Report of first Bandolier Conference

MEN'S HEALTH: BENIGN PROSTATIC HYPERPLASIA AND PROSTATE CANCER
Nov 1st /2nd 1995. EYNSHAM CONFERENCE CENTRE, nr OXFORD

The chairman, Dr Andrew Moore, welcomed delegates to the first Bandolier conference, outlined the history and purpose of Bandolier, thanked our sponsors, Anglia and Oxford RHA, Merck, Sharp and Dohme and the NHS Executive, and explained the purpose of the meeting. This was to share ideas between a wide range of people with a common interest in improving the care of men with BPH or prostate cancer, especially by addressing the use of guidelines and how best to improve clinical and economic effectiveness.

1st session: BPH.

Dr Colin Sanderson opened the session on BPH by discussing epidemiology, 'the size of the problem'. Here one immediately encounters a problem because there is no simple widely agreed definition of BPH. These vary from the physical `increase in size due to cellular proliferation', via the functional, including urine flow rates and residual volumes as well as estimated prostate weight, to symptomatic definitions based on standardised symptom score indices such as the AUA 7. (The American Urologists Association 7 questions - also now known as the IPSS, International Prostate Symptom Index).

Prevalence varies widely according to these different definitions. More than 90% of men over 80 have significantly enlarged prostates at autopsy though not all of these will have had troublesome symptoms. Studies such as those of Garroway which combine symptom scores >10, with weight >20gm and flow rate <15ml/sec give prevalences of about 30% at age 80.

Age is the only clear predictor of BPH. Many other potential risk factors varying from ethnicity and religion to diet and blood pressure have been examined but none have given convincing results.

Dr Sanderson reported a `needs assessment study' based on indications for surgery agreed by a consensus panel of 6 urologist and 3 GPs in the NW Thames region. Although there was difficulty standardising symptom questionnaires the study suggested that there would be about 540 cases per 250,000 population per year with symptom scores of >8 who would probably accept surgery if offered it. This figure drops to about 170 if the symptom threshold is set at >15. At present about 150 cases were treated in the NHS and 30 in the private sector per year. Dr Sanderson also presented a Prostate Outcomes Questionnaire designed by Dr Donna Lamping to help purchasers and providers to evaluate outcomes of prostate procedures for BPH.

In discussion Dr Moore noted the difficulty in reaching a logical decision about when to undertake surgery and asked if there was any particular indicator which could help. Dr Sanderson thought that no indicator was better than symptom severity or "bothersomeness". When asked if there was any correlation between pre and post-operative symptoms he said that there seemed to be a tendency to get down to similar levels.

Dr Melville noted that women also have bladders which are susceptible to ageing and that they may get similar symptoms to men. Such symptoms cannot automatically be attributed to the prostate gland.

Dr Logan Holtgrewe started by describing the prostate as "a delight in youth but a plague in old age". He outlined the background to the publication in 1994 of the US Agency for Health Care Policy and Research guidelines on the treatment of BPH. The guidelines took 2 1 /2 years and $1.5m to produce and started with a literature review of more than 200 relevant papers. Their prime objective was to:

* assist patients to make informed decisions about their treatment
* assist practitioners to conform to rational and effective practice.

The problem in the US is of great economic importance since trans-urethral resection of the prostate (TURP) which accounts for 90% of the surgical treatment of BPH averages $7000 a case, is the 3rd most costly (total) operation in the US, takes up 1 /4 of the workload of urologists, but has a 3x geographical variation in usage. The rapid increase in the number of men surviving over the age of 80 increases the importance of the problem.

The AUA7 Symptom Index Score, devised mainly by Dr Michael Barry, is the starting point for the guidelines. Scores range from 0-35

0-7 is regarded as mild
8-19 as moderate and
20-35 as severe

This symptom score should be part of a simple algorhythm combining history with physical examination including digital rectal examination (DRE), urinalysis, creatine, and perhaps prostate specific antigen (PSA) (see below)

Patients with mild symptoms should normally be treated by watchful waiting, those with moderate or severe symptoms will require further investigations including urodynamic studies. Upper UG tract imaging, cystoscopy or filling cystometry are not normally helpful and not recommended unless there are specific indications. If tests indicate obstruction rather than irritation then decisions about surgical or medical treatments will be needed and if surgery is thought to be indicated then TURP, open prostatectomy or one of the newer interventions must be chosen.

