Click here to download the excell file for PSA slope and lnPSA slope calculation: PSAslope and lnPSAslope.xls

AUA 2008 POSTER 1877, Orlando, FL, May 21 2008

lnPSA slope

 

Luigi Benecchi, Anna Maria Pieri, Michele Potenzoni, Andrea Prati, Roberto Arnaudi, Carmelo Destro Pastizzaro, Antonio Savino, Nicoletta Uliano, Domenico Potenzoni

Department of Urology, Fidenza Hospital, Parma, Italy

www.urologiaparma.com

urologiaparma@libero.it

 

ABSTRACT

OBJECTIVES To compare different tools for evaluate prostate-specific antigen (PSA) kinetics before prostate

biopsy, such as PSA velocity, PSA slope, natural logarithm PSA slope (lnPSA slope), and PSA

doubling time (PSADT).

METHODS This study was conducted involving 325 male patients evaluated with transrectal ultrasoundguided

biopsy of prostate. Patients with at least three consecutive PSA measurements taken in

at least 24 months entered in the study. We estimated PSA slope from the slope of the least

squares regression line fit to PSA versus time in years; PSA velocity was calculated as the running

average of the rate of change during at least three consecutive assays. The acceleration of PSA

(lnPSA slope) was calculated as the slope of lnPSA versus time, where ln is the natural

logarithm. PSADT was calculated using the formula: PSADT _ ln 2/(lnPSA slope).

RESULTS We found a total of 74 cancers at the ultrasound guided prostate biopsies. At the receiver

operating characteristic (ROC) analysis, lnPSA slope (area under the curve [AUC], 0.793)

evidenced better results than PSA (AUC, 0.585; P _0.001), PSA velocity (AUC, 0.734;

P _0.009), PSA slope (AUC, 0.752; P _0.043), and PSADT (AUC, 0.516; P _0.001).

CONCLUSIONS The results for PSA, PSA velocity, PSA slope, and lnPSA slope were significantly higher in

patients with prostate cancer than in controls. The results of the present study suggest that

lnPSA slope may be useful for prostate cancer diagnosis. At the ROC analyses, the lnPSA slope

AUC was better than that of PSA, PSA velocity, PSA slope, and PSADT.

INTRODUCTION

The aim of our study is to compare different tools for evaluate PSA kinetics before prostate biopsy such as PSA velocity, PSA slope, natural logarithm PSA slope (lnPSA slope) and PSA doubling time.

MATERIALS AND METHODS

Between January 2001 to June 2006, all men who underwent transrectal ultrasound-guided prostate biopsy with 6 or more cores and with at least 3 consecutive PSA measurements (done in our centralized laboratory) in 731 or more days before biopsy entered the study.

All patients were scheduled for transrectal sonography with biopsy because of abnormal digital examination findings and/or PSA levels of 4 micro/L or greater. 325 men entered the study.

For PSA velocity calculation only PSA measurements with a time interval from the previous more than 6 month were considered. We included in our study all PSA measurements if they were assayed in our centralized laboratory with the indicated technique.

PSA velocity was calculated as the increase of PSA per year from the first to the last PSA assay before prostate biopsy.

The PSA slope was calculated with the least square fit (PSA versus time) using an electronic sheet, so the line slope value and the intercept value was obtained for each patient. Specifically, we fit the equation: y=a+bx to the data of each patient, where "y" represents PSA and "a" the intercept. Parameter "b" is the slope and reflects the increase of PSA in one year 11.

The "acceleration" of PSA (lnPSA slope) was calculated as the slope of lnPSA versus time, where ln is the natural logarithm.

PSADT was calculated using the formula: PSADT=ln 2 ⁄(lnPSA slope) 12. Mann Wintney U test was used to assess the differences PSA between different groups (Statistica 6.0). The receiver operating characteristic (ROC) curve was generated by plotting sensitivity versus 1-specificity (MedCalc 7.0). We compared results by comparing the areas under the receiver operating characteristics curve (AUC) according to Hanley and McNeil 13. Stepwise logistic regression analyze was used to assess continuous variables (age, PSA, percent free PSA, PSA density, PSA velocity, lnPSA slope and PSA doubling time).

