A. Ruffion, X. Rebillard, S. Oudard

PSA doubling time and its calculation

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In addition to the various published nomograms for treatment decision-making in prostate cancer,the prostate specific antigen doubling time (PSADT) provides a dynamic parameter which mayhelp further refine the management and monitoring of patients. Numerous data have been publishedon the subject, and the PSADT is currently considered as an independent prognosis marker inmany situations of prostate cancer management, even though its value has not yet been confirmedin prospective studies.(1)

Most kinetic analyses of PSA reported in the literature are based on two measurements: the velocityof total PSA (PSAV) and the PSA doubling time (PSADT). As it is very easy to calculate, PSAV wasthe first to be used. However, it quickly became apparent that this method of calculation is notadapted to situations where PSA levels rise exponentially, as in prostate cancer.(1-3) The use ofPSADT thus appears as more logical in this indication. The main pitfall of PSADT is the need touse complex mathematical formulas,(4-8) which require specific software equipment.

Introduction

Why is the PSA doubling time (PSADT)preferred to PSA velocity (PSAV) to analysethe kinetics of PSA in prostate cancer?

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PSADT may help monitor more progressive cancers and guide the treatment: the shorter the PSADT,the more aggressive the treatment needs to be.(9) However, some cancers may progress despitea stable PSA level.(10) Prospective studies on this issue may cause patients and surgeons to rushinto a curative treatment based on PSADT values, but caution is required until prolonged follow-up periods provide sufficiently reliable data.(11)

Clinical use of PSA doubling time in prostatecancer

PSADT and simple monitoring:

PSADT may be a pre-treatment prognosis factor able to evaluate the tumour’s aggressivity.(12)

A short PSADT may suggest an aggressive tumour, except in certain moderately differentiatedcancers with low PSA secretion.(5) Short PSADTs are associated with a high Gleason score, a high pre-treatment PSA level, or a high TNM stage.(6) Short PSADTs appear to be significantlyassociated with the onset of a biological recurrence(3,4), and may predict a higher mortality riskspecific to prostate cancer following a curative treatment.(13)

The use of PSADT as a prognosis factor prior to acurative treatment:

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As seen in the previous chapter, a short PSADT may be an element in favour of early initiation ofhormone therapy, to increase survival without metastatic symptoms.(24)

Certain authors suggest that PSADTs may be useful after the initiation of hormone therapy. A lowPSADT (< 12 months) has recently been reported as still indicative of a poor prognosis in termsof specific and metastasis-free survival in patients with prostate cancer.(23) As expected, the PSADTis longer in localised disease (7.5 months) than in metastatic disease (2.5 months).(31) PSADTsunder 70 days may be a mortality risk factor, specific of prostate cancer in patients with a hormonedependent disease.(32,33)

PSADT and hormone therapy:

Several retrospective series analysed the prognosis value of PSADT following a curative treatment.PSADTs appear to have an independent prognosis value, like the time to biological recurrence andthe tumour’s Gleason score.(4, 14-23) For certain authors(18), the PSADT is the most important factor totake into account. PSADTs between 3 and 12 months may indicate a poor prognosis for the specificprostate cancer survival.(15,16,20) Certain authors consider that PSADTs below 12 months are indicativeof occult metastases, and would then justify early hormone therapy.(19,22,24,25)

The role of PSADT as a marker of local or general recurrence has raised numerous discussions andpolemics on the necessary interval before an interpretable PSADT is obtained (see below). Nocurrently available series has yet been able to provide conclusive evidence.(26,27)

Following curietherapy, a nadir at 1 year may be indicative of the treatment’s efficacy, whereasthere is few data available on patients in whom this treatment has failed.(28,29) However, it is possiblethat, given the frequency of the PSA “paradoxical rebound” in these patients, PSADT may be moredifficult to use following this type of treatment.(30)

Evaluation of the prognosis in curative treatment failurein prostate cancer:

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Precautions to take when using PSADT

In disease-free patients, PSA levels rise on a linear pattern(2) with physiological fluctuations. Followingan acute bacterial prostatis, urinary retention, prostate biopsy or endourethral prostate resection,total blood PSA rises exponentially for at least 2 to 4 weeks.(28) The literature reports a half-life ofPSA following acute prostatis of 14 to 16 days.(34,35)

Physiological, inflammatory, or iatrogenic variations of PSA:

