Prostate news article, February 2009

PROSTATE CANCER: WHERE ARE WE NOW?   Article by:   Professor Roger Kirby, Chairman, Prostate UK

Prostate cancer is now the most commonly cancer in men. More than 35,000 new cases are diagnosed annually and almost 10, 000 men die each year in the UK from this disease. In general, the earlier prostate cancer is detected, the better the outlook for the patient in terms of cure or arresting cancer progression. In the USA where PSA testing is widely adopted the death rate from prostate cancer is falling four times faster than in the UK¹

Now an increasing majority of patients present with an isolated increase in PSA, even though there is no firm evidence yet that universal screening will reduce mortality, although trials are on-going. Prostate specific antigen (PSA) is a glycoprotein responsible for liquefying semen. PSA measurement is currently the most effective single screening test for early detection of prostate cancer. Approximately 25% of men with PSA levels above the normal range (≥4 ng/mL) have prostate cancer, and the risk increases to more than 60% in men with PSA levels above 10 ng/mL. A particularly difficult clinical situation occurs when the PSA continues to rise in spite of a previous negative biopsy. A new molecular marker, known as PCA3, has been shown to be useful in this respect. A urine sample taken immediately after a prostatic massage is analysed. A value of greater than 35 indicates an increased risk that the prostate harbours a malignancy. Furthermore this new marker may be useful in stratifying men with clinically significant tumours from those with low risk cancers which can be managed conservatively².

Transrectal ultrasonography (TRUS) is the most commonly used modality to image the prostate gland and also to direct the biopsy prostate biopsy needle. Antibiotic treatment, usually with a quinolone, such as ciprofloxacin, is given before and after the procedure to reduce the risk of infection, which is currently estimated at around 2%. Usually 8-14 TRUS guided biopsies are taken from different regions of the prostate with an 18-gauge needle. This procedure is now routinely performed on an outpatient basis, preferably after infiltration with local anesthesia. Histological analysis confirms the presence or absence of cancer and provides a so-called Gleason score for each core. Firm evidence exists to confirm that the higher the Gleason score, the greater the risk of prostate cancer progression and metastasis. Magnetic resonance imaging (MRI) is widely used to stage prostate cancer locally and to diagnose or exclude lymph node metastases. Promising results have been reported with the use of ultra-small super-paramagnetic iron oxide particles as an aid to nodal metastasis evaluation by MRI. The addition of magnetic resonance (MR) spectroscopy (evaluation of chemical metabolites in a small volume of interest by MR technology) has also improved the accuracy of MR staging.

Radionuclide bone scanning is usually performed as a baseline assessment at the time of the initial diagnosis of prostate cancer. Bone metastases usually show up as "hot spots" affecting the vertebrae, pelvis or long bones. If the PSA value is <10 ng/mL and Gleason score is below 8, it may be permissible to omit this test, as it is rarely positive in such circumstances. The use of this technique in routine follow-up has declined as PSA measurements have been shown to be the most accurate and cost-effective means of monitoring bony metastases.

The aim of active treatment in patients with localized prostate cancer is usually cure - whether eliminating the tumor or preventing death from prostate cancer (as opposed to death with prostate cancer). As men with localized disease often do not experience significant disease-related morbidity for several years after diagnosis, and curative treatment itself may result in some morbidity, those with a shorter life-expectancy are likely to benefit least from radical treatment. Radical prostatectomy involves surgically removing the entire prostate, the seminal vesicles and a variable amount of adjacent tissue. It is most appropriate for men for whom it is believed the tumor can be removed completely by surgery and who have no co-morbidity. The procedure is most commonly performed via the retropubic route, though the perineal approach can also be used. The major advantage of radical prostatectomy is that it excises all prostatic tissue and provides precise histological information and definitive cure in patients in whom the tumour is specimen-confined. Thus, the patient's anxiety is relieved during the postoperative period; given that prostate cancer has a long natural history, this is an important consideration in terms of the patient's quality of life. Long-term studies have shown normal life-expectancies in those with complete excision of specimen-confined disease. Ten-year survival for men with clinically localized disease treated with radical prostatectomy is 98%, 91% and 76% for Gleason scores 2-4, 5-7 and 8-10, respectively. Moreover, the procedure also offers definitive treatment of concomitant BPH.

The principal adverse events associated with radical prostatectomy are stress urinary incontinence (<2-3%) and erectile dysfunction (>50%); the latter is age-related, tends to improve with time and can be minimized by nerve-sparing approaches. Moreover, erectile dysfunction after surgery can now be treated effectively. Radical prosatectomy, by whichever means achieved, is believed by many urologists to offer the best opportunity for cure in patients with localized prostate cancer. A randomized study from Sweden showed that at a median 8.2 years of follow-up, radical prostatectomy decreased prostate-cancer-related mortality by 44% and overall death by 26% ³. Recently laparoscopic radical prostatectomy has been described. The minimally invasive approach decreases blood loss and post-operative pain. It can be facilitated by robotic assistance with the da Vinci device which provides 3D vision and 10 times magnification⁴.

