Prostate cancer is the second most common cancer in European males, with a lifetime risk approaching 10%. It is predominantly a disease of older men.
The usual type of prostate cancer is an adenocarcinoma and this arises from the cells that line the secretory ducts of the prostate. A measure of the aggressiveness of the cancer is made by the pathologist from the biopsy using Gleason scoring, which is a scoring system that grades by different characteristics associated with aggressiveness and leading to scores between 2 (very indolent) to 10 (very aggressive). Research assays may, in the future, detect more aggressive characteristics by other means. One research assay detects mutated copies of the gene (p53 in the healthy form being a tumour suppressor gene). Damaged versions occur in many malignancies and are associated with tumour progression. Other genetic assay work may become relevant in the future.
Symptoms of prostate cancer
The patient usually comes to the doctor with complaints of slow urinary stream, hesitancy of initiating urination and often of frequency of urination (e.g. having to get up several times at night to pass urine). These are the symptoms of ‘bladder outflow obstruction’ which is most usually associated with the commoner benign prostatic hypertrophy of older age, but occasionally they may augur the development of a cancer in the prostate. Nowadays, with the earlier diagnosis of prostate cancer due to the PSA screening programme, we are more frequently diagnosing prostate cancer in patients who have no new symptoms referable to the urinary tract.
Occasionally, the patient comes with back pain or some other symptom caused by spread (metastasis) of the tumour but this is unusual and most patients present without overt evidence of spread of this cancer.
Treatment of prostate cancer
If the tumour is localised to the prostate (i.e. the staging tests reveal no evidence of spread), then there are three well validated curative options, not all equally relevant to every case.
The first option is radical surgery where a skilled surgeon removes the whole gland at operation, either by 'open' operation or robotically via key-hole surgery. (There is currently a slight question mark over the key-hole approach as the achievement of microscopically clear margins, a basic tenet of any cancer operation, seems to be inferior to the open operation in at least some major series).
The operation (either open or robotic) is a moderately large one and recovery times are a month or so – only the first week or so usually in hospital. There are slight risks of major complications, as with any major abdominal operation, and then there are the more specific risks. These include a small risk of incontinence of urine and a risk of sexual impotence, although the modern operation aims to spare the nerves that subserve this function (nerve sparing, radical prostatectomy). The PSA falls rapidly in cured patients, to zero or thereabouts (less than 0.01).
If there are positive microscopic margins or there is residual detectable PSA in the blood, then the patient may well require post-operative radiotherapy to the prostate 'bed' as it is likely that residual disease remains.
For patients with obstructive problems (slow urinary flow) there are merits for the operation over other methods as not only is the cancer treated but also the obstructive element.
For localised prostate cancer, the cure rate of radiation therapy is comparable with surgery. There are those who psychologically feel the need to have their gland cut out but others who do not want a large operation if the alternatives carry the equivalent chance of cure.
The classical form of radiotherapy is the external beam, conventionally fractionated course, which takes place over a period of some seven to eight weeks.
The modern linear accelerator that delivers this type of therapy catches the target volume (the prostate gland) in the cross-fire of three/four beams or more (often a front beam and two beams coming in from the sides of the patient) to effect a highly concentrated radiation course on the gland/tumour. The patients attends every week day for seven to eight weeks (35-38 treatments , called fractions within the profession) and towards the end of the course he may feel slightly tired, have some symptoms of cystitis (urinary frequency and discomfort) and often some temporary rectal discomfort. These symptoms have been minimised since the routine use of ‘conformal’ methodology of which IMRT is one form (a method of in-field, fine-tuned shielding using many beams with intra-treatment modifications of the beams). The IMRT methodology in particular reduces the dose to the rectum. Following therapy, the PSA falls over six months and the late side effects should be minimal. However, some loss of sexual potency occurs in 30-40% of men, interestingly, this usually responds to Viagra, Cialis or other non-hormonal methods.
External beam radiotherapy is particularly appropriate for the elderly (where no anaesthetic or operative procedure is appropriate) and those with some evidence of transcapsular disease on the staging MRI scan of pelvis (T3 disease). For these latter patients, it is now recommended that they start off their treatment with anti-hormonal therapy to both, downstage the disease and facilitate later radiotherapy, which starts a few months later. Indeed, the patient usually stays on the anti-hormonal therapy for two years in total for T3 cases (i.e. those patients whose cancer is through the prostate capsule on high quality MRI staging). For patients with T3 disease, operation is not appropriate as clear microscopic margins will not be achieved and better results obtained by the anti-hormonal therapy and IMRT beam radiotherapy option.
A third method of curative therapy now has good ten years of follow-up to defend its position side by side with radical surgery and conventional radiotherapy as another acceptable definitive method of therapy. This interstitial radiotherapy implant method, also called brachytherapy (Greek word meaning ‘close therapy’) involves the implantation of radioactive seeds into the prostate gland, where they remain to radioactive extinction delivering an ablative radiation dose to this organ. The ability of a template against the perineal skin to direct the seed deposition in two planes (x and y axes) and a trans rectal ultrasound probe to call the depth of implantation in the third axis (z axis) has allowed very exact seed deposition in the current methodology and it has the advantage of relative simplicity for the patient who can go home the same or next day. The figure photo shows on the left the distribution of seeds within the prostate on a frontal x-ray. The middle panel shows the seeds within the prostate on a CT scan at different levels within the prostate from top (nearest the bladder) to bottom (nearest the perineal skin) and the right panel shows the computer plan from which the seeds were deposited.
