Prostate cancer is the commonest male malignancy and with the advent of PSA both the incidence and its prevalence have increased hugely. Despite a great deal of research it is still not possible to be completely certain from the evidence that we have, precisely what our attempt to treat prostate cancer will achieve.
I think it is important therefore to reflect with the evidence that we currently have in June 2007 whether when we recommend a course of therapy be it surgical, radiotherapeutic, or medical are we trying in the patient prostate cancer to achieve;
A. A cure
B. Control of the cancer
C. To increase the patients survival
D. To improve the quality of life.
It is always helpful to look back to see how a disease and its therapies have evolved and what we have learnt perhaps more importantly what may be unchanging over a reasonable passage of time.
In 1980 we knew these things about prostate cancer;
1. This was a disease of old men. The average age of presentation
was 73.5 where the average life expectancy of men was probably just 70, in the Western Hemisphere.
2. Fifty percent of these patients had metastases at diagnosis and at least 90% died from prostate cancer.
3. The other 50% had localised disease and most appeared to die with prostate cancer not from it.
4. Androgen ablation either orchidectomy or oestrogens were known to be palliative, there was an intense debate then as to whether that palliation should be given immediately or deferred until the patient became symptomatic, usually from bone metastasis. In patients who were symptomatic all known therapy was both expeditious and effective in hormone naive patients.
Role of surgery
In 1972 Jewett et al from the John Hopkins data showed that a man having a radical prostatectomy for a G3 (poorly differentiated tumour equivalent to a Gleason 8 to 10 showed that there were no cures and no survivors in men undergoing radical prostatectomy for this stage of disease. This paper has formed the basis of the choice of patients for radical prostatectomy in the new radical prostatectomy era and especially since the PSA era commenced in 1990. Sadly this is the data that is relied until the Scandinavians arranged their trial comparing radical retro pubic prostatectomy versus watchful waiting (Bill-Axelson et al 2005). The concern with respect to the outcomes from radical surgery is that at ten years there was only a 5% absolute difference in survival between patients having active treatment and watchful waiting. It is quite possible that the active treatment arm will, when the analysis is looked at at fifteen years, show a better performance. These data have not enquired as to what happens to patients with poorly differentiated tumours who historically we know are the ones that are likely to die from prostate cancer, neither has it been able to identify the patients who need radical intervention in order to prevent death. The current results show that far too many operations (at least twenty) need to be carried out for one patient to survive.
The premise on which all treatments are based currently is that patients with Gleason 6 and 7 if not treated will inevitably progress to Gleason 8, 9 or 10 metastasize and die. The premise further holds that early intervention prevents this occurring and therefore not only should active intervention be undertaken early at diagnosis but that we should actively seek to find prostate cancer early and treat it radically. Despite the enthusiasm for that contention, the Scandinavian trial remains the only one that shows in a prospective randomized manner a possible benefit for a small group of patients having active treatment but has not been able to define or discern who that small group of patients may be.
It is therefore worrying that on the slightest of evidence (one incomplete randomized prospective trial), there has been a great surge to screen patients by means of PSA to make an early diagnosis of prostate cancer. Thanks to the efforts of Professor Schroeder and his colleagues, the European Prostate Cancer Screening Programme is happening and will deliver an outcome that many people have pre-empted the result of this by assuming that screening is beneficial.
I believe that the Prostate Cancer Prevention Study first published
by Thompson et al in 2003, is a study that needs to be looked at with a great deal of care and caution.
The life-time risk of males developing prostate cancer is given as variously between 12 and 14%. In the two arms of the Thompson Study, the arm receiving Finesteride as part of the Cancer Prevention Trial and the placebo arm, both groups showed prostate cancer in higher percentages than this – 25% in the patients having no treatment and 19% in those taking Finesteride.
These figures need to be looked at carefully because if translated
into conventional ways of treatment, ie, extirpative surgery, radical radiotherapy, brachytherapy, one in four males will need active treatment and there is no health care system in the world that can sustain that degree of treatment or its costs.
Of equal importance from the Thompson Study, is no value of PSA could be ascribed to a male that would say that they had no risk of having prostate cancer. Even at a value of 0.5 mg/ml, 6.3% of the cohort were found to have prostate cancer on the terminal biopsy which all patients underwent. It needs very seriousconsideration, open-minded debate to determine just what we are doing in labelling so many patients with prostate cancer and therefore leading them to believe that unless they seek active treatment they will inevitably die of prostate cancer, a fact we know to be untrue, as in no Country is 19% let alone 25% of all males dying of prostate cancer.
