Treatment for Local Disease
What is the rationale for treating localised prostate cancer?
Prostate cancer is a relatively slow growing disease with a doubling time of about 2 – 4 years in localized tumours. This means that the prostate tumour will double its size on average in this period of time. The majority of men when diagnosed with this disease are elderly and may well have other diseases affecting their life span and or quality of life. Most localised tumours are not symptomatic. Also the incidence of prostate cancer in autopsy specimens of men dieing from other causes is much higher than in the clinical setting of prostate cancer prevalence. Thus it is a valid question to ask ‘Why should I be treated for a localised prostate cancer?’ The best answer to this poser is that the majority of prostate cancers detected clinically on rectal examination or picked up on PSA screening are already clinically significant and advanced. These tumours will most likely cause early death and or morbidity if not treated. As men live longer and healthier lives, the number of prostate cancers detected will rise and with it the need to treat chronologically older but physiologically younger men. A rule of thumb was not to operate on men older than 72 years of age with prostate cancer but this maxim will be pushed outwards as life expectancies increase.
At least fifty percent of prostate cancers will not be detected during a mans life span and more than likely cause no harm. This is because these tumours are so small that they cannot be felt and do not cause an elevation in the PSA. These people will thus have no indication to undergo a biopsy in the first place and will remain in blissful ignorance of their disease. A problem arises however, when a man has a prostate operation for an unrelated problem such as benign enlargement of the prostate gland. In the resected tissue a small, incidental tumour can be picked up by the pathologist. Should this patient now have further cancer therapy? The answer is not necessarily straightforward. The patients overall clinical condition and life expectancy; the patients own standpoint on the disease; and the surgeons inclination all play a role in the decision making process. Urologists have recently developed models or algorithms that can predict if a tumour is going to indolent or aggressive. Unfortunately the predictive power of these tools is not good enough to be used safely in men younger than 65 years.
The various treatment options for localised disease will now be discussed.
Active Watchful Waiting
This approach to prostate cancer involves the regular assessment of an individual’s clinical situation by the clinician. If there is evidence that the tumour has changed from an indolent or quiescent state to one of accelerated growth then more formal action is indicated. This is a different way of monitoring disease to the more traditional method of passive watchful waiting where the clinician waited for symptomatic disease to present and then suggested the use of hormonal treatment. In most men when prostate cancer becomes symptomatic it is already disseminated disease and can not be cured with current treatment modalities. Men managed on watchful waiting programs include the very elderly; the patient with co-morbidities affecting the ability to tolerate active treatment or having a significant negative weighting on lifespan; and in men not wishing to have any form of treatment for various personal reasons. PSA alone can not be relied on to reliably indicate when a cancer is becoming more aggressive. Those men who feel that they can self monitor their disease are not doing themselves any favours. Evidence has now come to light that in men younger than 65 years, watchful waiting is a poor therapeutic option. These people should be well encouraged to choose an active form of treatment. Furthermore an ongoing large study of locally advanced prostate cancer has shown conclusively that those patients managed with watchful waiting have a reduced life expectancy. The data is strong enough possibly to influence the very conservative Scandinavians who are arch proponents of watchful waiting.
The Curative Options
So if watchful waiting is not the answer for the majority of patients, what is the chance of actually being cured of the disease after definitive treatment? A great deal of data has now been collected on this profound issue. It is generally accepted that radical prostatectomy has a slight edge over other modalities in terms of overall cure. Also a pathological specimen is obtained providing much information for prognostication not available to the non surgical forms of treatment. The majority of specialists involved in prostate cancer treatment will agree that surgery has a slight edge over other forms of treatment in terms of long term results. I will therefore discuss the role of radical prostatectomy first of all.
Radical prostatectomy is a major operation where the entire prostate gland is removed along with the seminal vesicles and depending on the surgeon; a pelvic lymph node clearance will also be performed. After the specimen has been removed, the bladder neck needs to be reconstructed and the bladder is then reattached to the urethra. A catheter drains the bladder for between ten and fourteen days. The operation can be done either from the abdominal approach or from a perineal direction. The perineum is the area behind the scrotum. Each technique has its proponents. At the end of the day either method when performed by a skilled surgeon will provide similar outcomes.
Radical prostatectomy should be reserved for patients likely to be cured and who will long enough to derive benefit from the cure. Thus age, concomitant diseases as well as the nature of the prostate cancer must all be assessed before the decision to operate is taken. It is important to be aware that whatever the treatment, the chances of being cured are directly related to the grade of the tumour and the stage of the tumour. The odds of dieing after ten years from prostate cancer when a well differentiated tumour has been treated are about 13 percent. For a poorly differentiated tumour that figure is closer to 67 percent. The chances of distant or metastatic spread of disease at ten years are 19 percent for men with well differentiated disease and 74 percent for poorly differentiated disease. Moderately differentiated patients fall in the middle with a value of 42 percent. Comparing men having prostate cancer with men of a similar age free of prostate disease reveals a definite loss of life span. At a mean age of 71 years the group with disease will have a shorter of life expectancy of around four to five years. After the operation certain complications related to the procedure can occur.
