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January 2007: PCA3 improves diagnosis of prostate cancer

How should PSA levels be interpreted?

What does state-of-the-art prostate surgery entail?

Should GPs recommend brachytherapy?

How should PSA levels be interpreted?

What does state-of-the-art prostate surgery entail?

Should GPs recommend brachytherapy?

Prostate cancer is the most commonly diagnosed internal malignancy in men, and causes almost 10,000 deaths in the UK every year.1 Benign prostatic hyperplasia?(BPH) is even more prevalent, with an estimated 43 per cent of men over 65 years of age suffering either symptoms or prostatic enlargement. Symptomatic BPH is strongly associated with a reduction in quality of life, sexual dysfunction and a risk of disease progression.

Diagnosis

A single prostate specific antigen (PSA) measurement is of limited use in differentiating between prostate cancer and BPH, unless it is significantly elevated. When the most frequently used PSA cut-off point of 4.0 ng/ml is employed, a significant number of patients with BPH are identified as false positives for prostate cancer. Men with a PSA of between 4.0 and 10.0 ng/ml have around a 20 per cent chance of having prostate cancer; in those with a PSA of >10.0 ng/ml, the chance of a positive biopsy is 62 per cent.

However, the recent Prostate Cancer Prevention Trial (PCPT) demonstrated that 17 per cent of men who were identified with prostate cancer in fact had a PSA value below 4.0 ng/ml, and some patients had a value below 2.5 ng/ml.

Annual measurement of PSA may improve accurate diagnosis, but is also controversial. Several studies have suggested that a PSA increase of > 0.75 ng/ml/year2,3 may be indicative of prostate cancer, and there is evidence that the rate of PSA increase before diagnosis correlates negatively with survival after treatment for localised disease.4

In general, an elevated or rising PSA level will necessitate a transrectal ultrasound (TRUS) guided biopsy of the prostate under local anaesthesia with broad spectrum antibiotic cover. However, the recently developed PCA3 test may reduce the number of patients requiring TRUS biopsies.

The new test is based on the molecular analysis of prostate epithelial cells, obtained from the first 50 ml of urine passed after a relatively vigorous prostatic massage. The analysis is based on measurement of PCA3, which is over-expressed by more than 60 times in patients with adenocarcinoma of the prostate. Early results suggest that the sensitivity and specificity are better than those for PSA, and that there are fewer false-positive results.

New treatment options for BPH

Traditionally, symptomatic BPH has been managed by either watchful waiting or transurethral resection of the prostate (TURP). The development of effective medical therapy with ?-blockers and/or 5?-reductase inhibitors has resulted in a steady decline in the number of TURPs performed. The five-year Medical Treatment Of Prostate Symptoms (MTOPS) trial confirmed that a combination of these two drug classes provided maximum improvement of symptoms, as well as preventing disease progression, thereby reducing the need for surgery.

The advent of Greenlight laser vaporisation and Holmium laser enucleation of the prostate (HoLEP) has recently altered surgical options. Laser technology permits the almost bloodless relief of bladder outflow obstruction, so patients can be admitted for day surgery or a 24-hour hospital stay. Some patients may prefer surgical resolution of the problem to prolonged drug therapy, especially when medical treatment has failed to resolve symptoms completely.

Localised prostate cancer

The diagnosis of prostate cancer at an early stage, when the tumour is still confined to the gland, is increasing because of PSA testing and TRUS biopsy.

While this is encouraging, the situation poses several dilemmas. First, when small foci of well differentiated disease are found, it is not clear if they will pose a threat to the individual within his natural lifespan. In this situation a policy of active surveillance may constitute the main course of action.

In cases of more extensive and less well differentiated disease, surgical removal of the prostate is still the most reliable means of eradicating the disease and achieving an undetectable PSA level. It is also the only treatment option that has been demonstrated in a randomised controlled trial to reduce the development of metastases by around 50 per cent, and improve overall survival and prostate cancer specific survival.5

The disadvantages of surgery include the potential side-effects of incontinence and erectile dysfunction, as well as the recovery time. Surgical outcomes have been improved by the development of laparoscopy, and more recently robotically assisted laparoscopic radical prostatectomy (RALRP).

The laparoscopic approach reduces blood loss because the raised intra-abdominal pressure discourages venous bleeding. The da Vinci robot improves the precision of the dissection, and its 10x magnification and 3D visualisation allows more precise nerve sparing and more accurate anastomosis. Early data from the USA, where more than 350 robots are in service (compared with only six in the UK), suggest that these advantages translate into an improved recovery of potency after surgery.6

Radiotherapy may be delivered by a six-week course of external beam radiotherapy (EBRT). The improved accuracy of conformal EBRT technology has been shown to reduce the incidence of side-effects, which mainly result from the inclusion of the anterior rectal wall in the treatment field. Rectal irritation and bleeding is common, but usually transient.

One way of avoiding irradiation of the rectum is to employ brachytherapy. This involves the implantation of up to 100 radioactive seeds into the prostate under general anaesthesia and TRUS guidance. Satisfactory outcomes from this treatment modality have been reported in patients who present with lower risk tumours.

The Gleason histological score is a measure of the aggressiveness of a tumour (see table 1, attached). A tumour scored eight to 10 is considered aggressive, and tumours scored below six are considered potentially indolent. For men with higher risk disease (T3 tumours and/or Gleason scores > seven), EBRT or high dose rate brachytherapy, often preceded by androgen ablation with a luteinising hormone releasing hormone (LHRH) analogue, is usually more appropriate.

A number of patients still present with metastatic disease, or develop metastases despite previous treatment. For these individuals androgen ablation therapy is still the main treatment, and responses to LHRH analogues can be sustained for many months, as evidenced by prolonged PSA suppression. Eventually, however, hormone relapsed prostate cancer (HRPC) develops and the PSA begins to rise. Such a situation is usually premonitory to the development of metastatic symptoms, especially bone pain. Recent data suggests that survival may be prolonged by the judicious use of chemotherapy with docetaxel. Zolendronic acid has also been shown to delay the development of skeletal-related events by up to six months, but does not improve survival.

Conclusion

Prostate problems continue to be a significant issue in older men, and as the population ages and becomes more aware of prostate cancer and BPH, their impact on primary and secondary care will inevitably increase.

This situation could be viewed as an opportunity, as men have traditionally avoided contact with healthcare professionals. Men presenting with lower urinary tract symptoms or anxieties about prostate cancer could be opportunistically evaluated for other comorbidities, such as diabetes, hypertension and dyslipidaemia.8 Key health messages about diet, smoking and exercise could also be discussed.9

Much work remains to be done to improve the evidence base that surrounds prostate disease, but the broader issue of men's health is beginning to be considered at last.

Key points Table 1: Prediction of tumour risk Useful information

The Prostate Research Campaign UK provides useful information on all prostate conditions for patients and clinicians
www.prostate-research.org.uk

UK Prostate Link provides links to other websites, with an assessment of the reliability of the information
www.prostate-link.org.uk

Men's Health Forum is a registered charity providing information on all aspects of men's health
www.menshealthforum.org.uk

The Prostate Cancer Charity offers information and support for patients and healthcare professionals
tel: 0800 074 8383
www.prostate-cancer.org.uk

Cancer Backup offers information on all types of cancer for patients and healthcare professionals
tel: 0808 800 1234
www.cancerbackup.org.uk

Author

Professor Roger Kirby
MA MD FRCS
Director, The Prostate Centre, London

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