# Radiation Oncology/Prostate/PSA

* Front Page: Radiation Oncology | RTOG Trials | Randomized Trials
Prostate Specific Antigen (PSA)
    For PSA screening, see Screening and Prevention.

## History of PSA

Defining "PSA era":
* The beginning of the PSA era is the late 1980s.
* In the early PSA era (beginning approx. 1987), there was an abrupt rise in the incidence of prostate cancer, with a peak in 1992, then a decrease through 1995. The incidence remained stable between 1995 and 1999, but at a higher rate than in the pre-PSA era.
* Approved by FDA in 1986 for disease monitoring. Approved in 1992 for diagnosis.
PSA use in early clinical trials:
* EORTC 22863 (trial began 1987) - PSA in all pts at baseline
* RTOG 85-31 and 86-10 (trials began 1987) - PSA was not widely available at the beginning of the study. Made mandatory in 1990.

## PSA Measurement

PSA level may be affected by a number of processes:
* Minimal impact - DRE, TRUS, cystoscopy
* Impact unclear - ejaculation (some studies show no impact, others show elevation at 24 or even 48 hours)
* Significant impact - prostatic massage, needle biopsy, TURP, prostatitis

### Impact of Ejaculation

* 1998 PMID 9569113 -- "The effects of ejaculation on serum prostate-specific antigen (PSA)." (Yavascaoglu I, Int Urol Nephrol. 1998).
** Conclusion: No relation between seminal plasma levels or total amounts expelled and the difference in serum levels due to ejaculation
* 1998 PMID 9510352 -- "The effect of ejaculation on prostate-specific antigen in a prostate cancer-screening population." (Stenner J, Urology. 1998)
** Conclusion: For the total screened population, ejaculation has no clinically significant effect. Men should not be asked to abstain from sexual activities before a PSA-screening test
* 1997 PMID 9255295 -- "Effect of ejaculation on serum total and free prostate-specific antigen concentrations." (Herschman JD, Urology. 1997)
** Conclusion: Both total and free PSA increase immediately after ejaculation, with differing rates of return to baseline levels. PSA testing within 24 hours after ejaculation may lead to an erroneous interpretation of the results of both total and percent free PSA measurements in a small proportion of men.
* 1997 PMID 9126226 -- The effects of prostatic manipulation on prostate-specific antigen levels. (Klein LT, Urol Clin North Am. 1997)
** Minimal effect on PSA level - DRE, TRUS, cystoscopy, and ejaculation
** Significant effect on PSA level - Prostatic massage, needle biopsy, TURP, and prostatitis
* 1997 PMID 9266232 -- "Postejaculation serum prostate-specific antigen level." (Zisman A, Eur Urol. 1997)
** Conclusion: A significant postejaculation serum PSA elevation does occur, it is thus recommended that men abstain from ejaculation for 24 h prior to PSA sampling.
* 1997 PMID 8976253 -- "The influence of ejaculation on serum levels of prostate specific antigen." (Heidenreich A, J Urol. 1997)
** Conclusion: Ejaculation does not affect serum PSA concentration in young men, and there seems to be no physiological relationship between ejaculation and PSA level.
* 1996 PMID 8638359 -- "Ejaculation increases the serum prostate-specific antigen concentration." (Tchetgen MB, Urology. 1996)
** Conclusion: Ejaculation causes a significant increase in the serum PSA concentration in men between 49 and 79 years of age that may persist for up to 48 hours. This change appears to correlate with age and baseline PSA. It is recommended that men abstain from ejaculation for 48 hours prior to having a serum PSA determination.
* 1995 PMID 7544734 -- "Effect of ejaculation on prostate-specific antigen levels in normal men." (Kirkali Z, Eur Urol. 1995)
** Conclusion: Ejaculation does not seem to affect the serum PSA concentration at 5 consecutive days after ejaculation.
* 1993 PMID 7684542 -- "Effect of digital rectal examination (and ejaculation) on serum prostate-specific antigen after twenty-four hours. A randomized, prospective study." (McAleer JK, Urology. 1993)
** Conclusion: DRE had no clinically important effect on PSA values twenty-four hours later. Ejaculation had no meaningful effect on the serum PSA values.
* 1992 PMID 1384015 -- "Prostate-specific antigen: establishment of the reference range for the clinically normal prostate gland and the effect of digital rectal examination, ejaculation, and time on serum concentrations." (Glenski WJ, Prostate. 1992)
** Conclusion: Digital rectal examination and ejaculation have no significant effect on the serum concentration.

