Prostate cancer: avoiding risk of over treatment

Urologists, oncologists and research scientists gathered at the Royal College of Medicine, London, to examine the latest clinical research and discuss how this might affect the treatment and management of prostate cancer, both now and in the future.

Leading urologist, Professor Freddie Hamdy, from the Royal Hallamshire Hospital, Sheffield, examined the debate over screening for localised prostate cancer. In the 1980s it was discovered that prostate specific antibody (PSA) was raised in early prostate cancer and a simple blood test was developed that allowed small prostate cancers to be detected. Surgeons also refined the removal of cancer through radical protatectomy to perform the operation. But the huge increase in early symptomatic disease diagnosis, which followed, has prompted controversy over screening.

The number of radical prostatectomies doubled each year between 1990 and 1995, and in 1993 Chisholm warned of the prospect of a “prostate holocaust”, with prostates being removed without good reason. He wrote in the British Journal of Urology: “It must be clear that this debate cannot be resolved because there has never been an appropriate trial either of screening or radical surgery or no immediate treatment. Indeed, until randomised trials are performed, we do not know if early detection with or without radical treatment improves cancer-specific survival.”

Since the PSA test came into practice, thresholds have been established to indicate whether a patient is at risk or not. But Prof Hamdy warned that these thresholds are not based on proven clinical evidence. “There is no single PSA level at which we can say a man does not have prostate cancer,” he commented. Prof Hamdy also pointed out that not all prostate cancers are life threatening. (Cancer Research UK cites figures that half of men over 80 have cancer cells in their prostate but only 1 in 25 will die from prostate cancer.)

“The dilemmas presented by screening include a significant risk of over-detection and over-treatment,” he said. He cited figures that if 1 million asymptomatic men agreed to receive a PSA test, 100,000 will receive biopsies, 20,000 will have cancer, 10,000 may receive radical prostatectomy, 10 will die, 300 will have some degree of incontinence, and 4000 will have erectile dysfunction. (Frankel et al, Lancet 2002).

He added that there is a lack of “Level 1” evidence that aggressive treatment of screen-detected clinically localised prostate cancer improves survival or quality of life. Furthermore, reductions in prostate cancer mortality in some countries are apparently unrelated to the screening and treatment of clinically localised disease. When comparing survival rates between patients with cancer detected through PSA testing and those that are symptomatic, he said there was no evidence that survival time is increased with screening. However, the length of time the patient has to live with the knowledge of having prostate cancer is prolonged.

He outlined the challenges and pointed out that clinicians are currently awaiting the results from studies to ascertain the effectiveness of screening and treatment. There is a need to establish the screening age range (when to start and stop), the interval (~4 years, PSA kinetics) and assess how to establish a targeted screening population. There is a need to avoid overdetection and over-treatment, to develop algorithms to identify indolent disease and discover reliable novel biomarkers for diagnostic, predictive and prognostic purposes.

BIOMARKERS

He highlighted the availability of one such molecular diagnostic test for Pca. The PCA3 gene test is carried out on urine samples taken after digital rectal examination to help clinicians make a decision on whether or not to proceed to prostate biopsy.

“These biomarkers should have a significant impact on the diagnosis and staging of prostate cancer, delineate men that need treatment and reduce the number of unnecessary biopsies,” he added.

Prof Hamdy also pointed out a lack of clinical trails to compare the effectiveness of radical prostatectomy, radical radiotherapy and watchful waiting or active surveillance – making it difficult for clinicians to recommend one option over another. Trials are underway to address this lack of clinical evidence, he revealed. Prof Hamdy is a principle investigator for a randomised control trial to evaluate and compare treatments for localised prostate cancer. The “ProtecT” study is a research project is taking place in nine parts of the UK (Birmingham, Bristol, Cambridge, Cardiff, Edinburgh, Leeds, Leicester, Newcastle and Sheffield). It will investigate general health, quality of life, prostate cancer development, treatment outcome, length of life, and cost implications.

The first phase looked at whether community-based PSA testing is possible in the UK and whether men would accept randomisation of surgery. The second phase, currently in progress, tests the effectiveness and cost-effectiveness of the treatments, survival rates at 5, 10 and 15 years, disease progression (biochemical and clinical), the impact of treatment such as urinary/bowel symptoms, quality of life, sexual function and any complications. The study opened for recruitment from June 2001 and closes in May 2008, but follow-up will continue for 10-15 years.

TO TREAT OR NOT TO TREAT

Dr Chris Parker, from the Royal Marsden Hospital, Sutton, examined active surveillance of localised prostate cancer and addressed the question “to treat or not to treat?”

