Summary
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.
Causes
The cause of prostate cancer is not known.
There is evidence for a genetic predisposition for this disease as evidenced by the increased incidence in families with a history of the illness. For example, the risk of an individual whose father or brother has suffered prostate cancer is approximately two-fold higher than the background population and when there are two close relatives three and a half times higher of developing the disease.
Some oncogene testing is worthwhile in some patients (e.g. BRCA-2), and very interesting predictive testing can now be performed to identify those who, quite apart from any family history of the disease, may be at greater genetic risk of developing the disease (see below). Recently, it has been shown that prostate cancer is associated with chromosomal re-arrangements that bring about the over-expression of members of the ETS family of transcription factors, the most common of these re-arrangements is the fusion of coding sequences of the ERG gene to androgen-(male hormone)-regulated sequences in the promoter of the prostate specific TMPRSS2 gene. Other fusions between other ETS family members and TMPRSS2 and ETS re-arrangements involving other fusion partners (including androgen suppressed and androgen insensitive genes) occur. In the future, the evaluation of these genetic markers may be of diagnostic and prognostic value.
Even now, there are genetic predictive tests that may help to forecast the risk of an individual from developing prostate cancer, apart from family history of the disease. Thus the deCode ProCa 8 marker genetic profile of men can identify those individuals (white European males) with a twofold chance of developing the disease. This genetic profiling is now available to well men (the controversy is as to how far this extension to screening programmes should be promoted to the public).
There are also well recognised racial and geographical differences in the incidence of the disease. For example, there is an almost two-fold higher incidence of prostate cancer amongst black Americans than amongst whites. Interestingly, environmental studies demonstrate a higher incidence of prostate cancer occurring over the generations in migrants from a lower risk area to a higher risk one.
In general, the incidence of the disease is lower in Far East and Asia through the Middle East than in the West.
Links of incidence to dietary influences, such a dietary saturated fat intake, has been documented but the link is not strong.
Whilst there is some epidemiological evidence for a link between exposure to some pollutants such as heavy metals and chemical fertilisers, any such link is weak.
The hypothesised link between incidence and either sexual activity or some venereal diseases (e.g. herpes or cytomegalovirus) is unfounded. However, there is no doubt that the male hormone: testosterone has some/a lot of influence on the risk of developing the disease (eunuchs do not develop prostate cancer).
In general, prostate cancer is a disease of the elderly, although, with PSA screening, the disease is now being detected at earlier ages.
Incidence
Prostate cancer is the second most common malignancy of men in the Western world and its incidence has been increasing over the last decade (a higher prevalence being partly due to the PSA screening programme). There are 6500 deaths in the UK annually from this cancer and a lifetime risk of developing this disease of around 7-10 %.
With the increased usage of PSA screening, the disease is being more readily picked up in its early stages and it is in this group of patients that very high cure rates (90% +) are now being achieved, either by surgery, external beam conformal radiotherapy or prostate seed brachytherapy.
(Brachytherapy is becoming more popular, over radical surgery in the last few years).
Symptoms & diagnosis: 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.
Diagnosis
Prostate radiation brachytherapy using a transrectal ultrasound probe to ‘map’ the prostate. This figure is shown here to illustrate the transrectal ultrasound probe. For diagnosis, the biopsies are made transrectally.
A DRE (digital rectal exam) and a PSA serum test are routine tests and if the doctor is suspicious from the results of these (possibly augmented by a PCA-3 test) he will order a trans-rectal ultrasound (TRUS) directed biopsy (actually 4-12 biopsies by fine needle) from different areas of the prostate, but particularly any suspicious areas that are seen on the ultrasound.
The specimens from the biopsy are then carefully examined by microscopy and any cancer confirmed and graded (Gleason grading; see introductory section).
Stages
Once the diagnosis has been established by biopsy of the gland (with the microscopic diagnosis of carcinoma of prostate), the doctor will order an MRI scan of the pelvis (the modern high resolution MRI being more sensitive than CT or ultrasound for picking up any extracapsular extension of tumour and is also an excellent imaging method for detecting spread to pelvic lymph nodes). The MRI scan will hopefully demonstrate no disease outside the gland i.e. ‘organ confined disease’).
He will also order a bone scan (although this test is not indicated in everyone presenting with a very early prostate cancer) as the bones are the first site of more distant spread, if this has occurred.
Other tests are of a more routine nature.
