Summary

The proposed “Riskman” randomised controlled trial will evaluate a significantly improved approach to prostate cancer screening focussing on how we screen and who we screen. If successful it would completely change the debate on prostate cancer screening within 5 years.

Background

Cancer represents a failure of control of cellular growth and cancer becomes more difficult to treat the later it is diagnosed as a cascade of molecular and pathological events occur, as such early detection is key. For cancers that have no obvious early symptoms that uniquely identify them, early “biomarkers/tests” are required and need to be applied to large populations at risk in order to go and find the disease at an earlier time that it would symptomatically present.

Such “screening” for disease identification and subsequent management represents a philosophical and practical difference in approach compared to treating disease per se and raises significant issues that need to be further considered and balanced. Philosophically, screening changes the approach from treating disease as it presents to actively seeking asymptomatic individuals who may/will develop a more serious disease at a later time. As such many doctors argue that some screening approaches are potentially not in keeping with the Hippocratic Oath in that a physician should “first do no harm”. Furthermore and most pertinently from a practical point of view, screening tests need to be offered to large sections of the “normal/healthy” population to identify the smaller subset that have the early stages of the disease of interest. As such, screening programmes might appear to be inefficient and consume an inappropriately large share of limited resources in that the majority of participants in a screening programme do not have the disease of interest. Such limitations, however, need to be offset against the alternatives, both in terms of “costs” to the individual and the NHS in leaving the disease to its natural course and hence later diagnosis and poorer treatment options available at a later stage.

Proposed approach.

Prostate cancer itself represents a classic dilemma for consideration for screening and as such has been the subject of intense debate and controversy for the past 10 years. The position has not actually been helped much by the recent large scale European evaluation of screening for prostate cancer using the PSA test as although this ultimately shows a benefit in terms of improved survival it also shows that many more men have to be diagnosed and potentially “over-treated”. Although this issue itself is also keenly debated if the screening programme performance could be significantly improved it would rapidly change the balance of “pros and cons” that all recognise in the current rather unfocussed approach and it becomes much more likely that a screening approach will be adopted. It is against this background that the Riskman trial is proposed – a position strongly and actively supported and advocated by the majority of the patient support groups including the Prostate Cancer Support Federation. The key elements of the trial centre on the fact that there already exist two key ways in which the screening approach to prostate cancer can be substantially improved - although the approach still needs to be demonstrated in practice through the Riskman trial.

The first change to a threshold PSA approach to defining who should be referred for biopsy and further investigation and possible treatment is to use more markers of early disease systematically in the initial screen. Such is the approach of many “risk calculators” which have been proven to more accurately identify men at elevated individual risk. As such we advocate the Sunnybrook risk calculator which combines several easily available and inexpensive tests in identifying subsequent risk of PCA. The acceptability and costs/cost effectiveness of such an approach still needs to be determined although our current survey of over 1000 healthy men overwhelmingly shows that men support the approach and would join a trial set up to evaluate the approach further.

The second change to a population based screening approach is to change the population invited for screening. At present the population chosen to be screened is based on risk as defined by age alone (50 although some recommend a combination of age and ethnic group e.g. 50 in Caucasians and 45 in blacks or those with a “significant family history”). As such this is based on an approximate estimate of 2% or higher risk of developing prostate cancer in the next 10 years. As such the population at risk defined as eligible for being screening is currently only crudely and imprecisely defined.

There exists a better/more precise way of identifying the population at risk by adding a simple and cheap blood test which can be done at any age and scores a number of newly establishing genetic markers (SNP’s) of susceptibility to effectively rule out those at low/very low risk (eg the lowest third of the population) and or rule in those at normal or higher risk. Such assessments already have value in more precisely defining the population that should be included in the screening programme. They may indeed also in the future, as more of these markers are identified, have clinical utility in adding to the individual assessment of risk but at the moment there best use is in reducing the population that will benefit from entering the screening programme.
For the proposed Riskman Trial, as the optimum use for incorporating such assessment of genetic susceptibility has yet to be fully defined they will not be used to define risk per se at the start of the trial but appropriate samples will be taken and using the adaptive trial design their optimal use will be established as part of the trial itself such that by the end of the trial period both the performance of the risk scoring algorithm at the individual level and the evaluation of the precise “best” population subgroup to screen (based on predisposition gene score) will be established.

Taken together the results of the Riskman trial would dramatically change the arguments for prostate cancer screening and greatly increase the likelihood of an effective and cost effective prostate cancer screening programme for the UK being established.