He considered the rationale for active surveillance and said that it is encouraging that the number of men opting for active surveillance is increasing. Some men with prostate cancer benefit from radical treatment, but it also has adverse effects and should be given only to those who stand to benefit. Most men with screendetected prostate cancer do not need treatment and delayed radical treatment appears to be as effective as immediate treatment. He suggested that it is acceptable to take a few years to decide. He also examined the risks of delaying treatment. Out of the 20% of all men with screen-detected prostate cancer, immediate treatment leads to 7.5% mortality (1.5/20), while a 10-14 year delay leads to 15% mortality (3/20).

Dr Parker emphasised that PSA is not an exact science. PSA may increase for reasons other than prostate cancer and there is a risk that the patient may opt for treatment unnecessarily. Furthermore, a stable PSA is not sufficient reassurance that an individual will not need treatment. A repeat biopsy is essential, he said. The Prostate Cancer Charity, which participated in the event, also highlights these problems. Around two thirds of men with a raised PSA do not have prostate cancer, while up to a fifth of men who have prostate cancer will have a normal PSA level. It cannot tell whether a prostate cancer is likely to be fast or slow growing, so there is also a risk that some men may have unnecessary treatment for tumours that would have posed no significant problems.

Dr Parker highlighted a randomised trial comparing radical prostatectomy with watchful waiting in early prostate cancer, by the Scandinavian Prostatic Cancer Group. This study found that out of 347 patients who had a radical prostatectomy, 118 patients died (due to any cause) after ten years. Compared to patients undergoing watchful waiting, where 104 died out of at total of 348, this figure was not significantly different. The most mature outcomes of an active surveillance policy are those reported from a prospective cohort study in Toronto. In 231 patients with a median age of 71 years at diagnosis, eight-year diseasespecific survival was 98%. There were two deaths from prostate cancer in comparison with 16 deaths from other causes. The Royal Marsden prospective study of active surveillance has recruited 326 men, with a median age of 67 years. At a median follow-up of 22 months, 65 (20%) patients have had radical treatment, 16 (5%) have switched to watchful waiting due to increased co-morbidity, 7 (2%) have died of other causes and 238 (73%) remain on surveillance. No patients have developed metastatic disease and none has died of prostate cancer.

In light of these results, active surveillance is a reasonable option for men who are fit for radical treatment and who have a clinical stage T1/T2a disease, a Gleason score £3 + 4 and initial PSA <15ng/ml. Active surveillance is particularly attractive to men with initial PSA <10ng/ml and % free/total PSA >20%, because they are most likely to avoid the morbidity associated with radical treatment.

FUTURE OF ACTIVE SURVEILLANCE

Dr Parker said that the optimum active surveillance policy is not yet defined. Unresolved issues include how to make the best use of PSA kinetics, the role and timing of repeat prostate biopsy and the indications for radical treatment. With improvements in MRI techniques, it is predicted that imaging may prove useful for both patient selection and monitoring. He added that men on active surveillance are candidates for clinical trials of low-toxicity interventions to delay disease progression. But, ultimately, the role of active surveillance can only be established by randomised clinical trials against immediate treatment, such as the ProtectT study highlighted by Prof Hamdy. He stressed the fact that research into prostate cancer has been woefully neglected. The challenges faced by prostate cancer research are: the lack of completed randomised controlled trials, difficulties in recruiting and the time it takes to perform such trials.

Dr Parker pointed out there are significantly more randomised trails for other forms of cancer. He reinforced this shortfall with a graphic representation showing the large number of trials dedicated to testing the effects of postoperative radiotherapy in breast cancer.

This was in contrast with a virtually blank page for post-operative radiotherapy in prostate cancer.

“It is standard practice after surgery for other common cancers to give extra treatment such as radiotherapy or drug therapy. But in the case of prostate cancer, we don’t know whether extra treatment should be given routinely after the operation,” said Dr Parker. He used the conference to announce a new study, RADICALS, which aims to establish whether this extra treatment should be given. It is currently looking to recruit over 4000 men from across the UK and from Canada and will be funded by Cancer Research UK.

Dr Chris Hiley, the Prostate Charity’s head of policy and research, said: “We need more information about the best timing and delivery of both radiotherapy and hormone therapy. The results of this trial will help reduce unnecessary side-effects in men who do not need more intense treatment while offering the most aggressive treatments to men who do.”

