Cumulative Prostate Cancer Risk Assessment with the Aid of the Free-to-Total Prostate Specific Antigen Ratio

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1 European Urology European Urology 45 (2004) Cumulative Prostate Cancer Risk Assessment with the Aid of the Free-to-Total Prostate Specific Antigen Ratio Gunnar Aus a,*, Charlotte Becker b, Stefan Franzén c, Hans Lilja d,e,pär Lodding a, Jonas Hugosson a a Department of Urology, Sahlgrens University Hospital, S Göteborg, Sweden b Department of Clinical Chemistry, Malmö University Hospital, Malmö, Sweden c Oncological Center, Sahlgrens University Hospital, Göteborg, Sweden d Department of Laboratory Medicine, Division of Clinical Chemistry, Lund University, University Hospital (UMAS), Malmö, Sweden e Department of Clinical Laboratories, Urology and Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Accepted 10 September 2003 Published online 2 October 2003 Abstract Objective: To evaluate the cumulative risk of having a prostate cancer diagnosis in a repeated screening situation in relation to the free-to-total prostate specific antigen ratio (F/T-PSA). Patients and Methods: The present study includes 1385 men (aged years) who underwent prostate biopsy for the first time in the screening program that started in In case of a benign finding, the men have been followed biennially and new biopsies performed in case of persistently elevated PSA. The cumulative risk to be diagnosed with prostate cancer until July 1, 2002 was calculated by the Kaplan Meier method and comparison was made between different levels of T-PSA and F/T-PSA ratios. Results: Of 2129 biopsies 469 showed cancer. The cumulative 5-year risk to be diagnosed with prostate cancer was significantly dependent of the F/T-ratio. The risk for men with a T-PSA of ng/ml was 16% [6 25%] for those who had a ratio of >30% and 44% [34 60%] for those with a ratio of <10%. The corresponding difference for patients with a T-PSA of ng/ml was even more pronounced: 21% [0 42%] vs. 80% [64 96%]. Conclusion: By completing the T-PSA measurement with the F/T-PSA ratio it is possible to significantly better assess the cumulative prostate cancer risk within the next five years (without the aid of further urological work-up). # 2003 Elsevier B.V. All rights reserved. Keywords: Prostate cancer; Diagnosis; Prostate specific antigen; Free-to-total PSA; Screening 1. Introduction Prostate cancer is one of the most important health problems facing men in the Western world. The disease constitutes about 11% of all male cancers in Europe and accounts for 9% of all cancer deaths among men within the European Union [1,2]. A strategy aiming to change this situation is based on more widespread use of treatment with curative intent. This demands patients to be diagnosed with early stage disease in order to be successful. Of the * Corresponding author. Tel. þ ; Fax: þ address: gunnar.aus@vgregion.se (G. Aus). various pre-diagnostic screening tests available, measurement of serum prostate specific antigen (PSA) has been the major breakthrough for early detection of prostate cancer [3]. But the PSA test is not prostate cancer specific, resulting in a low specificity. A moderately elevated serum level of total PSA (3 10 ng/ml) is associated with the diagnosis of prostate cancer in only percent of the cases [4,5]. The ratio between free (F) and total (T) PSA (F/T- PSA) was described by Christensson et al. and was introduced as a possible way to better distinguish between benign conditions and prostate cancer [6]. A low ratio of F/T-PSA is associated with prostate cancer and a high ratio with benign prostatic hyperplasia [7] /$ see front matter # 2003 Elsevier B.V. All rights reserved. doi: /j.eururo

2 G. Aus et al. / European Urology 45 (2004) Usually, urologists do not primarily see patients who seek medical advice where prostate cancer is a possible differential diagnosis. Instead, general practitioners or specialists in other medical fields are the first doctors to advice the patient about their risk of prostate cancer. These doctors do not have access to the full urological armamentarium, such as transrectal ultrasound and biopsy, but need to give an advice based on the serum level of T-PSA and possibly the findings at digital rectal examination only. The F/T-PSA ratio is widely available and adds but marginal costs in comparison with the T-PSA measurement only. Despite this, it is not commonly used, as there is no consensus on how the ratio should be translated into clinical practice. The Göteborg screening study has evaluated a randomly, population based sample of 10,000 men aged years offered biennial PSA screening since The aim of the present study