Management of Localised Prostate Cancer

Prostate cancer is the commonest cancer in men, with over 27,000 new cases diagnosed each year in the UK. Here we review the management of men with the early (localised) form of the disease.

Diagnosis

Localised carcinoma of the prostate (i.e. disease confined to the prostate gland) is usually diagnosed in a symptomatic men undergoing screening with a prostate specific antigen (PSA) test; in men undergoing investigation of lower urinary tract symptoms (which are usually due to benign prostatic hyperplasia rather than prostate cancer); or by histological diagnosis following transurethral resection of the prostate (TURP) for presumed benign disease.

The value of PSA testing in a symptomatic men is unclear. It can detect early disease, but many of such cancers would not cause clinical problems if left untreated. For example, estimates suggest that, using a PSA screening cut-off concentration of 4ng/mL or more, 13% of men with cancer will be missed but go on to present with the cancer in the next 4 years. And of the men identified with cancer by screening, a proportion will never develop clinically significant disease.

In men undergoing investigation for lower urinary tract symptoms, diagnosis of prostate cancer is made by digital rectal examination, PSA tests and prostate biopsy. How-ever, the palpation of an abnormal-feeling prostate does not necessarily signify malignancy. Also, the PSA rest does not clearly differentiate men who do and do not have prostate cancer. For example, in a study involving 300 symptomatic men aged at least 50 years, prostate biopsy revealed cancers in around 11% of those with a PSA concentration of up to 4ng/mL, in around 26% with a concentration of 4.1-l0ng/mL, and in around 64 with a concentration of l0ng/mL or more. Men with an abnormal digital rectal examination and a PSA above 4ng/mL are usually offered a biopsy of the gland under transrectal ultrasound guidance.

Histology and Tumour Staging

The histological characteristics of prostate cancer are described using the Gleason score (potential score 2-10). Gleason scores of up to 4 represent well-differentiated tumours, 5-7 moderately differentiated, and 8-10 poorly differentiated (and the poorer the differentiation, the worse the prognosis). Where radical treatment is being considered, accurate imaging using MRI, or lymph node staging by open or laparoscopic lymphadenectomy, are useful to assess the extent of apparently localised prostate cancer, in order to exclude nodal involvement.6 Bony metastases are unlikely if the PSA concentration is below l0ng/mL and the Gleason score is below 8, but are common among men with bone pain and a PSA concentration over 20ng/mL, and can be detected by radionuclide bone scanning.

Options for Localised Prostate Cancer

If prostate cancer is confined to the gland, the therapeutic options are conservative management (either 'watchful waiting' or 'active surveillance') or potentially curative radical treatment (radical prostatectomy, external beam radio-therapy, brachytherapy, hormone therapy, or combinations of these treatments). However, there is a lack of high-quality published evidence comparing different treatments in patients with localised disease, with data being limited largely to case series and retrospective observational studies.

Another difficulty in assessing the effectiveness of these options is that key published trials of radical treatment have predominantly included patients with locally advanced cancer rather than just those with localised disease; but, despite this, the results have often been extrapolated to this latter group. For example, randomised trials have shown increased cancer-specific survival for patients with locally advanced prostate cancer treated with hormone therapy plus radiotherapy, compared with radiotherapy alone; and, as a result, patients with localised disease are being treated with similar regimens in clinical practice.

Conservative Management

Watchful Waiting

Watchful waiting means giving the patient no treatment while he remains a symptomatic, but monitoring him (e.g. every 6-12 months) for onset of symptoms of metastases, particularly bone pain. Palliative hormonal therapy is offered to patients who develop significant symptoms; curative treatment is not the intention in this group. Watchful waiting is often a reasonable option fur older men with significant co-morbidities, limited life expectancy and well-differentiated prostate cancer. This is because such patients may he much more likely to die with, rather than from, their cancer. For example, in a retrospective cohort study, men aged 70-74 years who presented with symptoms and were subsequently diagnosed with well-differentiated prostate cancer had a 15-year risk of dying from the disease of 7% compared with a 73% risk of dying from other causes.