Treatment & outcomes: Prostate cancer
Early and ‘organ confined’ 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 vast majority of patients who have organ confined disease (that is no sign of cancer breaching the prostate capsule – that envelope that surrounds the prostate gland and forms a barrier to spread – on a modern multiparametric MRI scan) will be cured by all the options.
The first option is radical surgery, where a skilled surgeon removes the whole gland at operation, either by ‘open’ operation or nowadays more often robotically via key-hole surgery.
The use of surgery in high Gleason score (8+) disease is still contreversial as the patient is at increased risk of positive margins after surgery and therefore needing post-operative radiotherapy to the pelvis – where he might have done as well with anti-hormonal therapy and radiotherapy (without any surgery at all). Some surgeons argue that the debulking of the disease by primary surgery improves control rates, but the subject remians contreversial for high Gleason score disease.
The operation is a moderately large one and recovery times are a month or so to regain good continence of urination but, in the skilled hands of a good surgeon recovery is usually excellent and incontinence rates low. 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 four to seven weeks.
The modern linear accelerator that delivers this type of therapy catches the target volume – the prostate- to effect a highly concentrated radiation course on the gland/tumour (IMRT – vide infra). The patients attends every week day for 4 – 7 weeks depending on prostate size and other parameters (e.g. proximity of pevic small bowel etc.).
To spare the anterior rectal wall, which lies just behind the prostate and can receive full dose, we nowadays inject a hydrogel into this potential space to separate the rectal wall from the high dose zone encompassing the prostate. This gel is slowly absorbed but it creates this separation of the two organs for the length of the radiotherapy and then is slowly absorbed.
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 Intensity Modulated Radiation Therapy (IMRT), which allows beam shaping (by altering the flux across the radiation beams) such that the encompassment of even irregular shaped targets is better conformed than previously.
The IMRT methodology in particular reduces the dose to the rectum. However, even then the anterior rectal wall lies very close to the posterior prostate surface, which is receiving full dose. This can still harm the anterior rectal wall with the risk of an ulcer. Recently, we have started to inject Hydrogel into the potential space between the rectum and the posterior prostate wall to increase this space – vide supra. Where this is needed, this represents a new method of sparing that organ-at-risk viz. the anterior rectal wall.
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 sildenafil (Viagra) , or tadalafil (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 T3 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 (so long as the PSA is falling well at one month). 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 usually not usually appropriate as clear microscopic margins will not be achieved and good results are obtained by the anti-hormonal therapy and IMRT beam radiotherapy option.
A third method of curative therapy now has good fifteen 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 at the beginning of this section above 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 typically less than one (small glands) to a couple of hours. 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.
15 years ago, 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 four 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, for intermediate risk patients, we combine external beam radiotherapy (first) with a brachytherapy boost; this has 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 – with really high cure rates – up to 90% in the earliest stages of the disease.
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 85-90%+ 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.
Patients with obstructive symptoms (slow urinary flow – unable to achieve a flow rate in excess of 10 ml/second) or leaving a large residuum in the bladder after urination, may be best served by surgery – or at least a trans-urethral resection prior to radiotherapy. Those with very large prostates may also be so advantaged by surgery.
Brachytherapy is used for patients with organ confined disease as a low risk alternative to surgery and one that is usually much better tolerated than surgery – fast recovery time. Like surgery it is usually used for the lower Gleason grade tumours (up to Gleason 7) or, in combination with external beam radiotherapy and anti-hormonal therapy, for Gleason 8 disease. In patients with good urinary flow rates, it is an excellent and proven high cure rate therapy, with usually low risk of side effects.
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. Anti-hormonal therapy alone may be used for elderly and frail men, for whom any of the curative options are unable to be tolerated.
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.
I should emphasise that anti-hormonal therapy alone is not curative but assists radiotherapy to increase the cure rate in intermediate to higher risk patients
For intraprostatic relapse after radiotherapy, then cryotherapy or High Intensity Frequency Ultrasound (HIFU)are the preferred ablation techniques.
Advanced and metastatic prostate cancer.
For patients with metastatic cancer of the prostate, the first therapy will be systemic and either anti-hormonal therapy alone or anti-hormonal therapy with chemotherapy (usually and drug called docetaxel/taxotere).
For patients who present with high PSA levels and high volume metastatic disease and visceral metastases (e.g. liver metastases) then there are good data supporting the combination of chemotherapy and anti-hormonal therapy. For the elderly patient with low volume metastatic disease – such as some pelvic node involvement on the PSMA scan or one bony metastasis, then the case for combination chemotherapy and anti-hormonal therapy is less compelling and many Oncologists would place the patient on anti-hormonal therapy alone.
