Prostate Cancer symptoms and treatment

Tumours are usually staged using the TNM system. 2, 3 In brief, T1 and T2 tumours (‘early stage’) are confined within the prostatic capsule. T3 tumours have grown through the prostatic capsule and are known as ‘locally advanced’. T4 tumours are also regarded as locally advanced, assuming spread is confined to lymph nodes or nearby tissues.

The most common site of distant metastasis is the bones. Tumours are graded according to the histology of the malignant cells. The most widely used grading system for prostate cancer is the Gleason system. 4

To assess the Gleason score, biopsies must be obtained which are given scores. As prostate cancer may be histologically heterogeneous a primary (most common pattern) and secondary score are given and then added together. It is now recommended that the worst score is always included even if present in only a small proportion of the cancer. Gleason score effectively ranges from 6-10. Tumour size also has a bearing on prognosis.

Treatment options should be fully discussed with each patient. Many treatments have serious side-effects and men need access to evidence-based information in order to make informed decisions, alongside health professionals. 5

There is no consensus on best treatment for early prostate cancer. Treatment decisions may be based on the risk of disease progression, categorised into low, intermediate and high risk 6< ( Table 6.1). 5

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Low risk early tumours can be monitored with ‘watchful waiting’ or ‘active surveillance’. Watchful waiting is based on the premise that many patients are elderly with a relatively short life expectancy. Their prostate cancer is likely to progress very slowly, may not cause symptoms and will not cause their death.

Active surveillance is for low-risk men, suitable for radical treatment should their disease progress. If it does not, then over-treatment is avoided. Monitoring consists of PSA testing, digital rectal examination (DRE) and repeat biopsy as necessary - the optimum monitoring protocol has not been identified. 7-9 Radical treatment is an option, if the patient prefers.

There is no standard approach for intermediate risk tumours. Radical treatment is generally preferred, with active surveillance a viable alternative. High risk tumours are usually treated radically. Watchful waiting is acceptable in some circumstances, with fully informed patient consent.

Radical treatment options for curing localised disease include prostatectomy or radiotherapy. Erectile dysfunction and urinary incontinence are issues for both approaches but more likely with radical prostatectomy compared to external beam radiotherapy. 10 For intermediate and high risk disease, neo-adjuvant and/or adjuvant hormone therapy is an additional option.

A randomised trial comparing radical prostatectomy and watchful waiting management for men with clinically localised prostate cancer predominantly not detected by PSA testing, reported a statistically significant reduction in overall mortality and prostate-specific mortality at 12 years for men receiving surgery who were younger than 65 years. 11

There have been no adequate comparative trials between the different types of prostatectomy, or between surgical and radiotherapy approaches. A recent systematic review of treatments for localised prostate cancer suggests from cohort studies that there are likely to be, at most, small differences between the different radical treatment options. 12

Clinical trial entry should always be considered to help answer treatment uncertainties. The UK Prostate Testing for Cancer and Treatment (ProtecT) trial completes recruitment in 2008. It is evaluating treatment effectiveness (‘active monitoring’ vs radical surgery vs radiotherapy) for clinically localised prostate cancer in men aged 50-69 years identified through population-based PSA testing. 13

The increasing use of radical prostatectomy in England is shown in Figure 6.2. 14

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Radiotherapy is the standard of care for locally advanced prostate cancer which approximates to disease in men who have two or more high risk factors using the National Cancer Collaborative Network (NCCN) classification 6 as shown in Table 6.1. Neo-adjuvant hormone therapy can shrink tumours prior to radiotherapy. Post-radiotherapy adjuvant hormone therapy is advocated for men with a Gleason score above 7. An international trial investigating whether hormone therapy alone can produce similar results to radiotherapy (MRC PRO715) completed recruitment in 2005.

Some men, previously thought to have localised prostate cancer, are found to have involved margins at radical prostatectomy. Adjuvant radiotherapy has been shown to reduce the rate of biochemical and clinical recurrence but follow-up is presently too short to assess the impact on survival. 16 The widespread usage of super sensitive PSA assays to detect biochemical recurrence at an early time point has led to the establishment of the RADICALS Trial. This will compare immediate adjuvant radiotherapy with early salvage radiotherapy following a rise in PSA levels. If the latter is as effective, approximately half the men may avoid radiotherapy and its associated toxicities. 17