These specific data may not necessarily hold for current patients because the study was small and some men were treated with hormones alone from the time of diagnosis, unlike in current practice. Also, while it can be reasonably assumed that men with a well-differentiated cancer remain much more likely to die from causes other than the cancer itself, there have been falls in both the prostate cancer-specific mortality rate (due to the earlier stages of cancers now diagnosed using PSA testing) and mortality from other causes (due to general increases in life expectancy).

Active Surveillance

Active surveillance involves regular clinical review (e.g. 3-monthly) with PSA measurement and digital rectal examination. If the PSA concentration rises repeatedly within a year, the patient can be offered radical treatment while the disease is still potentially curable. Active surveillance aims to limit the number of men for whom the morbidity of treatment could outweigh any potential benefit.

Radical Management

Compared with men with lower Gleason scores, those with an initial score above 4 who are managed conservatively are at significantly and progressively higher risk of dying from prostate cancer. For example, in one non-randomised study, the 15-year risk with a score of 6 was 18-30%, and with scores of 8-10 was 60-87%. So radical treatments should be discussed with such patients.

Radical Prostatectomy

In radical prostatectomy, the entire prostate is removed and the bladder neck is anastomosed to the remaining urethra. Prostatectomy allows accurate tumour staging. If surgery is successful, PSA should be undetectable at 2 months postoperatively.

In an observational study involving 1,000 men aged around 38-81 years treated with radical retropubic prostatectomy and bilateral pelvic lymphadenectomy, the 5 year cancer-free survival was 89.4% for men with Gleason scores of 204, 84% for scores of 5-6, 59.9% for score of 7 and 48.7% for scores of 8-10. In a randomised controlled trial involving 695 men aged under 75 years with well- or moderately differentiated prostate cancer, prostatectomy reduced the likelihood of metastatic disease at 8 years (13.4% vs. 27.3% with watchful waiting, relative hazard 0.63, 95% CI 0.41-0.96), and of death from the cancer (7.1% vs. 13.6%, relative hazard 0.50, 95% CI 0.27-0.91), but not overall mortality.

In general, the operative mortality of radical prostatectomy is below 1%. Men older than 65 years are more likely to die in hospital after prostatectomy than younger men (3.1 times as likely in one series). Unwanted effects of prostatectomy include severe haemorrhage, thrornboernbolisrn, anastomotic stricture, fistula, ureteric injury, lymphocele, rectal injury and, later, erectile dysfunction (in up to 60% of men) and incontinence (8-33%). In men with normal erectile function preoperatively, use of nerve-sparing techniques during prosrtatectomy can maintain erectile function in up to 68%. In a follow-up study to a randomised controlled trial, involving 326 men aged under 75 years with prostate cancer, 80 reported having erectile dysfunction after prostatectomy (vs. 45% managed with watchful waiting). Also, 49% (vs. 21%) had urinary leakage at least once a week and 18% (vs.2%) had moderate or severe incontinence.

External Beam Radiotherapy

External beam radiotherapy is given on an outpatient basis over about 8 weeks. In a non-randomised study of such therapy, the 5-year disease-free survival was 85% for patients with pretreatment a PSA concentration of up to l0ng/mL and Gleason scores of up to 6, compared to 65% for those with a higher value for one of these indicators, and 35% for those with both indicators with higher values. External beam radiotherapy is contraindicated when a patient has had prior pelvic irradiation, or has active inflammatory bowel disease, a permanent Foley catheter or morbid obesity. Compared with external beam radiotherapy, conformal radiotherapy (matching the irradiated volume to the tumour volume) and intensity-modulated radiotherapy (where the intensity of the radiotherapy beam is varied across the treatment field) allow a larger dose to be delivered to the prostate while minimising the dose to surrounding tissues. In a retrospective study of 1,677 patients treated with conformal radiotherapy, the proportion with metastases at 5 years was up to 15 for those with a Gleason scores of 2-4, up to 17% for scores of 5-7, and up to 42% for scores of 8-10.

