in prostate cancer mortality [HR 0.32; 95% CI 0.19–0.54; P < 0.001]. The reduction in prostate cancer mortality associated with salvage radiotherapy was greatest in men with a PSA doubling time of <6 months.
Biopsy of the prostatic bed should not be performed in men with prostate cancer who have had a radical prostatectomy [V].
Biopsy of the prostate after radiotherapy should only be performed in men with prostate cancer who are being considered for salvage local therapy (e.g. HIFU, cryotherapy, salvage surgery) [V].
Hormonal therapy is not routinely recommended for men with prostate cancer who have a biochemical relapse unless they have:
symptomatic local disease progression; or
proven metastases; or
PSA doubling time of <3 months [III, A].
follow-up after radical therapy
Routine DRE is not recommended while the PSA remains at baseline levels [III, B].
Men presenting with symptoms consistent with radiation-induced enteropathy should be fully investigated, including flexible sigmoidoscopy, in order to exclude inflammatory bowel disease or colorectal malignancy [V].
Androgen suppression using bilateral orchiectomy or an LHRHa should be first-line treatment. Short-course anti-androgen should be used to prevent disease flare on starting an LHRHa. The recently developed LHRH antagonists appear to offer equivalent testosterone reduction without the need for an anti-androgen to control transient testosterone surge. Mature results are awaited of intermittent hormone therapy approaches though early results suggest equivalence with contiuous hormone ablation. Patients with castration-refractory disease should have continued androgen suppression [I, A].
A number of trials have examined maximal androgen blockade based on the addition of anti-androgens to LHRHa therapy (or orchiectomy). In a meta-analysis of 27 trials, the 5-year survival was 25.4% with maximal androgen blockade compared with 23.6% for androgen deprivation alone (P = 0.11). However, an analysis of trials combining a non steroidal anti-androgen with androgen deprivation suggested a small survival advantage (27.6% versus 24.7%; P = 0.005). A larger difference was found with earlier trials when LHRH delivery may have been less reliable and a more recent large trial comparing orchiectomy with orchiectomy + flutamide did not demonstrate any benefit of the maximal androgen blockade but did show inferior quality of life. Considering the possible minimal survival benefit together with the cost and toxicity of the additional anti-androgen, first-line hormonal management of prostate cancer should be based on androgen deprivation.
Patients with castration-refractory disease should receive second-line (e.g. anti-androgen), third-line (e.g. corticosteroid) and be considered for fourth-line hormonal therapy (e.g. oestrogen or ketoconazole) [II, C].
The anti-androgen flutamide has been investigated in castration-resistant metastatic prostate cancer and leads to objective responses in ∼15% of patients but with no survival benefit.
Low-dose corticosteroids decrease adrenal function including production of androgens and either prednisone or dexamethasone can be used in CRPC with responses in approximately one-third of cases.
Oestrogens can also lead to responses in 20%–40% of patients who have failed hormone deprivation though side-effects including gastrointestinal irritation, fluid retention and venous thrombosis are not uncommon.
In those that have responded to the addition of anti-androgen, there can be a further response to withdrawal of the anti-androgen.
Docetaxel using a 3-weekly schedule should be considered for symptomatic, castration-refractory disease.
There may be an initial PSA rise in some patients responding to chemotherapy. The best level of PSA response to use as a surrogate endpoint for survival gain is controversial. Mitoxantrone can be considered if there is a contraindication to docetaxel, but is inferior in palliation and does not prolong survival [I, B].