Treatment efficacy in prostate cancer is complicated by side-effects that may profoundly affect quality of life, such as erectile dysfunction and urinary incontinence. 18, 19 Both are common following radical treatment. Bowel toxicity can occur following radiotherapy to the prostate or pelvic nodes.For both early and locally advanced disease, conformal radiotherapy is standard. It delivers high, effective doses of radiation to the tumour while minimising damage to the healthy surrounding tissue, thereby reducing side-effects, particularly to the bowel. 20

Intensity modulated radiotherapy (IMRT) ‘shapes’ the radiotherapy dose, as well as the field, and is in research. Recruiting until at least 2011, the CHHiP trial is currently investigating hypofractionated IMRT for both efficacy and side-effect incidence. 21, 22 Brachytherapy using radioactive prostatic implants is an alternative to external beam radiation for localised prostate cancer: main side-effects are impotence and urinary symptoms. Brachytherapy is approved by NICE as a monotherapy 23 or as a booster dose, alongside external beam radiotherapy. 24

Surgical developments include laparoscopic (keyhole) surgery and intra-operative nerve sparing surgery (IONS). The latter aims to preserve erectile function where possible. Laparoscopic surgery may or may not be carried out with the assistance of a robotic device (robotic-assisted laparoscopic prostatectomy). Both approaches result in less blood loss during surgery than during open surgery 25 but meta-analyses indicate that urinary incontinence and erectile dysfunction rates are similar to that of open surgery. 26, 27

Side-effect profiles between treatments are not clear. Brachytherapy may provide better sexual function than either external beam radiotherapy or surgery but can cause more urinary problems. 28-30 Radiotherapy generally produces more bowel toxicity than surgery. 29, 30 Long term quality of life may be better overall with surgery than with either brachytherapy or external radiotherapy although to some extent it evens out over time. 31

In the UK, approximately 20-30% of men with primary prostate cancer present with incurable metastatic disease. 32, 33 Hormone treatment can give good short-term disease control by lowering androgen levels, principally testosterone. Options for androgen withdrawal are surgical castration (bilateral orchidectomy) or drug therapy with luteinising hormone-releasing hormone (LH-RH) analogues . These show similar efficacy and side-effect profiles. 5

Side-effects include impotence, hot flushes, osteoporosis, gynaecomastia, tiredness and metabolic alterations. 34 Androgen deprivation achieves an overall median survival time of approximately two and a half years and around 80% of patients have symptomatic relief. 35 Hormonal treatment trends over time are shown in Figure 6.3. 14 The fall in orchidectomy rates can be seen in Figure 6.2.

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The effect on survival of intermittent androgen withdrawal (as opposed to continuous therapy) is being investigated. Short periods of treatment are followed by periods of monitoring, with treatment restarting following PSA progression or should symptoms occur. This can preserve potency during periods off treatment.

A third hormonal therapy option is anti-androgen treatment . This is not as effective in controlling metastatic cancer, but is less likely to affect sexual function. The most troublesome side-effects are gynaecomastia and breast pain. A single radiotherapy fraction to the breasts or the anti-oestrogen tamoxifen is a useful preventative measure. Combining anti-androgens with androgen deprivation (medical or surgical) is known as maximum androgen blockade or MAB. This may give a modest survival advantage but increases morbidity. 36-38 Additional hormonal treatments include low dose corticosteroids or oestrogen (stilboestrol).

Metastatic prostate cancer will nearly always become refractory to hormone therapy. The main treatment option is then chemotherapy with docetaxel and steroids. 5 This is not recommended for men with a Karnofsky performance status below 60%. 39

Bone pain is the biggest problem with castrate resistant metastatic disease. Radiotherapy and analgesics should be tried first for palliation. 5 Radiotherapy provides effective pain relief while surgery may be necessary for pathological fractures. 40 Bisphosphonates may be used if these treatments fail. 5 The precise role of bisphosphonates in treating advanced prostate cancer is under investigation. 41-43

Various biological therapies are in trials, including cancer vaccines and monoclonal antibodies. Other research is investigating treatment combinations such as chemotherapy, bisphosphonates and strontium 89, or hormone therapy with or without chemotherapy, bisphosphonates and Cox-2 inhibitor. Recently the CYP17 inhibitor, abiraterone acetate, which ablates androgen and oestrogen synthesis from all tissue sources has shown significant activity in castrate resistant disease and is entering phase III trials. 44

For localised disease, though both are approved by NICE, high-intensity focused ultrasound (HIFU) and cryotherapy are not recommended outside clinical trials. Research continues into their use as primary therapy or salvage following prior radiotherapy. NICE assert that evidence is sufficient regarding safety but lacking in long term efficacy and effect on quality of life. 45-47