RESULTS

A total of 74 cancers were found at the ultrasound guided prostate biopsies.

PSA, PSA velocity, PSA slope, lnPSA slope were significantly higher in patients with prostate cancer than in controls. To confirm the validity of our date, in the table it is reported the significant difference also for free to total PSA, PSA density, and PSA transition zone density too.

No significant differences were found for PSA intercept, number of PSA assays and the time interval between the first and last PSA.

At the ROC analysis lnPSA slope (AUC 0.793; 95% confidence interval 0.745 to 0.836) evidenced better results than PSA (AUC 0.585; 95% confidence interval 0.530 to 0.639; p<0.001), PSA velocity (AUC 0.734; 95% confidence interval 0.683 to 0.782; p<0.009), PSA slope (AUC 0.752; 95% confidence interval 0.701 to 0.798; p<0.043) and PSADT (AUC 0.516; 95% confidence interval 0.460 to 0.571; p<0.001) (table 2).

At lnPSA slope equal to zero, the sensitivity resulted as being 95.9% with a specificity of 35.1%, a positive likelihood ratio of 1.48 and a negative likelihood ratio of 0.12. At lnPSA slope equal to 0.41 the sensitivity resulted as being 90,3% with a specificity of 50,2%.

Of the 325 patients reviewed 275 presented all clinical data (age, PSA, percent free PSA, PSA density, lnPSA slope) for multivariate logistic regression. At the multivariate logistic regression only percent free PSA (0dd Ratio 0.905) and lnPSA slope PSA (0dd Ratio 173.48) showed a statistical significance.

COMMENT

In the current study we compared different methods for evaluate PSA kinetics before prostate biopsy. Specifically PSA velocity, PSA slope and lnPSA slope were higher in patients with prostate cancer than in controls. It is interesting to note that PSADT didn't show any difference between prostate cancer patients and controls. PSADT as PSA velocity, PSA slope and lnPSA slope were analyzed as continuos variables (i.e., they could take on negative or positive values). In fact in our analyze even in men with PSA decreasing, the PSADT was easily calculated with the logarithm transformation of PSA. In previous article there was reported that PSA doubling time and log slope PSA are equivalent 17, we think that PSA doubling time is related with lnPSA slope (PSADT=ln2/lnPSAslope) but they are mathematically different. PSADT correlate with tumor progression, therapeutic outcome and cancer specific mortality 17, 18 but in our patients showed no value as diagnostic tool for prostate cancer. In contrast with theoretically supposed advantages for screening program 19, 20. PSADT is so dependent upon the baseline PSA measurement that it only works when men start out at the same baseline (such as an undetectable PSA after surgery) and doesn't work well to compare subsequent PSA rises between men starting at all different PSA levels. Recently Stephen et coll reported that PSADT was of limited utility in selecting patients for a prostate biopsy 21.

For a clinical utilization of lnPSA slope it is better to use 3 or more PSA values in a period of 2 or more years. In case that the time interval is less than 2 years it is better to use the PSA slope 11.

LnPSA slope permits evaluation of the "acceleration" of PSA in men with prostate cancer, in fact indicate the value of its exponential growth 23.

D'Amico evaluated PSA velocity within one year before prostate cancer diagnosis in 1095 men who underwent radical prostatectomy 9. D'Amico used linear regression analysis to calculate the PSA velocity, so the term PSA velocity in his work should be considered as PSA slope. Instead lnPSA slope needs more time than PSA velocity or PSA slope to evidence a pathological variation.

The major limitation of lnPSA slope is the availability of 3 or more PSA values made with the same laboratory technique in 2 or more years.

The ideal threshold for a cancer marker is at 95% of sensitivity, that for lnPSA slope corresponds to zero, but the slow-growing and indolent nature of prostate cancer, coupled with the fact that a man will be tested again and again in his lifetime, makes a false negative test of less importance. So we promote to limit the sensitivity at 90% that corresponds to an interesting specificity of 50%. In another words, above 0.041 lnPSA slope every 2 prostate biopsies, 1 will result positive.