External-beam radiotherapy is widely used in the treatment of localized prostate cancer; it offers a particular advantage in patients who are unsuitable for surgery because of comorbidity or evidence of extraprostatic extension of cancer. As Dr Heather Payne describes our UPDATE newsletter, the treatment generally involves a 7-week course of radiotherapy. Ten-year survival of patients undergoing external-beam radiation for clinically localized, prostate cancer with Gleason score 2-4, 5-7 and 8-10 is reported to be approximately 89%, 74% and 52%, respectively. The principal side effects are due to bladder, urethra and rectal damage from the radiation scatter. Urinary frequency and urgency are common. In its severe form, urinary bleeding and pain may occur in 2-3% of patients. Rectal side-effects consist of urgency, frequency and tenesmus. If severe, rectal bleeding, pain or fistula may very occasionally require a colostomy. Erectile dysfunction due to damage to the neurovascular supply to the corpora cavernosa can also occur, typically over a 6-18 month period.

Low-dose seed brachytherapy involves placing either iodine-125 or palladium-103 seeds into the prostate via the transperineal route, using a template and TRUS guidance. The results of seed brachytherapy in low-risk men (PSA <10 ng/mL, Gleason score <7 and ≤cT2b) is equivalent to radical prostatectomy at 10 years, but they are highly dependent on the quality of seed placement. The results in patients with intermediate risk are worse, however, with freedom from recurrence approximately 66% at 10 years. The method is popular, particularly in the USA, because of its low morbidity - the side effects include lower urinary tract symptoms which are a direct result of the seeds. Rectal symptoms and incontinence are unusual, but erectile dysfunction may develop over time.

Active surveillance is usually reserved for men with small volume and low-to-moderate grade prostate cancer, who have a low risk of death from prostate cancer. These men would be eligible for curative therapy, but this option is deferred until objective signs of progression are observed⁵. This approach means the majority of men are spared the side effects of curative therapy when they do not require it. During active surveillance, men are followed closely with repeated PSA measurements and DREs, and repeat prostate biopsies. If the cancer appears to progress significantly, curative therapy is initiated before the cancer becomes incurable. The cancer-specific survival in men who fit the criteria for active surveillance is 99% at 8 years' follow up⁶. While men avoid the physical side effects of cancer treatment, they do have to live with the psychological effects of having an untreated cancer.

Although there is a marked trend towards earlier detection of prostate cancer, many patients still present with metastatic disease. In contrast to localized or locally advanced disease, metastatic prostate cancer is associated with high mortality - approximately 70% within 5 years. Androgen deprivation can be achieved by orchidectomy, treatment with a luteinizing hormone releasing hormone (LHRH) analogue or an antiandrogen. In most cases, advanced prostate cancers treated with any form of androgen deprivation eventually begin to progress, a phenomenon known as 'hormone-refractory' or 'androgen-independent' disease. Docetaxol, a chemotherapy agent, has recently been tested in a randomized trial against mitoxantrone and prednisone in men with androgen-independent prostate cancer. The results of this study (TAX-327) showed docetaxol, given in a 3-week schedule, to be superior to mitoxantrone/prednisone in terms of decreasing disease progression, PSA response and improving pain⁷. In addition, docetaxol significantly improved survival from a median of 16.4 months for mitoxantrone/prednisone to 18.9 months for 3-weekly docetaxol, which correlates to a 24% relative reduction in death. The side effects associated with docetaxol include neutropenia, skin reactions and gastrointestinal problems.

Although many conundrums surround the diagnosis and management of prostate cancer considerable progress is now being made. Recent guidelines for the management of localised prostate cancer have been issued by the National Institute of Clinical Excellence (NICE) in the UK. http://www.nice.org.uk/guidance/index.jsp?action=byID&o=11924 have been helpful and readers are referred to these.

References:
1. Collin SM, Martin RM, Metcalfe C, Gunnell D, Albertsen PC, Neal D, Hamdy F, Stephens P, Lane JA, Moore R, Donovan J.Prostate-cancer mortality in the USA and UK in 1975-2004: an ecological study. Lancet Oncol. 2008; 9:445-52
2. Nakanishi H, Groskopf J, Fritsche HA, et al. PCA3 Molecular Urine Assay Correlates with Prostate Cancer Tumor Volume: Implication in Selecting candidates for Active Surveillance. J Urol, 2008, 179: 1804-10.
3. Bill-Axelson A, Holmberg L, Ruutu M et al. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med 2005;352:1977-84
4. Goldstraw MA, Patil K, Anderson C, Dasgupta P, Kirby RS. A selected review and personal experience with robotic prostatectomy: implications for adoption of this new technology in the United Kingdom. Prostate Cancer Prostatic Dis. 2007;10(3):242-9.
5. Klotz, L. Active surveillance with selective delayed intervention is the way to manage 'good-risk' prostate cancer. Nat Clin Pract Urol 2005;2:136-42.
6. Albertsen PC, Hanley JA, Fine J. 20-year outcomes following conservative management of clinically localized prostate cancer. JAMA 2005;293:2095-101.
7. Petrylak DP, Tangen CM, Hussain MH et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513-20.