was to evaluate if supplementing total PSA with the F/T-PSA ratio, but without utilising further urological examinations, could aid in the cumulative prostate cancer risk assessment of males in the age groups where early detection of prostate cancer might be relevant. If so, this information could be potentially useful for all doctors involved in men s prostate cancer risk assessment. From the sample of men who were randomized to active screening, 7165/9972 (71.9%) have participated at least one time during the four invitation rounds of these men turned out to have an elevated T-PSA (>3 ng/ml) in at least one of the screening rounds (irrespective of calendar time) and all were offered prostate biopsies each time they had increased T-PSA. These men, with at least one occasion with an elevated T-PSA, form the base for the present study. The F/T-PSA has not been taken into consideration in the evaluation of these men prior to the biopsy procedure. The incidence of prostate cancer after the first occasion with increased T-PSA was evaluated with the Kaplan Meier method. The observation time started (time 0) at the first elevated T-PSA irrespective of when this actually occurred from January 1995 to May The eventual diagnosis of prostate cancer was entered as uncensored observation. Men were censored either when they had moved from the area, when they reached the age of 71, at the time of death from other causes or at July To ensure that all cancer cases were included, the file has been cross-matched against the national and regional cancer registry and this way eventual interval cancers diagnosed up to December 31, 2000 have been included. The study population thus consists of a truly randomly selected, population-based sample of men aged years who has been further evaluated after the occurrence of their first elevated T-PSA level. Differences in risks of being diagnosed with prostate cancer were compared between different levels of T-PSA and F/T-PSA ratios as measured at the first occasion with increased T-PSA (3 ng/ml). Significance in observed differences was tested with the log-rank test. The impact on the hazard rate for being diagnosed with prostate cancer of T-PSA and F/T-PSA ratio was tested with the Cox regression analysis [10]. 2. Method In the community of Göteborg, Sweden (population 440,000) there were as of December 31, 1994, 32,299 men alive who were born between January 1, 1930 and December 31, Following permission from the ethical committee, with the aid of the Swedish Population Registry, 10,000 men aged 50 to 65 years were randomized to prostate cancer screening and 10,000 men were randomized to serve as at control group. Males with prevalent prostate cancer were excluded resulting in an intervention group of 9972 men and a control group of 9973 men. All these men have received an invitation to have blood drawn for PSA-testing at 2-year intervals with the first invitation between January 1995 and May Serum was separated from blood cells, frozen and stored at 20 8C within three hours. T-PSA and F-PSA were analyzed within two weeks of sample collection and less than three hours after thawing. T-PSA and F-PSAwere detected with Delfia Prostatus PSA F/T Dual Assay (Perkin-Elmer Life Sciences, Turku, Finland). The assay for T-PSA measures F-PSA and PSA in complex with a 1 -antichymotrypsin in an equimolar fashion [8]. All men with a T-PSA of 3 ng/ml were invited for further examination. The follow-up examination included a digital rectal examination (DRE) and a transrectal ultrasound of the prostate (TRUS) with laterally directed sextant biopsies. Men with negative biopsies and persistently elevated T-PSA in the subsequent biennial testing may thus have been invited for biopsy up to four times. The biopsy technique and outcome of the first screening round has previously been described in detail [9]. 3. Results Of the 1385 men (mean age 61.1; range years) who had a PSA 3 ng/ml for the first time in the study, 1349 accepted further examination with DRE and TRUS and 1304 (94.2%) accepted biopsy. The number of patients who accepted further evaluation in the subsequent rounds is presented in Table 1. The median T-PSA at first evaluation was 3.96 ng/ml (mean 5.92; range ) among the men who accepted biopsy. Table 1 Number of patients and biopsy outcome at the follow-up examinations after the first time the men had an elevated PSA (3 ng/ml) in the screening program DRE þ TRUS DRE þ TRUS þ Biopsy Benign Cancer First examination (24.8%) Second examination (21.1%) Third examination (13.3%) Fourth examination (8.6%) Total (22.1%) The outcome is related to the number of biopsies that each individual has undergone, not the screeninground.