Firstly there is stricture or narrowing at the bladder urethra junction. This can lead to a weak urinary stream and even urinary retention. The incidence of this complication is between one and ten percent. This problem may require intermittent dilatation or incision of the anastamosis. Another solution is to remove the stricture completely and insert an artificial valve.
Secondly incontinence can occur. This problem can be really vexing. Its reported incidence varies. In some series up to thirty percent of patients have some form of permanent incontinence. In centres of excellence fifty percent of men should be continent after forty five days from the operation and only about five percent are still incontinent after two years. Important factors contributing to a better chance of continence are younger patients, superior anastamosis techniques and preservation of the neurovascular bundles. Most men can be managed with incontinence pads or pouches. The use of regular Kegel’s exercises speeds up recovery. Those men permanently incontinent can be offered an artificial valve.
The third complication is impotence. Again its incidence is variable but outside the major academic centres of excellence the rate is as high as eighty to ninety percent. In the best centres the figures can be as low as thirty percent. Again, the younger the patient the better the chance of recovery for good erectile function. Pre-operative erectile function is also important. Multiple therapies are tried to improve the erectile function of patients. Often the success rate is not wonderful and thus careful counselling of men prior to the operation is required.
After the operation the most common method for assessing tumour reoccurrence is the use of regular PSA checks. As already mentioned on other pages of this site, PSA is now recognised to be a flawed tool to diagnose prostate cancer but is excellent for monitoring the return of detectable disease. The majority of PSA failures will occur within the first two years of operative treatment strongly suggesting that those patients were understaged in the first place. At ten years post treatment there are almost no further PSA failures. The world wide figures show a non PSA progression or success rate of between 75 and 80 percent at ten years for men with localised disease at the time of treatment. The onset of a PSA rise usually precedes clinical disease by 6 to 8 years. Clinical stage, Gleason grade and PSA level pre-operatively directly correlate with the chance of PSA progression after the operation.
When the prostate gland is removed, the pathologist will examine it and provide a pathological or true staging of the disease. Remember the pre operative assessment is not always correct but rather an approximation that can sometimes be way off the true reality. The pathological staging provides the most important prognosticating parameter for disease reoccurrence. Tumour confined solely to the prostate gland will have a 90 percent chance of a disease free state at five years with an almost similar figure at ten years. Tumour found to have escaped to the seminal vesicles or the lymph glands has the worst prognosis. Microscopic invasion only of the capsule of the gland is not so bad and seventy percent of patients will be clear of disease at ten years.
There are two forms of radiation therapy, namely external beam radiotherapy and brachytherapy. Brachytherapy is dealt with under another page on this web site. Only external beam radiotherapy will be discussed in this section.
External Beam Radiotherapy
Patients suitable for radical prostatectomy are also acceptable candidates for radiotherapy. That is patients with locally confined disease. Furthermore more advanced disease such as T3a and high Gleason scores above seven that are not suitable for radical prostatectomy may be offered radiotherapy as an option. Treating more advanced disease has somewhat skewed the results of radiotherapy towards a more unfavourable overall outcome. Patients need to be carefully informed that if they have more advanced disease the chances of treatment failure rise.
The actual technique of radiotherapy for prostate glands has become very sophisticated and is no longer the hit or miss affair seen even in the early nineties. In days gone by collateral damage to other organs around the prostate gland was common and failure rates of treatment high. The position of the prostate gland was inferred rather than actually known. So the high energy beams could quite easily miss their intended target. This is called conventional radiotherapy. Now, the prostate gland is imaged in three dimensions prior to any treatment using a CT scanner. This allows the oncologist to plan how much radiation dose is required for a given size of prostate and how to direct the beams to focus on the prostate gland. This is known as conformal radiation therapy. Additionally conformal therapy allows much smaller windows of skin to be used to focus the beams onto the prostate gland thus reducing dose to surrounding tissues. Secondly today instead of the old low energy cobalt sources, most facilities use high energy beams generated by linear accelerators. High energy beams penetrate body tissue much deeper before they cause any cell damage. Therefore superficial tissues today are mostly spared from radiation injury. As the prostate gland is located deep in the pelvis the energy beams can now reach the gland more effectively. Lastly a further innovation known as intensity modulated radiotherapy, (IMRT) has started to appear in most advanced centres for radiotherapy. IMRT further improves the dosage delivered to the prostate gland whilst minimising the dose to the surrounding tissue. It does it using a sophisticated mathematical algorithm to either attenuate or intensify areas or aspects of individual high energy beams during any one course of radiation treatment. It requires expert planning, advanced planning systems and radiation oncologists experienced in these techniques.