The anti-hormonal therapy will usually be be an anti-gonadotropin (gonadotropin is the hormone form the pituitary that is needed to keep the testis active in secretion of the male hormone: testosterone). Blocking the gonadotropin renders the patient medically castrate – no testicular production of testosterone. Of course, surgical castration does the same job but is nowadays socially less acceptable.
There are LHRH agonists and antagonists – the former creating an initial stimulation of testosterone before paralysing it long-term (this only being of relevance if there is an imminently threatening metastasis – such as one about to cause spinal cord compression, in which scenario the LHRH antagonist is preferred). These drugs effect a medical castration and render the patient devoid of testicular testosterone. As >80% od prostate cancer is dependent on testicular testosterone, this therapy causes a very good remission in most patients with the PSA falling to very low levels
In addition (or alternatively) there are the androgen receptor antagonists: of which the drug bicalutamide and the next generation one: enzalutamide. These are both powerful on their own but are best in conjunction with LHRH inhibitors (or castration).
The important new drug is abiraterone. In the absence of testicular testosterone, there is a small amount of androgen synthesis taking place in the adrenal glands and androgen target tissues.
After the elimination of the testicular androgens, there remains a small source of androgens in the body, synthesised in the adrenal glands and also in the androgen target tissues. Abiraterone inhibits the biosynthetic pathway at a criticalstep between the base molecule of cholesterol and the C-19 androgen. It inhibits P 450 17alpha-hydroxylase (CYP 17) and this leads to a marked lowering of the post-castration male’s circulating androgen and even more so in the androgen target issues as this is where this source of androgen is synthesised.
As the abiraterone inhibits the adrenal biosynthetic pathways, the lowering of output of adrenal hormones is sensed by the pituitary feed-back loop and increased ACTH is released into the circulation which could at least partially overcome the inhibitory effects of abiraterone on the adrenal androgen production line – by ACTH stimulatory effects. For this reason (and others), we give low dose glucocorticoid steroid (typically prednisolone 5mg twice daily orally) to prevent this phenomenon.
There are now strong data demonstrating that an LHRH analogue plus abiraterone (with low dose prednisolone) will lead to very good and durable remissions in the majority of men with metastatic prostate cancer.
Eventually, however, and this may be after many years, the cancer will become resistant to the anti-androgens and the mechanism of how this occurs are of interest. typically, the ligand binding domain of the androgen receptor (to which the male hormone binds to effect stimulatory events and to which the anti-androgens bind to effect inhibitory events – becomes mutated and then constitutively activated (i.e. is in a constant state of stimulation). The AR-V7 splice variant is the best example of this and the evolutionary appearance of this in a prostate cancer harkens the development of anti-hormonal resistance.
When the cancer becomes resistant to anti-hormonal therapy, the next step is chemotherapy. As has been stated above, in high risk patients, there is a case for giving chemotherapy with the anti-hormonal therapy up-front.
In the setting of metastatic prostate cancer that has resisted anti-hormonal therapy, the first chemotherapy drug of choice is a taxane (doctaxel/taxotere or cabazitaxel) and there are patients who respond to cabazitaxel having failed front-line taxotere. The side effects of the taxanes include hair loss, allergy, low blood counts and peripheral neuropathy. Where the patient’s cancer has become resistant to these taxanes, the interesting drug: mitozantrone is a second line chemotherapy, which can induce remissions – although they tend to be short-lasting in patients who have already received a lot of prior chemotherapy. Mitozantorne is an anthracenedione and works in a different manner from the taxanes.
Particularly in men carrying the BRCA gene in their base genome (and thereby in the cancer;’s genome, the PARP inhibitors may be active and their use is advised in this particularly group of men with metastatic prostate cancer (see more about this interesting group of drugs in BRCA breast and ovarian cancer sections of this website. In short they exploit the DNA repair fault that is present in BRCA positive cells and produce increased cell death (‘synthetic lethality’). They are less active in non-BRCA patients , although the cancer can acquire this mutation as it evolves.
For patients with bone metastatic disease, the administration of bone strengtheners (such as bisphosphonates or denusumab) can retard progress in bone and should be considered.