"TURP works best in those that need it most" ie significant symptom relief is achieved in 93% of patients with severe symptoms and 75% of those with moderate ones.

The complications of surgery, though not insignificant, are reducing progressively in specialist centres. Mortality is about 2% for open prostatectomy and c. 0.7% for TURP, somewhat higher in the over 80s. Incontinence is about 1% after TURP and even less after open surgery. Reports of impotence after surgery vary widely from about 3% to 40%, it has been almost impossible to get accurate and meaningful data.

The measurement of treatment outcomes usually involves flow rates and residual volumes but it is probably more useful to use an Impact Index which acts as a bridge to assessing overall health status. One such index assesses:

physical discomfort on urination,
how bothersome is urination,
interference with normal activities,
general concern about health.

Dr Holtgrewe thought that balloon dilatation should no longer be used and that various new technologies such as laser and other `thermal' therapies had not been adequately assessed. There was an element of "new technologies looking for a disease to treat".

The most important criterion of success for any new therapy must be its durability. Outcomes should be measured in years/decades to relapse rather than months.

Decision making, (by the patient, not the doctor) must ultimately rest on the balance between the probability of symptom relief against the risks of harm.

Dr Holtgrewe ended his talk by reminding the meeting that the AHCPR guidelines are available in 3 formats; a full version and a summary for doctors and a simpler version for patients. They are available on the Internet and direct
from 1 800 358 9295

There is some uncertainty about the future funding for the AHPCR but the AUA will update the guidelines after examining new data on the existing and newer therapies.

In Discussion Dr Moore emphasised the importance of randomised controlled trials (RCTs ) of new treatments to justify the latters inclusion in the range of purchased therapies. He wondered how far purchasers currently use guidelines.

Dr Holtgrewe agreed the importance of RCTs. The AUA has stated that all proposed therapies should be subjected to RCTs with at least 1 year follow up. "old men know too much that is no longer true". However several of the devices used for the newer interventions are produced by smaller companies who cannot afford to fund clinical trials and they are finding ways of getting around the regulations intended to ensure adequate testing of such interventions.

The value of guidelines becomes even greater when rationing of services is introduced. In their absence there is a danger that the influence of accountant/managers will predominate. Dr Mike Kirby was concerned that rigid guidelines might lead to legal problems

Dr Sanderson was concerned that excessive zeal for RCTs might inhibit innovation in surgical treatments but Dr Holtgrewe thought that this was not so and that it would just encourage the pursuit of properly evaluated new studies. On the question of whether guidelines were addressd more to urologists than GPs Dr Holtgrewe admitted that this tended to be the case at present but that it shouldn't be so in the future. Better education and dissemination were needed to reach a wider audience. The fact that the guidelines were developed by leaders in the field, under the auspices of the AUA, was important in maximising their acceptance.

Dr Richards said that he represented a group of `confused GPs' who, on the one hand receive advice about all the new tests available to assist decisions and then hear at meetings such as this that most of them are not justified. What is needed is `a one stop shop' where advice can be coordinated and consistent.

Mr Mark Emberton in introducing his work for the National Prostatectomy Audit said that the meeting was now moving from "the purity of the first session to the dirty linen of the second"

The audit was undertaken on behalf of the Royal College of Surgeons, The British Association of Urological Surgeons and the London School of Hygiene &Tropical Medicine. It aimed to recruit all surgeons undertaking prostatectomies in 4 NHS regions over a 6 month period; to collect pre and post-operative data and to assess the patients perceptions of their outcomes at 3 months.

96% of eligible surgeons were recruited. 3 refused and 1 was not identified.
89% of patients were identified.
The overall rate of surgery was 219/100,000 population but the rate in the southern regions was about 2x that in the north.
The number of operations per surgical team varied from 1 to 140 with a mean of about 60.
Mean AUA scores were: pre-operative c21: post-operative c 5.
60% of operations were on patients with AUA 20-35, 37% 8-19 and 3% 0-7.
Perceived results were good in 70%, marginal in 20%, and worse in 10%.
The most frequent adverse effect was incontinence, up to 1/3 of patients suffer to some extent, some of these had not reported pre-operative incontinence.