Radiotherapy works by sending a high energy photon or electron crashing into a cancer cell during the mitotic stage. That is when the cell is dividing. During mitosis the cell becomes very sensitive to radiation. The exposed DNA is thus easily damaged irreparably by the energy source and the cell dies. Current linear accelerators produce high energy photons in the gamma range and electrons. Research is at present looking at neutrons and protons which are much heavier particles as a possibility for future treatment. The total time for treatment with external beam therapy for prostate cancer is about seven weeks. Each day the patient will come in and lie on a special table for a short period of time and receive a fraction of the total intended dose. During this treatment period it is not unusual to feel somewhat tired and possibly nauseas.
After the treatment is completed several adverse events can occur. These include gastrointestinal, urinary and sexual problems. The gastrointestinal complications include pain in the rectum, bleeding from the rectum and chronic diarrhoea. The symptoms can range from mild to severe. Possible urinary events comprise of bleeding into the urine known as haematuria, urgency and frequency of urination, reduced bladder capacity, urethral stricture with obstruction, incontinence and even bladder destruction. Rarely an overwhelming toxic bladder condition can lead to death. Once again these various problems can run from mild to severe. However, severe side-effects are virtually unheard of with the use of the new planning systems, despite the use of higher dosage regimes that have now become standard treatment. Sexual problems involve accelerated erectile dysfunction compared with men who have not received radiotherapy. As with surgery prior sexual function is important in determining the degree of fall off after treatment. Radiation oncologists do not have access to prostate tissue after treatment like a surgeon does so it makes it more difficult for them to determine treatment success. Because the gland is not removed the PSA never falls to zero after treatment completion. There is always some surviving normal tissue that continues to produce PSA.
Radiation oncologists have taken a level of 0,5 ng/ml as an accepted endpoint to reach. It takes the PSA a long time to reach it nadir or lowest level, in the region of two to three years. In comparison radical surgery should reduce the level to zero after a few days. Oddly enough the longer the PSA takes to reach its nadir the better the chance of a successful cure. The reason for this situation is as follows. PSA sources include benign prostatic tissue , the intracapsular tumour and metastastatic disease. The longer it takes the PSA to reach its lowest level the less likely that there is metastatic tissue which is of course not treated by the radiation. In addition all the cancer cells should have been permanently damaged during the treatment period and a persistently falling PSA is merely reflecting atrophy of normal tissue. Radiation oncologists therefore determine treatment failure as either a patient’s PSA not achieving a specific nadir or alternatively demonstrating three consecutive rises in the PSA. In terms of PSA nadir if the level falls to 0,5 ng/ml or less there is an eighty five percent chance of being disease free at five years. Note this is a figure similar to surgery. At PSA nadirs between 0,6 and 1 ng/ml the treatment success at five years falls to forty percent. In patients where the PSA does not fall to 1 ng/ml the success rate is only twenty percent at five years.
Radiation oncologists also use a different classification to surgeons to prognosticate on possible treatment success. This classification is also used to determine if additional therapy is required. Oncologists call this adjuvant therapy . Adjuvant therapy is discussed further on the page dealing with combination therapy. Patients are stratified into low risk (Gleason score less than 6, PSA less than 10 ng/ml and stage T1c or T2a). These patients have an eighty five percent chance of having a stable PSA at five years. The next group is intermediate risk (Gleason score of 7, PSA between 10 and 20 ng/ml and stage T2b). Patients in this group have a fifty percent chance of a stable PSA at five years. Lastly high risk patients (Gleason score greater than 7 or PSA greater than 20 ng/ml or Stage T3a) Patients in this group have a thirty percent chance of showing no PSA rise at five years.
Biopsy of prostate glands at some time after radiation treatment has never become a standard part of the post treatment assessment. Biopsy results can be very difficult to interpret after radiation treatment. The only place at present, to biopsy a prostate gland after treatment is when there appears to be biochemical failure and the physician wishes to know if the disease is local or disseminated.
This form of treatment is not an option in South Africa. Unless the medical aids have a change of heart or the government restores academic medicine to its rightful place at the forefront of research this treatment is unlikely to ever appear in this country. For this form of treatment one will need to travel to The United States or the Asian countries. Patients are chosen for treatment using the same criteria as for surgery. Once again the worse the disease in terms of the current parameters evaluated, the worse will be the chance of curing the patient The technique involves the freezing of the prostate gland to kill the prostate cells. Until the nineties the results of cryotherapy were basically awful. However technology marches on and with the advent of rectal sonar to guide the cryoprobes and a urethral warmer to protect the urethra subsequent treatment protocols have much improved outcomes. Cryotherapy kills cells directly. This why freezing astronauts for long space flights is pure science fiction. Water expands when it is frozen and this will cause the cell membranes to rupture. When the tissue thaws, fluid floods into the cells and the damaged walls allow the cells to burst open and hence die. The freezing also induces clots in the blood vessels going to the prostate gland. The subsequent tissue hypoxia also contributes to cell death. For the best results, the tissue needs to be frozen to -40°C. The freeze thaw cycle also needs to be repeated during the procedure to maximise cell damage.