Common unwanted effects arising during or within 90 days after radiotherapy include mild urinary frequency and urgency, diarrhoea and fatigue. Delayed, long-term effects include erectile dysfunction (in up to 50% of patients); gastrointestinal toxicity including radiation proctitis (around 3-12%); rectal bleeding (around 7%; severe in around 0.8%); mucous discharge or diarrhoea (around 1.8%); urinary incontinence; haematuria; urinary frequency, urgency and nocturia (around 7%); and urethral strictures (around 1%). Conformal radiotherapy appears to be associated with a lower morbidity than external beam radiotherapy (e.g. gastrointestinal symptoms requiring treatment in 19% vs. 32%; radiation proctitis in 4.4% vs. 12.6%). Data on intensity-modulated radiotherapy is limited; it may be less toxic than conformal radiotherapy.

In a retrospective study comparing patients treated with either conformal radio-therapy or prostatectomy, similar proportions of those under the age of 70 years maintained erectile function, but among those aged over 70 years, more maintained erectile function following radiotherapy (around 79%) than following prostatectomy (around 33%).

Brachytherapy

Brachytherapy ('brachys' being a Greek word for a 'short distance') involves the permanent placement of a radioactive source (most commonly iodine-125 or palladium-103 seeds) transperineally into the prostate under transrectal ultrasound guidance at a single session under general or spinal anaesthesia.

This treatment helps to minimise the radiation to the rectum and adjacent neurovascular structures. Large glands cannot be treated with brachytherapy because the pubic arch blocks accurate insertion of the seeds. Also, brachytherapy is contraindicated in men who have had a TURP as they are particularly likely to develop incontinence following treatment.

Urinary (low problems are relative contraindications to brachytherapy, which may worsen such symptoms. Al-though there have been many studies on the safety and effectiveness of brachytherapy, there is a lack of long-term out-come data, and no published randomised comparisons with other therapy that have controlled for factors such as tumour stage, grade or initial PSA concentrations.

Early unwanted effects of brachytherapy include prostate oedema, which can cause nocturia, dysuria, hesitancy, frequency or retention. These can reduce quality of life for up to 3 months.'' The risk of long-term unwanted effects, appears low, with proctitis in 1-2% of patients and incontinence in fewer than 2% at 12 months." However, urethral stricture may occur, and requires surgery or a permanent urinary catheter.

Erectile dysfunction occurs in up to 40% of patients with previously normal erectile function. Brachytherapy can lead to a rise in PSA concentration (1-2 years after the procedure), which makes interpretation of follow-up concentrations difficult.

Hormone Ttherapy

Hormone therapy using luteinising hormone-releasing hormone, gonadorelin analogues (e.g. goserelin, leuprorelin) or anti-androgens (e.g. cyproterone acetate, flutamide) can be used in patients with more advanced forms of prostate cancer, or in combination with other therapies in early disease. However, data suggest an increased mortality rate in men with localised prostate cancer treated with the anti-androgen bicalutamide alone compared to placebo (5-year mortality 25.2% vs. 20.5% with placebo, hazard ratio 1.23, 95% CI 1.0-1.5). This has led the Committee on Safety of Medicines to recommend that the drug is not used as primary treatment in such individuals.

Common unwanted effects of hormone therapy include hot flushes, loss of libido or erectile function, weight gain, gynaecomastia and osteoporosis. These effects are less of a concern during the short courses (e.g. 4 months) of hormone therapy used (with other treatments) in early prostate cancer than in their long-term use for advanced disease, but still need to be weighed against the potential benefit.

Treatment Combinations

Prostatectomy Followed by Radiotherapy

Radiotherapy to the prostate bed can be given for so-called 'biochemical failure' (i.e. a rise in PSA concentration after prostatectomy) and can achieve a biochemical response (undetectable PSA). Radiotherapy may also be given when pathological examination of the surgical specimen indicates a high risk of local failure (e.g. surgical margins not clear of disease).

However, local recurrences or metastases may still occur after radiotherapy, and the effect of the combined treatment on survival is not known.