There are two radioisotopes of bone seeking elements (Stronium-89 and Radium-223), which have been used to target bone metastases – i.e. by preferentially concentrating in bone, they deliver their radioactivity mainly in these bone metastases and can thereby cause remissions in the metastases. Both are well tolerated but can have a long-term suppressive effect on the bone marrow in patients with heavily infiltrated bones. Recently, there has been concerns raised that the Radium-223 isotope can increase the risk of bone fracture (interestingly particularly in combination with abiraterone – although that data is preliminary). Such isotope therapy is usually used after all other systemic therapy and as a single agent of therapy (or in combination with gonadotropin antagonist therapy). Isotope therapy can be useful for helping bone pain in patients with advanced bone metastatic prostate cancer, who have progressed through anti-hormonal and chemotherapy options.
What to do in patients with refractory and metastatic prostate cancer?
In patients with refractory prostate cancer and advancing metastatic disease, the options are limited if he foregoing therapies have been delivered and failed. A new biopsy of the cancer (or cell-free cancer DNA from a blood draw) is analysed by next generation sequencing (NGS) to see if there are genetic mutations that are driving the cancer and which are potentially ‘druggable (i.e. there is an inhibitor of their down-stream effector pathways- BRCA mutation would suggest a role for a PARP inhibitor (vide supra)..
Sometimes the escaping prostate cancer shows signs of a large cell neuroendocrine cancer and this, and other peculiarities, may predict for some actionable mutations – only found by genomic analysis – as above.
The use of immunotherapy in advanced prostate cancer is still in its infancy but the testing of PDL1 expression and the testing for mismatch repair deficiency (MMR deficiency) – which predicts for hypermutation (and antigenicity) in such resistant cancers – is worthwhile. Positive predictive tests would argue that at trial of immunotherapy should be offered (see lung cancer and melanoma sections for deeper analysis of checkpoint inhibitor immunotherapy in this context).
Credit: P N Plowman MD, The Oncology Cinic, 20 Harley Street, London W1P 9PH. (Advanced Genomics). Tel: +44-207-631-1632
Outcomes
Most patients with early disease stand a very good chance of cure by one of the methods outlined above.
Those patients whose PSA fails to almost disappear (<0.05) after surgery or who suffer a rise in the first six months after surgery are likely to have metastatic disease. Those who have a late and slow rise in PSA (e.g. a rise to 0.1 after 2 years and then 0.3 after 2.5 years) are likely to have disease relapse in the prostate ‘bed’ and it is this group that is likely to benefit from radiotherapy to the ‘bed’
If, microscopically examination of the surgical specimen shows positive margins (i.e. the cancer is present at the edge of the surgically removed specimen), then early post-operative radiotherapy to the prostate ‘bed’ is to be recommended.
Screening
The digital rectal exam (DRE) of the prostate is the age old and extremely crude method of screening and will only pick up definitely abnormal glands, which will be at a later stage of the disease than we would wish.
PSA (prostate specific antigen) is a protein that is secreted within the lumen of the prostate ducts at very high concentrations and some gets into the blood stream where the levels may be easily and accurately assessed. Assay methods have greatly improved over the last decade and with controlled calibration standards the results are very accurate. In general, the development of prostate cancer leads to a rise in the serum PSA early in the course of the disease allowing for this blood test to be a potentially important screening test for healthy males The problem is that the normal range is difficult to exactly define and rises with age and the majority of slight rises in PSA are due to benign prostatic hypertrophy. It is largely for this reason (and the fact there is a slight risk to biopsying everyone with a slightly raised PSA) that the routine adoption of the PSA screen is not universal. Several attempts have been made to refine the PSA test such that it is more specific for detecting cancer.
Age specific PSA cut-off’s, have been taken into account to acknowledge that PSA gradually increases with time. PSA density is a method of adjusting the serum value with respect to the gland size/volume.
PSA velocity looks at the rise of the PSA over time, as the latter will be faster in cancer than in benign disease.
PSA isoforms can be used to establish the ratio of free: total PSA in the serum, which leads to a lower ratio in cancer.
With these refinements, the PSA test is an important health screen test for males (and particularly in those with a positive family history) and has allowed the diagnosis of early prostate cancer to be made more frequently. Although the ‘controlled trials’ upon which the medical profession puts so much weight are still running, the PSA screening ‘revolution’ is well and truly here.
(N.B. Whilst most regard PSA as also standing for ‘Providentially Sent Antigen’ there are those men who get hooked on measuring a trivially raised result and for them it has also been known as ‘Promoting Stress and Anxiety’.