The potential limitations of this study must be considered. The time from first to last PSA and the number of PSA assays are different in controls than in patients (p=0.038), this because with prostate cancer diagnosis the longitudinal evaluation ends, but in controls this continues without interruption. Another limitation of our paper is the cut-off of 4.0 ng/ml of PSA used as threshold for biopsy according to our strategy at that time. We are aware that the current conventional strategy for biopsy is to reduce PSA threshold 2, so we promote prospective study to confirm our analysis.

CONCLUSIONS

This is the first work about the use of natural logarithm PSA slope in prostate cancer diagnosis. PSA, PSA velocity PSA slope, lnPSA slope were significantly higher in patients with prostate cancer than in controls. The results of the present study suggest that lnPSA slope may be useful for prostate cancer diagnosis, instead PSA doubling time showed no diagnostic usefulness. At the ROC analyses the lnPSA slope AUC is better than that of PSA, PSA velocity, PSA slope, and PSA doubling time.

REFERENCES

  1. Kirbly S.R, Christmas T.J. and Brawer M.K.: Prostate Cancer (second edition). Mosby 2001

2 Zhu H., Kimberly A. Roehl, Jo Ann V. Antenor, AND William J. Catalona: Biopsy of men with PSA level of 2.6 to 4.0 ng/mL associated with favorable pathologic features and PSA progression rate: a preliminary analysis. Urology 66 (3): 547-51, 2005

3. Karazanashvili G., Abrahamsson PA.: Prostate specific antigen and human glandular kallikrein 2 in early detection of prostate cancer. J Urol 169: 445-457, 2003

4. Benecchi L: Neuro-fuzzy system for prostate cancer diagnosis. Urology, 68(2):357-61, 2006.

5. Carter HB, Pearson Jd, Metter EJ, et al: Longitudinal evaluation of prostate specific antigen levels in men with and without prostate disease. JAMA 267: 2215-20, 1992

6. Roobol m.J, kranse R., De Koning H.J., Schroder F.H.: Prostate-specific antigen velocity at low prostate-specific antigens levels as screening tool for prostate cancer: results of second screening round of ERSPC (Rotterdam). Urology 63(2), 2003

7. Komatsu K., Wehner N., Prestigiacomo A.F.: Physiologic (intraindividual) variation of serum prostate-specific antigen in 814 men from a screening population. Urology 47:343-346, 1996

8. Pound CR, Partin AW, Eisenberg MA, et al: Natural History of progression after PSA elevation following radical prostatectomy. Jama 281(17):1591-7, 1999

9. Patel A., Dorey F., Franklin J. Et al: Recurrence patterns after radical retropubic prostatectomy: Clinical usefulness of prostate specific antigen doubling times and log slope prostate specific antigen. J Urol 158: 1441-1445, 1997.

10. D'Amico A., Moul J., Carroll PR., Sun L., Lubreck D., Chen M.: Prostate specific antigen doubling time as a surrogate end point for prostate cancer specificity mortality following radical prostatectomy or radiation therapy, J Urol, 172: S42-S47, 2004

11. Benecchi L.: PSA velocity and PSA slope. Prostate cancer and prostatic diseases 9: 169-172, 2006

12. Choo R., Klotz L., Deboer G., Danjoux C., Morton G.: Wide variation of prostate -specific antigen doubling time of untreated, clinically localized, low-to-intemediate grade, prostate carcinoma BJU International 94: 295-298, 2004

13. Hanley J.A. and McNeil B.J.: A method of comparing the areas under receiver operating characteristic curves derived from the same cases. Radiology, 148: 839-43, 1983.

14. Carter HB., Morrel CH., Pearson JD., Brant LJ., Plato CC., Metter EJ. Et al: Estimation of prostatic growth using serial prostate specific antigen measurements in men with and without prostate disease. Cancer Res, 52:3323-8, 1992

15. Schmid HP., McNeal Je., Stamey TA.: Observation on the doubling time of prostate cancer. The use of serial prostate-specific antigen in patients with untreated disease as a measure of increasing cancer volume. Cancer 71: 2031-40, 1993

16. Bidart JM., Thuillier F., Augereau C., Chalas J., Daver A., Jacob N., Labrousse F., Voitot H.: Kinetics of serum tu or marker concentrations and usefulness in clinical monitoring. Clinical Chemistry 45: 10, 1695-1707, 1999