In benign prostate hypertrophy, PSA levels follow a curvilinear pattern.(2) The expected PSADT isvery long, around 25 years.(36) The half-life of PSA following an adenomectomy is 3.4 days,versus 2.4 days after a radical prostatectomy.(37) The shorter PSA half-life after radical prostatectomyis explained by the fact that the whole prostatic tissue has been removed, thus preventing anyresidual PSA synthesis.(37)

PSA variations in benign prostate hypertrophy:

There are no “good practice” rules available to calculate the PSADT, as this prognosis factor isstill under evaluation, as mentioned above. However, most of the published articles recommendcalculating the PSADT with at least three successive values of PSA, each separated by at leastthree months. It is also important to know that the accumulation of too many PSA tests too closeto one another may artificially reduce the PSADT.(1)

What are the optimum timing and minimal number ofPSA tests to calculate the PSADT?

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References

_1. Maffezzini M., Bossi A., Collette L. Implications of prostate-specific antigen doubling time as indicator offailure after surgery or radiation therapy for prostate cancer. Eur Urol 2007;51:605-13; discussion 13.

_2. Carter HB., Morrell CH., Pearson JD., et al. Estimation of prostatic growth using serial prostate-specificantigen measurements in men with and without prostate disease. Cancer Res 1992;52:3323-8.

_3. Hanks GE., Hanlon AL., Lee WR., Slivjak A., Schultheiss TE. Pretreatment prostate-specific antigendoubling times: clinical utility of this predictor of prostate cancer behavior. Int J Radiat Oncol Biol Phys1996;34:549-53.

_4. Pound CR., Partin AW., Eisenberger MA., et al. Natural history of progression after PSA elevationfollowing radical prostatectomy. Jama 1999;281:1591-7.

_5. Choo R., Klotz L., Deboer G., Danjoux C., Morton GC. Wide variation of prostate-specific antigendoubling time of untreated, clinically localized, low-to-intermediate grade, prostate carcinoma. BJU Int2004;94:295-8.

_6. Loberg RD., Fielhauer JR., Pienta BA., et al. Prostate-specific antigen doubling time and survival inpatients with advanced metastatic prostate cancer. Urology 2003;62 Suppl 1:128-33.

_7. Guess B., Jennrich R., Johnson H., Redheffer R., Scholz M. Using splines to detect changes in PSAdoubling times. Prostate 2003;54:88-94.

_8. 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 1997;158:1441-5.

_9. Zhang L., Loblaw A., Klotz L. Modeling prostate specific antigen kinetics in patients on activesurveillance. J Urol 2006;176:1392-7; discussion 7-8.

10. Stephenson AJ., Aprikian AG., Souhami L., et al. Utility of PSA doubling time in follow-up of untreatedpatients with localized prostate cancer. Urology 2002;59:652-6.

11. Ali K., Gunnar A., Jan-Erik D., et al. PSA doubling time predicts the outcome after active surveillance inscreening-detected prostate cancer: results from the European randomized study of screening for prostatecancer, Sweden section. Int J Cancer 2007;120:170-4.

12. Bidart JM., Thuillier F., Augereau C., et al. Kinetics of serum tumor marker concentrations and usefulnessin clinical monitoring. Clin Chem 1999;45:1695-707.

13. Hanks GE., D'Amico A., Epstein BE., Schultheiss TE. Prostatic-specific antigen doubling times in patientswith prostate cancer: a potentially useful reflection of tumor doubling time. Int J Radiat Oncol Biol Phys1993;27:125-7.

Remis Tps Dbl PSA VAv3 7/02/08 16:26 Page 6

14. Cannon GM. Jr., Walsh PC., Partin AW., Pound CR. Prostate-specific antigen doubling time in theidentification of patients at risk for progression after treatment and biochemical recurrence for prostate cancer.Urology 2003;62 Suppl 1:2-8.

15. Albertsen PC., Hanley JA., Penson DF., Fine J. Validation of increasing prostate specific antigen as a predictorof prostate cancer death after treatment of localized prostate cancer with surgery or radiation. J Urol2004;171:2221-5.

16. Freedland SJ., Humphreys EB., Mangold LA., et al. Risk of prostate cancer-specific mortality followingbiochemical recurrence after radical prostatectomy. Jama 2005;294:433-9.

17. Hanlon AL., Diratzouian H., Hanks GE. Posttreatment prostate-specific antigen nadir highly predictive ofdistant failure and death from prostate cancer. Int J Radiat Oncol Biol Phys 2002;53:297-303.

18. Ward JF., Blute ML., Slezak J., Bergstralh EJ., Zincke H. The long-term clinical impact of biochemicalrecurrence of prostate cancer 5 or more years after radical prostatectomy. J Urol 2003;170:1872-6.