Dr Parker highlighted key areas of research that are expected to make significant contributions. In the United States, the largest-ever prostate cancer prevention trial “SELECT” (the Selenium and Vitamin E Cancer Prevention Trial) is taking place. Previous studies suggest that selenium and vitamin E (alone or in combination) may reduce the risk of developing prostate cancer by 60% and 30%, respectively, but only a large clinical trial can confirm these initial findings. SELECT began enrolling patients in August 2001, and closed enrollment in June 2004, with 35,534 participants. A 12-year follow-up is underway. The Prostate Cancer Charity also revealed at the conference that it is supporting seven different research projects across the UK with grants totalling £800,000. This includes funding of another ground-breaking study, by Dr Parker, into tissue markers of prostate cancer behaviour.

Most screen-detected prostate cancers are “irrelevant”, in the sense that, even without treatment, they would never have caused any symptoms. Radical treatment of early prostate cancer should ideally be targeted to men with significant cancers, so that the remainder are spared the treatment’s side-effects.

Accurate prediction of an individual’s prostate cancer behaviour at the time of diagnosis is not currently possible, and immediate radical treatment for all cases is a standard approach. Many men are left impotent or incontinent as a result of treatment for a “disease” that would not have troubled them.

THE SOLUTION

Many biomarkers have been found that predict prostate cancer recurrence after treatment. A key question is whether these biomarkers also provide information about early prostate cancer to distinguish the clinically significant cases – the ones that act the way most people expect cancer to behave – from the majority, with “irrelevant” disease. Biomarkers that predict treatment outcome are useful. However, biomarkers that demonstrated treatment to be unnecessary could be far more valuable.

THE WAY FORWARD

If men with prostate cancer receive treatment, it is impossible to distinguish the “irrelevant” cancers from those that were significant but successfully treated. In contrast, men with prostate cancer who choose not to have immediate treatment provide a valuable opportunity to study the natural history of the disease. Dr Parker’s project at The Royal Marsden hospital will measure a number of biomarkers in biopsy samples from several hundred men with prostate cancer, and analyse the results to determine the rate of disease progression. The project will take three years and should identify which biomarkers best predict disease progression.

Biomarkers that accurately predict the course of individual cases would enable radical treatment to be given promptly to those men who need it and avoided for those who do not.

FOCAL TREATMENT

The conference also examined a number of focal treatments that could potentially avoid the removal of healthy areas of prostate and minimise side-effects as a consequence. Mark Emberton, University College Hospital, London, discussed the potential for such focal therapies, in his presentation on: Ablative treatments for prostate cancer. He highlighted the following treatments:

• Tissue ablation technologies.
• Cryotherapy.
• High Intensity Focused Ultrasound (HIFU).
• Vascular targeted photodynamic therapy.
• Radio frequency ablation.
• Electroporation.

In particular, he has been heading trials into the way that HIFU is delivered. Previously this treatment was used for whole gland ablation, but Mark Emberton believes it is possible to exclusively target the diseased areas within the prostate. He has also been involved in trials of hemi-ablation, to examine the possibility of treating just one side of the prostate. This will avoid significant side-effects such as erectile dysfunction, by having just one side of the prostate treated, and may be performed on an outpatient basis, he explained.

Vascular targeted photodynamic therapy (VTP) was further examined by Professor Avigdor Scherz, from the Weizmann institute of Science, Rehovot, Israel. In the last decade, a novel class of bacteriochlorophyll (Bchl) derivatives that enable VTP has been developed. This is an approach in which activation of a light sensitive agent (a photosensitiser) in the circulation of the target tissue leads to rapid hypoxia and concomitant production of reactive oxygen species that cumulatively initiate rapid impairment, preferentially occlusion and blood stasis of the tissue’s vasculature. Necrosis or apoptosis of the cellular compartment result from subsequent deprivation of cells from nutrients and oxygen as well as intoxication by secondary radicals. This approach is in clinical trials for the treatment of prostate cancer and age-related macular generation using two drugs: Tookad (WST09) and Stacel (WST11). In patients that failed radiation therapy of localised prostate cancer, at appropriate drug and light doses, Tookad-VTP resulted in a 50% cure rate after one treatment. The conference concluded with an afternoon session dedicated to the patient perspective entitled Medicine and Me, which gave men diagnosed with prostate cancer the opportunity to question the experts and to share their own experiences of deciding on the right treatment and, in particular, their participation in clinical trials. The event discussed how this might increase patient empowerment. As one patient pointed out, there is a lack of information on this “neglected disease”.

“I wanted to know ‘which treatment is best?’ But for prostate cancer patients the answer is not clear,” he told the audience. The event concluded with a motivational speech by a patient who had experienced an excellent result through his participation in a clinical trial. He urged others to take the same positive approach in the fight against the disease.

USEFUL WEBSITE

www.prostate-cancer.org.uk