17. Patel A., Dorey F., Franklin J., DeKernion JB.: Recurrence patterns after radical retropubic prostatectomy: clinical usefulness of prostate specific antigen doubling times and log slope prostate specific antigen. J Urol 158, 1441-1445, 1997

18. Svatek RS:, Shulman M., Choudhary PK., Benaim E.: Clinical analysis of prostate-specific antigen doubling time calculation methodology. Cancer 106(5), 1047-53, 2006

19. Semjonow A., Hamm M., Rathert P.: Half-Life of Prostate-Specific Antigen after Radical Protatectomy: the decisive predictor of curative treatment? Eur Urol; 21: 200-205, 1992

 

All

Prostate cancers

Controls

P value

 

N

Median (range)

N

Median (range)

N

Median (range)

 

Age (yr)

325

65.6 (45.2 - 83)

74

64.34 (50.6 - 82.4)

251

65.8 (45.2 - 83)

0.49

PSA (ng/ml)

325

7.11 (0.8 - 52.7)

74

8.1 (2.12 - 52.7)

251

6.81 (0.8 - 35.2)

0.025 *

free -to-total PSA (%)

287

17.41 (3.23 - 65)

64

11.96 (4.26 - 35.76)

223

18.4 (3.23 - 65)

0.0000000012*

Days between first and last assays

325

1321 (739 - 4581)

74

1245 (739 - 3723)

251

1343 (740 - 4581)

0.038

numbers of PSA assays for patient

325

5 (3 - 28)

74

5 (3 - 12)

251

6 (3 - 28)

0.0014

PSA velocity (ng/ml/yr)

325

0.392 (-3.72 - 19.17)

74

0.776 (-0.61 - 19.17)

251

0.189 (-3.7 - 5.9)

0.0000000008 *

PSA slope (last square fit) (ng/ml/yr)

325

0.404 (-3.28 - 18.07)

74

0.849 (-0.53 - 18.07)

251

0.24 (-3.2 - 5.8)

0.00000000004*

PSA intercept

325

5.58 (-294.2 - 209.9)

74

4.096 (-279 - 12.86)

251

5.9 (-294 - 209)

0.000022

LnPSA slope

325

0.068 (-0.61 - 0.996)

74

0.162 (-0.074 - 0.99)

251

0.04 (-0.6 - 0.74)

0.00000000000002

LnPSA intercept

325

639 (-149 - 1758)

74

541 (-149 - 1018)

251

658 (-109 - 1758)

0.0000853

PSADT (yr)

325

4.1 (-367 - 1758)

74

3.9 (-59 - 549)

251

4.1 (-367 - 1076)

0.678

Prostate volume (cm3)

265

50.8 (10 - 151)

57

35 (10 - 130)

208

53.2 (15 - 151)

0.000000046 *

PSA density(ng/ml/cc)

265

0.148 (0.03 - 1.01)

57

0.208 (0.055 - 1.01)

208

0.137 (0.03 - 0.62)

0.0000002401*

Transition zone volume (cm3)

179

33 (4-120)

41

15.6 (5 - 74)

138

35.2 (4 - 120)

0.000000595*

PSA trasition zone density(ng/ml/cc)

179

0.243 (0.052 - 2)

41

0.466 (0.085 - 2)

138

0.22 (0.052 - 1.3)

0.0000049 *

Table 1) Descriptive statistics of 325 men. The last column reports p value of differences between controls and prostate cancers (Mann Wintney U test), * p<0,05.

 

 

 

AUC

Std

95% Confidence interval

PSA

0.585

0.039

0.530 to 0.639

Free to Total PSA

0.749

0.031

0.695 to 0.798

PSA density

0,723

0,041

0.665 to 0.776

PSA trasition zone density

0,735

0.048

0.664 to 0.798

PSA velocity

0.734

0.036

0.683 to 0.782

PSA slope

0.752

0.035

0.701 to 0.798

LnPSA slope

0.793

0.033

0.745 to 0.836

PSADT

0.516

0.038

0.460 to 0.571

 

Table 2) ROC analyses

 

Example L.G 11/1/1936 T2aN0M0G7(4+3)