Do improving treatments suggest that we are effecting more cures? If we consider the improvements that have occurred in the management of localised prostate cancer over the last twenty five years we have to consider what if anything has actually made a difference, (a) surgery, although the operation anatomic open prostatectomy has massively increased the outcome for an individual patient by reducing the incontinence rate and the impotence rate in the nerve sparring procedures it has shown no greater efficacy as it is still the same operation in its ablative effects in removing the prostate. Similarly laparoscopic prostatectomy or robotic laparoscopic prostatectomy have similarly merely removed the prostate, probably more expeditiously, certainly at less trauma and stress to the patient but the outcome oncologically is no different and one would not expect it to be so. Any benefit that radical prostatectomy has therefore conferred relies wholly on patients being operated upon at an earlier stage of disease when they are “curable” it is here that the lack of prospective trials leaves us with many Level 3 and Level 4 Evidence Studies but nothing that is scientifically confirmatory.
The one definite improvement that has occurred and being consistently validated follows the work of Bolla and his colleagues published first in 1997 showing that the addition of hormones to radiotherapy improved the surgical at five years by more than 25%. This has seen a complete change in the way radiotherapy and brachytherapy are delivered and has undoubtedly improved the outcomes of these treatments. However, we await the MRC and Canadian Study comparing hormones alone against hormones plus radiotherapy to see whether the radiotherapy has actually conferred any benefit at all over and above that which we know is obtainable by hormone treatment.
Problems with Palliation
We know that hormones are affective palliative treatment and in mestatic disease by the better and more judicious use of these agents and the fact that there are several now available rather than just an orchidectomy, the overall survival in prospective
studies has increased from 18-24 months to nearly four years, however, even in something that we know easily what to do there has been problems.
Because a significant number of patients following either surgery or radiotherapy showed a rise in PSA this was treated immediately with hormones, there has therefore led to a new disease - hormone resistant non metastic prostate cancer being evolved. We have been remiss in treating numbers and not patients. We have evidence from at least cohort studies (Pound et al 1999) and from prospective randomized trials Studer et al 2006, that deferring therapy until the patient develops objective metastases on average can last between seven and eight years and that the rush to treatment early gives rise to this new entity of hormone resistant disease when the cancer has not yet got into the bones and when it does so we are left with chemotherapy and radiotherapy as very poor substitutes for the palliation that we know hormone naive patients can benefit from. Given that we have at least a chemotherapeutic agent (Taxol) that actually works it is far more logical to look at its utility in the rising PSA patient rather than run the risk of exhausting all of the potential hormone manipulations in a fruitless endeavour to keep the PSA down.
The problems that have developed since 1980 - With the advent of PSA testing that prostate cancer has been diagnosed at earlier and earlier stages. In the Western Hemisphere less than 10% of patients now present with metastatic disease. Unfortunately these patients are all potentially treated by aggressive local therapy. A percentage, at least a third and possibly half will fail their local therapy and up to now the rise in PSA has been treated aggressively in the absence of symptoms despite advice and caution that it is not necessarily in the patients best interest. We now know that that caution was well considered as we have the advent of non metastatic hormone resistant prostate cancer and have at our disposal instead of a wonderfully effective palliative, a potentially toxic and significantly less effective chemotherapeutic agent to deal with these patients.
We now know emplifyed at its most extreme in the Prostate Cancer Prevention Study, that with ubiquitous use of PSA testing followed by prostate biopsy, far too many patients are being diagnosed with prostate cancer, and we need to look both at the upcoming results of the European Screening Study but more importantly our diagnostic criteria and the threshold related to age, risk and co-morbid factors as to who should actually be investigated and even if the diagnosis of prostate cancer made, who should be treated.
Professor Klotz from Toronto, Canada, has put forward a most sensible way of trying to help us through the current dilemma. He has proposed a study of active surveillance which is different from watchful waiting in that if parameters change during the period of active surveillance then active therapy can be utilized rather than in the watchful waiting series in which the inevitably of the development of metastatic disease in a portion of patients was watched and no attempt made to intervene at an early stage.
The outcome with active surveillance is to try and enable those patients with an inactive tumour that shows no evidence of progression be left on a surveillance arm whilst being able in those patients who by means of PSA, re-biopsy are showing evidence
of disease activity and/or progression can be subjected to new therapies or old interventional therapies that when we have clear evidence that there is a something happening to the cancer rather than merely because a cancer has been found.
I am certain that this is attempt to scientifically evaluate and to discriminate between patients who do not need treatment and in those that do to subject them to trials of new treatment including systemic chemotherapy as an initial therapy, will bear benefit and fruits for our patients. It is therefore vital that Urologists not become fixated on an operation, however delivered, but rather see the treatment of prostate cancer as their role and duty. If they do so, then all of the therapies as they evolve, will be delived by the Urologist and prostate cancer will stay a disease of the Urologist.
Sadly if they become fixated merely on a procedure, then when the procedure is superseded the physicians offering other treatments for localised prostate cancer will have already taken over that ground and when the surgery becomes obsolete so will the Urologist. It is something that we must not (as has happened
with the Cardiothoracic Surgeons) allow to happen.