3 162 G. Aus et al. / European Urology 45 (2004) Fig. 1. The cumulative risk of being diagnosed with prostate cancer in relation to the first measured elevated T-PSA level (n ¼ 1385) ( p < 0:0001). The cumulative risk of being diagnosed with prostate cancer in relation to the first measured elevated T-PSA level is presented in Fig. 1. Note that this is the level of PSA when it was the first elevated T-PSA, not at the time of eventual diagnosis. When the biopsy outcome was split according to discretized T-PSA and disrcretized F/T PSA ratio, the risk of prostate cancer was calculated and the results are presented in Fig. 2a c. A low ratio is associated with a significantly higher cumulative risk of being diagnosed with prostate cancer. As an example, the risk may vary as much as nearly 7-fold with different F/T ratios within the narrow T-PSA range of ng/ml (Fig. 2b). In order to estimate the separate effect of both T-PSA and F/T PSA on the risk of having prostate cancer, a Cox s linear regression analysis was performed. The p-value for T-PSA and for the F/T PSA ratio was < for each of these variables indicating that both factors have independent impact on the risk of being diagnosed with prostate cancer. 4. Discussion Primarily, the results from the present study clearly indicates that the F/T-PSA ratio adds new information, independent from T-PSA, concerning a patients cumulative risk for having prostate cancer within the next five years. The use of cumulative prostate cancer risk as an endpoint is a clear strength to this paper as it reduces the problems with sampling errors inherited in papers where only one set of biopsies has been taken Study design The study population was randomly selected from the male population in a defined geographic area. As 72% has undergone at least one PSA-test and more Fig. 2. The cumulative risk of being diagnosed with prostate cancer in the relation to different F/T PSA ratios. The starting point (time 0) is the time of the first elevated T-PSA and the ratio is measured at the same time. (a) T-PSA of ng/ml ( p < 0:0001), (b) T-PSA of ng/ml (p < 0:0001), (c) T-PSA of 10 ng/ml (p ¼ 0:0241). than 90% of those with elevated levels accepted biopsy, it should be possible to generalize the results to men in the pertinent age groups, years. The reason why we chose to consider only T-PSA and F/T-PSA ratio in this study, rather than including also factors as digital rectal examination and prostate volume, was that we wanted to evaluate the impact on the risk of prostate cancer that were available after a simple blood test only. In other words, the information

4 G. Aus et al. / European Urology 45 (2004) provided is thus available without the need for a urological evaluation F/T-PSA ratio and the risk of cancer in the first set of biopsies Catalona and co-workers evaluated the F/T-PSA ratio in a large multicenter study including a selection of 379 men with prostate cancer and 394 with benign disease [11]. They noted that the individual risk assessment varied from 8 to 56%, pending the F/T ratio, in patients with a T-PSA of 4 10 ng/ml. This is in total harmony with our results. The risk of being diagnosed with prostate cancer at the first biopsy (within 6 months after the PSA estimation) varied from 8.1 to 55.6% in the group of men with a T-PSA between 3.00 and 9.99 ng/ml (Fig. 2a and b). Similar data was presented by Finne and co-workers who noted that the risk of having prostate cancer was strongly affected by the F/T-PSA ratio in men with both positive and negative DRE and also in men with a prostate volume of </>37 ml [12]. In the same study, the impact of the ratio was also clear in patients with a T-PSA of up to 20 ng/ml, supporting our finding in the group of men with a T-PSA >10 ng/ml (Fig. 2c). In a recent article, Roehl and co-workers evaluated the F/T ratio in a non-randomized sample of 965 men included in a screening program with a T-PSA within the lower range of ng/ml and a benign DRE [13]. The found that patients with a ratio of <10% had a prostate cancer risk of 44% while it decreased to 19 20% for those having a ratio >21%. These data are also fully comparable to our results in the T-PSA ng/ml group (Fig. 2a). It thus seems that there is support in the literature for the results obtained in the present, randomized population-based study: The F/T ratio gives independent information regarding the risk of having prostate cancer at the first biopsy for men with an elevated T-PSA from at least 2.5 ng/ml to 20 ng/ml. There is a substantial, 5-fold variability in the risk from about 10 to over 50% within the same T-PSA range F/T-PSA ratio and the cumulative risk for prostate cancer There are, to our knowledge, no similar studies available for direct comparison with the present cumulative results. The finding that the risks for prostate cancer detection is lowered by repeat screening (Table 1) is in harmony with the findings from Smith et al. [14]. In their non-randomized study of 10,248 males offered serial screening they noticed that the number of men with elevated PSA decreased over time and that the cancer detection rate decreased from 3 to <1%. It is clear that the F/T ratio has a clinical and statistical significant