The operation is done as a single procedure and involves a stay in hospital of only one day. Cryoprobes are placed in the prostate gland mimicking the same technique used for real time brachytherapy. When correctly placed the probes are switched on for two freeze thaw cycles. After the procedure which is done under anaesthetic, a catheter is left in place for three weeks. The complications of the procedure can be substantial and would seem to outweigh the other forms of treatment. Impotence is very common. At least eighty percent of patients are impotent after the procedure. Some may recover potency after two years. The cause is due to freezing of the neurovascular bundles and blockage of blood vessels supplying the penis by thrombus. Incontinence is reported at variable rates in the literature varying between four and twenty seven percent. Tissue sloughing of the prostate gland is common especially when the urethral warmer is not used or is of poor design. Sloughing leads to bladder obstruction and infections. Often these patients require a prostate resection to sort out the problem. Unfortunately many of these patients will then be incontinent. Rectal pain can occur in ten percent of patients. Rectal urethral fistulas are a devastating complication occurring in up to three percent of patients. Many will require colonic diversion to treat the problem. Urethral strictures can occur at the bladder neck if necrosis occurs in that region. Injury to the ureters can lead to obstruction of one or both of the kidneys. A transient penile numbness has been reported.
Follow up of patients is by PSA monitoring. Initially the PSA rises to a very high level because of the tissue trauma. After three months it should have reached its nadir. There is still not consensus on what this nadir should be but it is recognised that if the level does not drop to 0,4 ng/ml or less then the long term cure rate is poor. Because cryotherapy is performed by urologists many patients are biopsied after the procedure to look for residual tumour. If biopsies are negative after one year then the chance of cure is very high. The long term outcomes are not yet well established and the high complication rates makes cryotherapy not a mainstream option as yet. Continual technological innovation may see the technique progress to offer similar results to the other forms of treatment.
Transrectal High Intensity Ultrasound (HIFU)
This mode of treatment has been around since the mid nineties. In the USA it is still considered experimental but it has become accepted technology particularly in Europe. There is a strong rumour that it might become available in South Africa. It was developed at first to treat benign enlargement of the prostate gland. Later the technology was adapted to ablate the entire prostate gland and thus kill the localised tumour. The high intensity sonar beam emitted by the rectal probe heats up the prostate tissue to round 90°C. The intense heat destroys the prostatic tissue. The probe heats up small areas of the prostate at a time and by computer control the entire gland can be sequentially covered until the entire gland is treated. Tissue traversed by the ultrasound waves is not damaged because the waves are not ionising and the focal point is placed within the prostate. Therefore damage to surrounding organs is very minimal.
The procedure is performed on an outpatient basis. The patient is anaesthetised and put in the lithotomy position as for brachytherapy. The prostate gland is imaged via the rectal probe and a three dimensional picture is built up in the computer. The computer calculates were to direct the high frequency probe and then the procedure commences taking between two and four hours to complete. The size of the prostate gland is a limiting factor and if above 40 gm it will need to shrink using initial hormonal therapy. After the treatment is complete a catheter is left in the bladder for up to four weeks because of the considerable swelling that occurs. The urine stream will be week for several months after the operation so an alpha blocker may be prescribed. A skilled HIFU surgeon can spare the neurovascular bundles thus preserving potency. Preservation of the bundles is NOT an option when the tumour lies adjacent to the nerves. As for surgery the indications for HIFU are similar. Again because of the nature of the treatment high stage disease can be treated such as T3 tumours, understanding that the cure rates will be lower. HIFU can be used to salvage failed radiotherapy patients.
Complications do occur with this procedure. Urinary retention and a poor stream have been mentioned. Tissue slough with obstruction and infection occur as for cryotherapy. The incidence would seem less. Patients therefore may require prostatic resection after the procedure. In Europe the urologists are starting to perform prostate resections prior to HIFU if there is doubt that the patient will be able to void after the procedure. Rectal injuries are rare but can occur. Patients are followed up in a similar manner to cryotherapy patients. PSA and prostate biopsies can be followed up. The outcomes of the procedure in the short and medium term look very promising. Long term data as yet has a paucity of numbers and the figures are adversely skewed by the use of inferior equipment on the initial patients who obviously had poorer outcomes.