The conclusions of the study were that there are wide variations in both management and outcomes of prostatectomy in this country, that there is much inappropriate use of resources and an urgent need for more consumer-based studies.

Dr Logan Holtgrewe, (using Peter Boyle's statistics), showed how much better the mortality figures are for BPH surgery in most western countries now, compared with 1950. Most are down to 5-10% of previous levels.

Interestingly the effects of the introduction of guidelines has varied widely in different countries so far. For example, although there is near to 100% awareness of the guidelines in Denmark, they have had little effect on practice, whereas in Belgium a 35% change in practice was recorded although there was apparently only a 49% awareness.

Dr Holtgrewe believes that there is much resource wasted on inappropriate investigations, such as IVP (60% of cases in Japan and 28% in the UK). In the US the number of patients having TURPs under Medicare schemes has recently fallen by 43% and correspondingly the number of patients given medical treatments such as alpha blockers and finasteride has risen several fold. This is now 55% of patients in primary care and 45% of patients seen by urologists.

Failure rates for treatments over a five year period are:

watchful waiting 38%
balloon dilatation 32%
alpha blockers 13-40%
finasteride 10-27%
TURP 10%
TUIP 9%
open prostatectomy 2%.

The role of a cascade of therapies starting with medical, and progressing via less invasive surgery such as lasers to TURP is attractive but may ultimately be the most expensive option.

A recent Gallop poll of US urologists practices showed a move towards more conservative treatments. 77% advocated watchful waiting for patients with 'mild' symptoms and 71% recommended medical therapies for `moderate' symptoms. In `severe' cases 34% still recommended medical treatments first, 6% used new devices and 41% advised TURP. However the level of media hype creates a constant pressure for the use of newer unevaluated treatments.

To combat this successfully would require the world's medical journals to reject all BPH studies that are not properly designed and do not contain economic evaluations. To achieve this it would probably be necessary to include health economics in all medical school curricula.

Muir Gray while accepting the need to gather cost as well as clinical information, emphasised the importance of:

* defining the research questions that need to be answered
* planning and carrying out appropriate trials.

Ros Meek reported the findings of a survey of Directors of Public Health and Chief Administrative Medical Officers attitudes towards men's health problems carried out by MORI for the Royal College of Nursing.

It was very clear that men's health was not a main priority for any of the respondents, although about a half thought it deserved more attention.
Whereas 92% of respondents had focussed on homosexual mens health and 75% on HIV infection only 36% had focussed on prostate disease.

The RCN were trying to improve the situation by forming a Men's Health Alliance involving bodies from both the medical and the voluntary sector. This model had worked well in Australia. The Alliance would draw up guidelines for good practice.

Angela Billington described how the North Herts NHS Trust Community Continence Service which she headed was carrying out an audit of prostate disease in the community. Patients over 50 with symptoms of prostatism were referred to the service by GPs.
Symptoms were assessed by questionnaire and functional studies such as peak flow rate and residual volume were carried out. Urinalysis, blood urea and electrolytes and PSA were measured. Protocols had been drawn up and permission sought to allow the service to do DREs.

Dr Mike Kirby talked about the role of shared care in BPH.

The CMO had highlighted the need for increased attentionto men's health and the only realistic way to achieve this was for primary care to be more involved.

A key question is "can GPs evaluate and treat prostate disease satisfactorily?"
Professor Chisholm has chaired a `shared care initiative' involving urologists and GPs. This had agreed consensus management guidelines except for PSA testing.

Experience to date of an open access service is that about half the patients can be managed in primary care and half require the specialist services of a urology unit. The use of medical treatments, alpha blockers and finasteride, has produced benefits in up to 60% of patients.

Dr Gill Hamilton described studies of finasteride (a 5 alpha reductase inhibitor, marketed by MSD, which blocks the conversion of testosterone to the more potent androgen, 5 dihydrotestosterone).