impact on the cumulative risk of being diagnosed with prostate cancer. In men with a T-PSA within the comparatively narrow range of ng/ml, the 5-year risk varies 2.5-fold from 16 to 44%, depending on the ratio. The risk of being diagnosed with prostate cancer increases over time. The only group where it seems safe to have longer screening intervals than 2 years is in patients with a ratio of >30% where the risk of having cancer detected within the first four years seems negligible after on set of benign biopsies (Fig. 2a). In men with a T-PSA of the variation in relation to the F/T-PSA ratio is more pronounced, from 21% risk if the ratio is >20% to 46% risk with a ratio between 10 and 20% and 80% 5-year cumulative risk if the ratio is <10%. In the two latter groups, is seems like the risk of being diagnosed definitely increases over time (Fig. 2b). Even if the 6-month risk was about 27% in the 10 20% F/T-group it increased to 46% at five years. Comparable data for the <10% group was an increase from 56 to 80%. Many of these tumors were probably present already at the first biopsy and it seems that vigorous efforts are warranted to rule out cancer in this group of men (i.e. early re-biopsy or more extensive biopsies). In men with a PSA >10 ng/ml over time is the risk substantial for the majority of men so the F/T ratio seems to be of comparatively limited value Limitations of the study It is well worth to point out that the exact limits for the F/T ratio presented in this paper is only valid for the specific assay used. Different free/total assays have been shown to have different cut-off points for the detection of prostate cancer and cut-off points presented here cannot be directly transferred to other assays. The doctor must be aware of which assay that is used in their own clinical practice [15]. It has been shown that including patients age, prostate volume and findings at DRE together with T-PSA and F/T-PSA in an artificial neural network could be used to further increase the accuracy for prostate cancer detection [16]. This would, however, introduce to call in patients for further urological work-up with both DRE and TRUS, something that is not needed in order to obtain the risk stratification presented in our study. Another possible limitation in the present study is related to the age groups examined. It is well known that the risk of being diagnosed with prostate cancer is related to age. We cannot say whether the risk of being diagnosed will increase further over time also for those

5 164 G. Aus et al. / European Urology 45 (2004) patients who are at a comparatively low risk at the moment. However, with the inevitable increase in lead time with PSA-screening and the fact that screening efforts should be restricted to men with more than 10 years of life expectancy, we have found it ethically difficult to continue screening in higher age groups at the present time. But, even with this limitation, the present study provides useful, new information regarding the use of the F/T-PSA ratio and the cumulative risk of being detected with prostate cancer In summary By complementing the T-PSA measurement with measurement of the F/T-PSA ratio it is possible to significantly better assess the cumulative prostate cancer risk within the next five years. We recommend that the F/T-PSA ratio should be analyzed whenever there is an indication for a T-PSA test in men without known prostate cancer. Physicians are used to performing risk assessment based on continuous variables without distinct cut-off values (such as sedimentation rate, blood pressure or hemoglobin concentration) for various clinical disorders in their everyday clinical practice. The F/T-PSA ratio is readily available and can be used in a similar fashion in men who want to now about their prostate cancer risk. It is worth to point out that there was no subgroup among these men with a T-PSA elevated to 3 ng/ml that had such a low cumulative risk for prostate cancer that it would be uncontroversial to avoid prostate biopsy, bearing the relatively young age groups included in the study in mind. However, we have in the present paper shown that the cumulative risk of having prostate cancer may vary significantly within narrow T-PSA ranges. In the common situation when competing diseases are present or the patient is in a border-line age group, the present risk group profiles based on the F/T-PSA ratio may be very useful in the choice whether to proceed with repeated PSA-testing only or an urologic evaluation including prostate biopsy. Acknowledgements The present study is a part of the European Randomized Screening for Prostate Cancer (ERSPC) study. The present study has supported by grants from the Swedish Cancer Society (Grant No 3792-B96-01XAB and No 3555-B99-08XBA) and the Swedish Research Council (Medicine, Grant No K X A). The study has also been supported by Wallac Oy, Turku, Finland, Schering Plough, Sweden and Abbott Pharmaceuticals, Sweden. None of the funding sources have had access to the data or been involved in the data collection, data management or writing of this paper. References [1] Bray F, Sankila R, Ferlay J, Parkin DM. 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