19. Zelefsky MJ., Ben-Porat L., Scher HI., et al. Outcome predictors for the increasing PSA state after definitiveexternal-beam radiotherapy for prostate cancer. J Clin Oncol 2005;23:826-31.

20. Zhou P., Chen MH., McLeod D., et al. Predictors of prostate cancer-specific mortality after radicalprostatectomy or radiation therapy. J Clin Oncol 2005;23:6992-8.

21. Yossepowitch O., Bianco FJ. Jr., Eggener SE., et al. The natural history of noncastrate metastatic prostatecancer after radical prostatectomy. Eur Urol 2007;51:940-8.

22. Tenenholz TC., Shields C., Ramesh VR., Tercilla O., Hagan MP. Survival benefit for early hormone ablation inbiochemically recurrent prostate cancer. Urol Oncol 2007;25:101-9.

23. Rodrigues NA., Chen MH., Catalona WJ., et al. Predictors of mortality after androgen-deprivation therapy inpatients with rapidly rising prostate-specific antigen levels after local therapy for prostate cancer. Cancer2006;107:514-20.

24. Pinover WH., Horwitz EM., Hanlon AL., Uzzo RG., Hanks GE. Validation of a treatment policy for patientswith prostate specific antigen failure after three-dimensional conformal prostate radiation therapy. Cancer2003;97:1127-33.

25. Hanlon AL., Horwitz EM., Hanks GE., Pollack A. Short-term androgen deprivation and PSA doubling time :their association and relationship to disease progression after radiation therapy for prostate cancer. Int J RadiatOncol Biol Phys 2004;58:43-52.

26. Symon Z., Kundel Y., Sadetzki S., et al. Radiation rescue for biochemical failure after surgery for prostatecancer : predictive parameters and an assessment of contemporary predictive models. Am J Clin Oncol2006;29:446-50.

27. Shipley WU., Desilvio M., Pilepich MV., et al. Early initiation of salvage hormone therapy influences survivalin patients who failed initial radiation for locally advanced prostate cancer : A secondary analysis of RTOGprotocol 86-10. Int J Radiat Oncol Biol Phys 2006;64:1162-7.

Remis Tps Dbl PSA VAv3 7/02/08 16:26 Page 7

28. Pruthi RS., Derksen JE., Moore D. A pilot study of use of the cyclooxygenase-2 inhibitor celecoxib inrecurrent prostate cancer after definitive radiation therapy or radical prostatectomy. BJU Int2004;93:275-8.

29. Potters L., Morgenstern C., Calugaru E., et al. 12-year outcomes following permanent prostatebrachytherapy in patients with clinically localized prostate cancer. J Urol 2005;173:1562-6.

30. Ciezki JP., Reddy CA., Garcia J., et al. PSA kinetics after prostate brachytherapy : PSA bouncephenomenon and its implications for PSA doubling time. Int J Radiat Oncol Biol Phys 2006;64:512-7.

31. Fowler JE., Jr., Pandey P., Seaver LE., Feliz TP., Braswell NT. Prostate specific antigen regression andprogression after androgen deprivation for localized and metastatic prostate cancer. J Urol1995;153:1860-5.

32. Semeniuk RC., Venner PM., North S. Prostate-specific antigen doubling time is associated with survivalin men with hormone-refractory prostate cancer. Urology 2006;68:565-9.

33. Svatek R., Karakiewicz PI., Shulman M., et al. Pre-treatment nomogram for disease-specific survival ofpatients with chemotherapy-naive androgen independent prostate cancer. Eur Urol 2006;49:666-74.

34. Game X., Vincendeau S., Palascak R., et al. Total and free serum prostate specific antigen levelsduring the first month of acute prostatitis. Eur Urol 2003;43:702-5.

35. Ulleryd P., Zackrisson B., Aus G., et al. Prostatic involvement in men with febrile urinary tract infection asmeasured by serum prostate-specific antigen and transrectal ultrasonography. BJU Int 1999;84:470-4.

36. Oesterling JE., Jacobsen SJ., Chute CG., et al. Serum prostate-specific antigen in a community-basedpopulation of healthy men. Establishment of age-specific reference ranges. Jama 1993;270:860-4.

37. Ravery V., Lamotte F., Hennequin CH., et al. Adjuvant radiation therapy for recurrent PSA after radicalprostatectomy in T1-T2 prostate cancer. Prostate Cancer Prostatic Dis 1998;1:321-5.

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