Evidence on the effectiveness of finasteride derives mainly from placebo controlled trials over 1 year, some of which have been continued in open extension up to 5 years. The drug often achieves a reduction in the size of the prostate of up to 20% and this is consistently maintained up to 1 year and in open extension up to 5 years. Flow rate is typically increased by 1-2mls/sec and this is maintained up to 4 years in 50% of patients and symptom scores (except dysuria) are improved sometimes out to 4 years. PSA values are characteristically reduced to about 50% after 6 months.

The results of a two year, double-blind placebo-controlled Scandanavian study of over 700 men with moderate symptoms of BPH, recently published, confirms that finasteride not only provides sustained symptomatic relief but often also reverses the prostate growth normally seen in men of this age.

Adverse effects are infrequent but include decreased libido and impotence.

Dr Angela Coulter demonstrated and discussed a US-produced interactive video system that is being evaluated by the King's Fund and Dr Mike Kirby and Mr Mike Mallinson demonstrated a user-friendly touch screen system produced by MSD.

Both systems were designed to inform patients about the facts of BPH and the risks and benefits of the treatment alternatives open to them.
2nd session: Prostate cancer

a) Screening Issues

In introducing the session on prostate cancer the chairman, Dr Holtgrewe noted that the prognosis for advanced disease remains stubbornly grim. The median survival of D2 stage disease is about 2 1/ 2 years and we still have no satisfactory way of tackling this. He also commented on the need to define the role of PSA tests ( p rovidentially s ent a ssistance (for urologists)) in the diagnosis and management of patients.

Dr Muir Gray claimed to be exceptionally well qualified to talk on the background to screening tests, "a vale of tears in which I have made every known mistake".

It must always be remembered that the ethic of dealing with healthy, non symptomatic individuals is different from that in treating patients. One must seek to balance the potential benefit to the population against the harm inflicted on healthy individuals.

There are significant cultural differences in attitudes to screening programmes in the US and the UK. Even so the NHS currently spends about [[sterling]]500m on screening programmes

Cancer screening suffers from two important biases:

i) length-time: more rapidly growing tumours are less likely to be detected by fixed interval screening
ii) lead-time: earlier detection may give an apparently longer survival, ie from diagnosis to death, although there is no actual prolongation of life, simply a longer time to be anxious about the cancer.

Dr Eric Sidebottom presented a speculative look at the genetics of prostate cancer. The latest information is easily accessible via the Internet in The Online Mendelian Inheritence in Man database (OMIM)
addresss-http://www3.ncbi.nlm.nih.gov/Omim/
This contains reports about the importance of family history in a small proportion of cases and leads to the conclusion that, in these cases, there must be a defective inherited gene, already named PRCA1 but not yet located.

The natural history of prostate cancer is, in many ways, similar to breast cancer and it would be surprising if they were not, to some extent, similar genetically. Indeed it is already clear that the mutant breast cancer susceptibility gene BRCA1 is involved in a small number of cases of prostate cancer.

Several methods are now available to track down genes and though these are at an early stage in prostate cancer, already about a dozen candidate sites have been identified. The identification of susceptibility genes will greatly assist research into elucidating the mechanisms of prostate hyperplasia and neoplasia and perhaps help us understand the fundamental differences between `pussycats and tigers'.

Dr Andrew Moore, in his talk, made a number of points about PSA values and their measurement:

1 There is great value in examining the rate of fall of PSA after prostatectomy or radiotherapy as a predictor of later recurrence. For chemotherapy the rate of fall of PSA on starting treatment has been shown to indicate its effectiveness. In particular circumstances like these, PSA is certainly of value.

2 Judgements made around particular "cut-off" levels are suspect. A value of 4.0 ug/L means that we are 95% sure that it is between 3.2 and 4.8 ug/L with the usual level of laboratory performance. It isn't that the labs are bad, but that the normal variance of laboratory tests is not being considered, especially as 40% of men diagnosed with prostate cancer have PSA values below 4.0 ug/L.

3 PSA velocity looks like a sensible method of differentiating `Tigers from Pussycats' in prostate cancer. The problem is that methods are unlikely to be able to measure with precision the (about) median 0.75 ug/L/year velocity of the PSA rise in Tigers. It might take 2, 3 or even 4 years of aggressive progression before the PSA value breaks out of the background noise.