Prostatectomy Plus Hormone Treatment

In one trial, 303 patients with localised prostate cancer were randomised to immediate radical prostatectomy or 3 months of neoadjuvant treatment (prior to prostatectomy) with leuprorelin and flutamide.

Brachytherapy Plus External Beam Radiotherapy

Men at higher risk of having disease that has spread outside the prostate capsule (e.g. Gleason score >6) are increasingly being treated with brachytherapy plus a boost of external beam radiation. However, whether such combination therapy increases survival is not known and it may lead to worse bowel function than with brachytherapy alone.

Hormone Therapy Plus Radiotherapy

In a non-randomised study involving 1,586 men, adding hormone therapy to conformal radiotherapy provided no additional benefit to patients in low-risk groups (i.e. PSA concentration <10mg/L and Gleason score £6), but it appeared to reduce the likelihood of cancer recurrence in intermediate-risk patients (PSA concentration 10.1-20mg/L or Gleason score of 7; RR 0.2, 95% CI 0.1-0.3) and in high-risk patients (PSA >20mg/L or Gleason score ³8, RR 0.4, 95% CI 0.2-0.8).

A randomised controlled trial involving 206 patients with early prostate cancer, with a PSA concentration of at least l0ng/mL or a Gleason score of at least 7, plus a life expectancy of at least 10 years, has assessed hormone therapy plus radiotherapy.

It found that overall survival at 5 years was higher in the patients treated with conformal radiotherapy plus 2 months each of neoadjuvant, concurrent and adjuvant androgen suppression therapy (using leuprorelin orgoserelin, plus flutamide) than in those given conformal radiotherapy alone (88% vs. 78%, p=0.04). No longer-term outcome data have been published.

Comparisons Between Treatments

No published randomised studies have compared surgery with either radiotherapy or brachytherapy for patients with clinically localised low-risk prostate cancer (PSA concentration

Quality of Life

A cross-sectional survey examined health-related quality of life in 671 men who had a prostatectomv, 147 who had external beam radiotherapy, 84 who had brachytherapy and 112 healthy volunteers. Compared with the volunteers, the patients reported more troublesome sexual dysfunction.

Prostatectomy was associated with adverse quality of life due to urinary symptoms; radiotherapy with bowel problems; and brachytherapy with urinary and bowel problems. Also, observational studies suggest a potentially lower quality of life with respect to sexual function after treatment with hormones plus radiotherapy than with radiotherapy alone.

In a study among men aged 55-75 years, conservative management gave the most quality-adjusted life years (QALYs) for men with initial Gleason scores of 2-4, while prostatectomy or radiotherapy gave more QALYs if the scores were 7-10. There was less difference between the options at higher scores.

In these circumstances, the choice must rely more on the patient's preferences regarding unwanted effects. Men differ in the importance they place on potential unwanted outcomes from different treatments.

For example, in a study assessing how many years of life 129 men with non-metastatic prostate cancer would, in theory, give up to avoid various unwanted effects of treatment, those aged over 70 years were less concerned than younger men about maintaining erectile function (i.e. indicated they were willing to give up 0.9 months vs. 1.8 months).

Helping Patients to Choose

There arc various information sources for patients and healthcare professionals to aid decision-making about which treatment option to pursue (e.g. CancerBACUP, Macmillan Cancer Relief, DIPEx [Database of Individual Patient Experiences]).

Conclusion

Localised prostate cancer is potentially curable with radical treatment (prostatectomy, radiotherapy, brachytherapy, or combinations of these treatments with each other or with hormone therapy). Observational studies suggest that radical treatment may improve survival in patients with poorly differentiated tumours and no significant co-morbidity, but there is a lack of randomised comparisons between different options. These treatments have different long-term unwanted effects, which are weighted differently by individual men. In men with a symptomatic localised well-differentiated disease, these treatments have not been shown to reduce overall mortality compared with conservative management, and may introduce more morbidity than the disease itself might cause. This emphasises the importance of actively involving patients in treatment decisions.

Source :
Drug and Therapeutics Bulletin.

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