This is the first time that these longitudinal reference ranges allowing individually calibrated predictions have been applied to PSA measures of men with PCa [14
]. We modelled the pattern of change of PSA level in two different large cancer populations and compared the results to those obtained from a model derived from a reference, noncancer population (Krimpen). The model derived from the UK cohort was very similar to the Krimpen model calibrated to that population. The model derived from the SPCG-4 cohort had a greater yearly increase in PSA than the calibrated Krimpen model. Hence, in men with PSA-detected PCa, the yearly PSA change is similar to that in cancer-free men, whereas in men diagnosed with PCa following clinical presentation, the yearly change in PSA level was considerably higher. There is an urgent need to develop protocols that allow safe monitoring and/or surveillance of men with low-risk and localised (T1c, Gleason <7) PCa, the majority of whom will not develop clinically important, let alone advanced, disease in their lifetimes [6
]. Many monitoring protocols have been developed, but there is little consensus about what should be measured or what constitutes evidence of risk of progression [11
]. The validation of such protocols is difficult, primarily because of the time required for clinically relevant outcomes (ie, death or the development of metastases) to occur, and there are few data sets with such outcomes from men with PSA-detected PCa. The method described in this paper attempts to take into account the benign growth of the prostate and consequent changes in PSA level over time. Further research, however, is required to investigate whether patients at the highest risk of progression can be identified when their disease is still curable by local treatment.
The differences found in the PSA patterns between the UK cohort and the SPCG-4 cohort may be due to their different participant characteristics. The UK study population consists of men diagnosed with PCa following communitywide PSA testing based at general practices, whereas SPCG-4 men presented clinically to urologic centres. The UK men were younger than those in the SPCG-4 study and had lower average PSA levels and Gleason scores. Calculations of lead times for PCa suggest that UK men will have been diagnosed some 8–12 yr before SPCG-4 men [21
]. It is also important to note that the SPCG-4 cohort had a much longer follow-up than the UK cohort (6.6 yr vs 2.6 yr) and, thus, contained many men who had progressed to locally advanced and metastatic disease. These factors are likely to account for the difference in age-related increase in PSA levels between the studies. Our model suggests a yearly change in PSA level of 15% in the SPCG-4 study versus 4% in the UK study. A study combining results from three longitudinal studies of PSA (up to time of diagnosis with cancer) suggested similar rates of change of 2% per year in men without cancer and 15% per year in men with localised disease [12
]. These studies were undertaken before the PSA screening era, so there may be many more men among the controls who had undiagnosed PCa, which could account in part for the similarity between the estimated age-related increases in the PSA-detected men in the UK study and those in cancer-free men from the earlier studies.
It is encouraging that the Krimpen model and the UK model show similar increases in PSA level with increasing age; a higher increase in the SPCG-4 cohort implies an increase in rate of change in PSA level with increased disease severity or time since diagnosis. Thus, as we hypothesised, age-related increase in PSA level seems to be higher for clinically detected symptomatic cancer than for PSA-detected cancers. A potential advantage of the reference-range method for monitoring men with PSA-detected PCa is its ease of use: serial PSA measures can be plotted against the pattern predicted using the first PSA measurement. Additionally, the method avoids concerns raised by day-to-day fluctuations in PSA level and takes into account age and PSA level at the beginning of monitoring rather than just observed PSA level, velocity, or relative increase, as in current protocols. It is unknown whether changes in PSA occur in advance of progression (indicating a role for PSA monitoring) or are an expression of it (so that rapidly increasing PSA could identify those who would benefit from early hormone therapy).
This study has some weaknesses. The original model is based on data from one community-based study in the Krimpen area of the Netherlands. While we anticipate that these findings should be generalisable, they may not be representative beyond Northern Europe. We have no PSA measurements of men both before and after they developed cancer, so we cannot examine a change-point model. Men in the Krimpen study were investigated for PCa if they had PSA >4 ng/ml [15
], so some men in the cancer-free
Krimpen model may have had undetected disease. This is, however, likely to be the case in any data set of men of this age [22
], and when later-detected cases of PCa were removed from the Krimpen data set, it made little difference to the fitted model [14
Considerable further research needs to be undertaken. These methods (and alternative formulations) must be assessed for their ability to predict progressive disease. This requires data on a large number of men undergoing active monitoring for many years, with information on progression of disease (presence of metastases, death) obtained independently of their PSA status (eg, all men restaged at the end of follow-up, regardless of PSA level).