4 The effects of ejaculation on serum PSA levels have not been considered. A paper in 1993 showed that in normal men with a mean (continent) PSA of 1.4 ug/L the level fell to 0.17 ug/L the day after an ejaculation, and was still only 0.29 ug/L a week later. Perhaps this should be taken this into account either by asking questions about the "ejaculatory-free period" before a sample is collected, by imposing a 7-day restriction, or preferably by doing some background research in this area. Even more importantly, this biological finding may be the source of a "dynamic" test to differentiate between cancers and BPH/normal prostate. Perhaps the disordered architecture of cancerous tissue would not result in falls in serum PSA after ejaculation.

Professor Brian Peeling addressed the knotty problem of "to screen or not to screen". The objectives of screening are clear:

i) to decrease mortality
ii) to decrease morbidity
iii) to increase quality of life.

The sceptics view of the current screening programmes is that:

i) the diagnostic methods are unreliable,
ii) treatment of early disease has not been proved to decrease mortality,
iii) it is unethical to create additional anxiety,
iv) screening is not cost effective.

However it has been predicted (Boyle) that incidence and mortality rates will both increase by 50% in the next 25 years. The dilemma is that only a very small proportion of microscopic tumours develop into invasive cancers (the pussy cats and the tigers) but that the tigers present late; at a time when treatment is largely inneffective.


How effective are current screening tests?

DRE (digital rectal examination) has a low predictive value and there is a high incidence of non palpable tumours. It has a low acceptibility for some patient groups. It is however quick, cheap and relatively easy to learn.

MRI can pick up some small tumours.

TRUS (trans rectal ultrasound scanning) is sensitive but at present only 1 in 5 of the identified, hypoechoic, lesions are cancerous.

CT imaging has no place in prostate screening at present.

PSA (see above). 20-40% of early cancers fall within the `normal' range

Dr Mike Kirby described a pilot screening trial conducted in his NHS practice to assess the incidence of prostate cancer and the acceptibility of the screening procedures to the patients.

Of 856 men invited to participate, 562 accepted. Of these 84 had a PSA >4ug/L and 78 went on to a TRUS. These scans led to 24 biopsies of which 12 were diagnosed as cancerous. This gives an incidence in the practice of 2.1%.

The acceptability appeared to be high to most patients. 95% said they would be willing to go through the process again and would recommend it to their friends. Screening did not increase anxiety in 69%, it caused `some' anxiety in 30% and only 1% admitted to great anxiety. Although TRUS and biopsy caused some distress in 63% of subjects, only 3% found it really distressing. However it might be argued that the individuals not accepting the original invitation (34%) are the ones in which anxiety is much increased by screening. Indeed harm might be done simply by inviting them to participate.

Studies such as this highlight the ethical dilemma in this field. Apparently healthy men want screening procedures, but does this make it justified to do them? The spontaneous presentation of prostate cancer is about 1-2 per 1000 men. This study revealed a 10x greater incidence. But how should these screen-detected tumours be treated?

In discussion Dr Raffle insisted that we should be more honest (with patients and ourselves) about prostate screening trials. Subjects must be told that these screening trials are mainly research and they must understand the drawbacks of participating as well as the possible benefits.

Professor Blandy also wished to emphasise the problems of discovering disease that we don't know how to treat.

Dr Holtgrewe said that it was the general policy in North America to undertake aggressive surveillance with annual DRE and PSA measurements and then institute aggressive treatment of the tumours discovered. "How can we wait until we are certain"? A delayed diagnosis of prostate cancer may indeed lead to litigation.


b) Treatment Options

Professor Brian Peeling discussed the surgical options. His straightforward message is that we simply do not at present have adequate evidence on which to judge the different treatment options. Views on radical prostatectomy vary from "an act of sado-masochism between consenting males" (Fellows ) to the best option when conducted by skilful, experienced surgeons. "One can only have a good quality of life when one has life" (Holtgrewe). There is an ongoing MRC controlled trial of radical prostatectomy but recruitment is slow and it is doubtful if an unequivocal answer will be obtained.