The seeds are implanted under general anaesthesia in a procedure that usually lasts a couple of hours only. Since the radiation dose falls off at the square of the distance from the seed (inverse square law), so a very intense dose is delivered within the gland and yet the surrounding structures receive a much lower radiation doses, thus sparing them damage. In 2003, prostate brachytherapy became the preferred cure option in the USA over radical surgery (radical prostatectomy) and the reasons are to do with the now proven equivalence as regards disease free survival/cure rates and the lesser nature of the post-procedure with regard to side effects. For example in our own experience and analysing three hundred consecutive patients implanted at our unit there was no case of urinary incontinence (although one man leaks just enough after urination such as to require a pad inside his underpants) and one man (only) requires to self-catheterise once daily - no other long term problems. These sorts of figures are now routine from experienced centres, practising brachytherapy and explain why this methodology is becoming more popular than surgery. Having said this, case selection is important as this methodology is not suitable for everyone (those with large glands and obstructive symptoms are particularly unsuitable). In an attempt to reduce the size of a large tumour/prostate gland prior to implant or radical external beam radiation therapy, it is now common for the doctor to prescribe a two month course of anti-androgen (anti-hormone/anti-testosterone) therapy prior to the radiation therapy. There are accumulating data to support this practice in terms of disease free survival advantages for the less good risk patients, and for continuing this anti-hormonal therapy longer term (e.g. two to three years after therapy). Sometimes, we combine external beam radiotherapy (first) with a brachytherapy boost; this is a perceived advantageous strategy of spreading the radiation dose wider over the first 2/3 of the dose and then adding a more focal boost to the gland itself; such a policy would seem most sensible for the tumours filling the gland and for which there might be early transcapsular spread (albeit not shown on the staging MR scan). From the foregoing it is clear that for the patient with localised prostate cancer there are three types of potentially curative therapy.
Other methods of curative therapy are now becoming available and cryotherapy and high intensity frequency ultrasound (HIFU) therapies are the two that spring to mind. Both are interesting methods of ablating the prostate but neither have the length of follow-up or 'pedigree' that the other methods discussed here have at this time.
How does the doctor and the individual patient make up their minds as to which they should choose? There has been no head to head trial of the main three types of therapy (surgery, brachytherapy and IMRT external beam radiotherapy) but a broad consensus of recommendations is as follows:
For patients with small gland and early tumours therein, and PSA values of less than 10 (the PSA being a prognosticator for the future), all three main methods seem to have comparable cure rates that should be up in 85%+ for such early disease. When the tumour fills the gland and there is extracapsular spread seen on the MR then external beam radiotherapy is the preferred option – nowadays preceded by anti-hormone (antiandrogen) therapy (as above). Certain other considerations apply: The patient who will not accept a risk of urinary incontinence might be best advised to accept a non-surgical option. Elderly patients are best served by external beam/IMRT radiotherapy.
A final word concerning the use of anti-hormonal therapies. Five of six men with prostate cancer will respond well to anti-hormonal therapy (either the use of injections which switch off the pituitary's driving hormone that keeps the testes secreting the male hormone, testosterone, or anti-androgen tablets: which block the testosterone receptors on testosterone target tissues such as the prostate; the use of orchidectomy/castration is less used nowadays, although a remarkably effective method that requires no repeating!) - but such treatment is not, in the long run curative.
For men with early prostate cancer, those with no evidence of metastatic disease (no spread beyond the environs of the prostate itself), anti-hormones are used in patients with local progression (such as spread beyond the capsule of the gland or into the seminal vesicles or high PSA), specifically in order to shrink the tumour back inside the gland/ downstage it prior to radiotherapy. The fall in the PSA can be dramatic. The anti-hormonal therapy may be continued for some time after the radiotherapy to maximise its usefulness.
The other use of anti-hormonal therapy is where the patient has been found to have metastatic disease on staging, most commonly either in bones or pelvic/abdominal lymph nodes. In this circumstance, the doctor will treat with anti-hormonal therapy alone and, if there is a good response, use no other therapy, monitoring progress by serial PSA measurements. Radiotherapy may be used for troublesome regions (e.g. the prostate itself if there is persistent large mass or problematic bone metastases that may persist to be painful.
Where the patient responds to anti-hormonal therapy well for some time but then the PSA rises (indicating relapse through this therapy) then 'second line' anti-hormonal therapy is tried in the therapeutic sequence of therapies. The doctor will either add an anti-androgen to the injection (that has been switching off the pitiutary's stimulatory driving force) or add this injection to the anti-androgen if that was used first. Then, if there is further rise in PSA after the above the patient may be offered the addition of low dose oestrogen therapy plus low dose glucocorticoid/steroid (in a dose that turns of the secretion of adrenal androgens into the blood) and this can effect a further hormonal response for a further period. The oestrogen will be omitted if the patient has a past history of thrombosis. A new drug, arbireterone may block adrenal synthesis of androgens by another method.
Where the cancer has become resistant to all anti-hormonal procedures, the use of chemotherapy will be offered and two drugs, notably taxotere and mitozantrone are the best validated. The drugs are usually given three weekly and the response is carefully monitored. A significant response rate with delay in tumour progression is well established from such therapy.