In a large international multicentre stage III trial (TAX327), two different schedules of docetaxel were compared with a combination of mitoxantrone and prednisolone. One thousand and six patients were recruited and randomized between weekly docetaxel at 30 mg/m2 for 5 weeks out of every 6, 75 mg/m2 with docetaxel every 3 weeks and mitoxantrone 12 mg/m2 every 3 weeks. Patients in all arms of the trial received prednisone. Median survival was 19.2 months in the 3-weekly docetaxel arm, 17.8 months in the weekly docetaxel arm and 16.3 months after mitoxantrone. Just under one-quarter treated with docetaxel had a significant improvement in quality of life. Almost half of the patients treated with docetaxel had a 50% decrease in PSA. The side-effects of docetaxel chemotherapy included grade III–IV neutropenia in 32% of patients treated with 3-weekly docetaxel but in only 1.5% of those treated with weekly docetaxel. Other side-effects included fatigue, alopecia, diarrhoea, neuropathy, peripheral oedema and male dystrophy. The conclusion was that 3-weekly docetaxel was superior to the other treatments in its palliative effects and in prolongation of survival. Docetaxel with estramustine is also an effective regimen but appears to be more toxic.
External beam radiotherapy should be offered for patients with painful bone metastases from castration-refractory disease (1 × 8 Gy has equal pain-reducing efficacy to multifraction schedules) [I, A].
A prospective randomized trial in 288 patients with painful bone metastases showed no benefit in either speed of onset or in duration of pain relief from 30 Gy in 10 fractions compared with 8 Gy in a single fraction. This has been confirmed in a number of trials and in systematic review.
Radioisotope therapy with strontium-89 or samarium-153 should be considered for patients with painful bone metastases from castration-refractory disease [I, B].
A single treatment with strontium-89 is more effective than placebo in reducing pain due to bone metastases from castration-refractory prostate cancer. A Canadian trial analysed 126 men who had received external beam radiotherapy to palliate bone metastases, and showed that strontium prolonged time to further bone pain. Samarium-153 has also been studied in randomized trials that included patients with prostate cancer.
Intravenous bisphosphonates should be considered for patients with bone pain resistant to palliative radiotherapy and conventional analgesics [I, B].
Saad et al. reported a prospective randomized three-arm trial in patients with castration-refractory metastatic prostate cancer which compared zoledronic acid at 4 mg iv every 3 weeks, 8 mg iv every 3 weeks or placebo. Patients continued with hormone deprivation therapy or other anticancer therapies as indicated. There were >200 men in each arm of the study. The primary endpoint was a skeletal-related event (SRE) such as pathological fracture, spinal cord compression, surgery or radiotherapy for bone pain or a change in anticancer treatment for bone pain. The higher dose of zoledronic acid caused renal damage and during the study those randomized to the 8 mg dosage had dose reduction to 4 mg. At 15 months, there were fewer SREs in men originally randomized to the 4 mg dosage than in those randomized to placebo (33% versus 44%; P = 0.02). However, the difference between those randomized to zoledronic acid at 8 mg and placebo was not significant and there were no differences in disease progression, performance status or quality of life scores among the groups. Thus the use of zoledronic acid in this patient population must be judged by balancing this modest level of benefit with the risk of toxicity. Toxicities of bisphosphonates include anaemia, fever, oedema, fatigue and myalgia and also include jaw necrosis.
MRI of the spine to detect subclinical cord compression should be considered in men with castration-refractory prostate cancer with vertebral metastases and back pain [III, B].
Spinal cord compression is a devastating complication of metastatic prostate cancer and early detection is critical for successful management. A retrospective analysis of patients with metastatic prostate cancer and no symptoms or signs of spinal compression showed that MRI was able to identify cord compression in 16% and radiological evidence of spinal cord compromise in a further 11%.
Levels of Evidence [I–V] and Grades of Recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the expert authors and the ESMO faculty.
This work was undertaken in The Royal Marsden NHS Foundation Trust which received a proportion of its funding from the NHS Executive; we acknowledge NHS funding to the NIHR Biomedical Research Centre. The views expressed in this publication are those of the authors and not necessarily those of the NHS Executive. This work was supported by the Institute of Cancer Research (ICR), and Cancer Research UK [CUK] grant number C46/A3970 to the ICR Section of Radiotherapy.