It is more generally agreed that radical prostatectomy should only be undertaken in men with a life expectancy of >10years, and aged less than 65 or 70.

Part of the difficulty in undertaking good trials and reaching rational treatment decisions arises from the innaccuracies with diagnosing and staging the disease. This situation should improve with better TRUS techniques and the ability to evaluate pelvic lymph nodes and do better bone scans.

The alternative surgical therapies, laser, cryo and thermotherapy remain unproved and should still be considered to be of doubtful value until proved otherwise in well controlled trials.

Watchful waiting still remains an attractive option for stage A1 disease. Present figures suggest a 16% mortality at 10 years and a 15-25% mortality for A2 disease at 5 years.

Dr David Cole discussed the role of Radiotherapy in prostate cancer. He noted that this disease is currently responsible for 13% of male deaths in Oxfordshire, which is more than colo-rectal cancer.

Once again we are faced with the problem that the evidence from clinical trials to date is not satisfactory and the ongoing MRC trial comparing watchful waiting with radical prostatectomy and radiotherapy, as noted above, is unlikely to give clear results. We don't yet know if local treatment can reduce eventual mortality from metastatic disease. Present results suggest that aC&#0;hough good radiotherapy regimeb&#0;can achieve 80% local control up to 5 years, there is often only 60% 5 year survival in such patient groups.

Radiotherapy has tended to have a bad press in the US, but when treatment is conducted in centres of excellence results are comparable to those achieved with radical prostatectomy. The rectal complications often associated with high doses of RT could be reduced if we had better technology to control dose delivery.

In this respect an interesting development is the introduction of proton beam therapy for the treatment of prostate cancer. It is possible to achieve more accurate localisation with proton beams and the Loma Linda Centre in California has already treated more than 700 patients this way. The first results of an RCT of proton therapy have just been published by Shipley but this has been conducted on patients with T3 or T4 cancers, surely the wrong group on which to establish the value of proton beams.

Professor Tim Oliver spoke about the roles of hormones and chemotherapy in treatment. He spoke of chemotherapy only to dismiss it as a routine treatment. It might have a justified role in a small sub-set of chemo-sensitive tumours but this remains to be established in experimental studies.

The ongoing MRC trial of immediate (on diagnosis) against delayed (when symptoms appear) hormonal therapy has not shown a difference so far. The need for total androgen block has not been established and the value of castration is not proven, indeed there appears to be no real danger in intermittent hormone therapy rather than the more conventional continuous treatment regime.

Prof Oliver thought that radical prostatectomy should not be the default treatment for early prostate cancer. Many such tumours do not apparently progress , some even regress. Watchful waiting offers educational opportunities in respect of, for example, smoking, diet and sexual behaviour. More thought needs to be given to the possible role of chronic prostatitis in the progression of tumours and to the role of immunotherapy in their prevention and treatment.

Dr Mike Kirby gave the final presentation to the meeting on the role of shared care of prostate cancer patients. Since there are only 380 urologists in the UK to look after the 12,000 new cases of prostate cancer each year as well as all the follow ups, it is clearly desirable for GPs to assist with the diagnosis and management of the disease.

However, since only a small part of a GP's work concerns cancer (1-3%) considerable support (?IT) will be needed. Agreed protocols and good lines of communication must be available. These should cover such areas as:

* diagnosis: which tests to use when, what are their specificities and sensitivities
* referral procedures
* interpretation of PSA results and their consequences
* staging of disease
* side effects of treatments, especially anti-androgens
* pain management and palliative care
* bereavement counselling.

A potential problem for shared care is shared costs. The price of drugs such as zoladex and CPA is considerable.

As a final comment our guest speaker Dr Logan Holtgrewe said that the key problem in prostate cancer was to screen early enough to find the younger patients who need treatment without frightening lots of normal people. Screening should not be undertaken in old men. Dr Holtgrewe's rule was not to do PSAs on men over 70 "unless they bring both parents with them".

In drawing the meeting to a close Dr Moore thanked all the speakers and discussants for their lively participation. He himself certainly thought that this 1st bandolier Conference had been a success and worth repeating in other contentious areas.

He asked delegates one final favour, namely to fax or write to him with their opinions on:-



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