## Percent-Free PSA

* Multicenter, 1998 - PMID 9605898 — "Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial." Catalona WJ et al. JAMA. 1998 May 20;279(19):1542-7.
** Prospective. 773 men with PSA 4-10, ages 50-75, no palpable disease, histologically proven prostate cancer or benign disease.
** Lower free PSA associated with a higher risk of prostate cancer. Using 25% free PSA cutoff lead to 95% sensitivity and avoided 20% of unnecessary biopsies.

## PSA Failure
### PSA Nadir (PSAn) Post Radiotherapy

In postradiotherapy patients PSA may never reach completely undetectable levels and rather will reach a very low nadir, typically below 1.0 ng/mL within 2 years after therapy. (0.2 ng/mL within 5 years in patients treated with simultaneous irradiation with a transperineal prostate iodine implant, followed by external beam irradiation) Of particular interest is the correlation of PSA nadir levels to outcomes among RT patients.
* PMID 12946753 - DWitt KD et al. "What does postradiotherapy PSA nadir tell us about freedom from PSA failure and progression-free survival in patients with low and intermediate-risk localized prostate cancer?" Urology. 2003 Sep;62(3):492-6.
** Patients were categorized by nPSA quartile groups with cutpoints of less than 0.3, 0.3 to less than 0.6, 0.6 to less than 1.2, and 1.2 ng/mL or greater.Freedom from PSA failure was strongly associated with nadir quartile groups (P <0.0001). PFS was also significantly different statistically among nadir quartile groups (P = 0.02). No statistically significant difference was found in overall survival associated with nPSA at this point. CONCLUSIONS: nPSA is a strong independent predictor of freedom from PSA failure and PFS in patients with low and intermediate-risk localized prostate cancer treated with RT alone. Longer follow-up and larger patient numbers are required to confirm these observations.
* PMID 12441934 - "Time to achieve a prostate specific antigen nadir of 0.2 ng./ml. after simultaneous irradiation for prostate cancer." Critz FA J Urol. 2002 Dec;168(6):2434-8.
** With rare exceptions to be potentially cured of prostate cancer by simultaneous irradiation men must achieve a PSA nadir of 0.2 ng./ml. within 5 years of implantation. Failure to reach this goal by 60 months of followup almost always indicates persistent disease."
Critz and colleagues found that a PSA nadir < 0.2 ng/mL defines disease freedom following brachytherapy plus EBRT, and that a PSA nadir > 1.0 ng/mL predicts for disease recurrence at a median of 5 years of follow-up. In addition, data from DeWitt and colleagues demonstrate that a PSA nadir > 1.2 predicts worse outcomes in measures of freedom from PSA failure and progression-free survival in patients undergoing EBRT at the same time point.

### Definition of PSA Failure Post-Radiation therapy

* ASTRO Consensus Statement
** Phoenix Definition; 2006 PMID 16798415 — "Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: Recommendations of the RTOG-ASTRO Phoenix Consensus Conference." Roach M 3rd et al. Int J Radiat Oncol Biol Phys. 2006 Jul 15;65(4):965-74.
*** 1. Biochemical failure is defined as a rise of 2 ng/mL or more above the nadir after EBRT w/ or w/o hormonal therapy.
*** 2. The date of failure should be "at call" (not backdated).
** Original; 1997 PMID 9169810 (No abstract). "Consensus statement: Guidelines for PSA following radiation therapy" Int J Radiat Oncol Biol Phys. 1997 Mar 15;37(5):1035-41.
*** 1. Biochemical failure is not justification per se to initiate additional treatment. It is not equivalent to clinical failure. It is, however, an appropriate early end point for clinical trials
*** 2. Three consecutive increases in PSA is a reasonable definition of biochemical failure after radiotherapy. For clinical trials, the date of failure should be the midpoint between the postirradiation nadir PSA and the first of the three consecutive rises
*** 3. No definition of PSA failure has, as yet, been shown to be a surrogate for clinical progression or survival
*** 4. Nadir PSA is a strong prognostic factor, but no absolute level is a valid cutpoint for separating successful and unsuccessful treatments. The nadir PSA is similar in prognostic value to pretreatment prognostic variables
* Vancouver rules (1999) - 1) True nadir is the lowest post-therapy PSA value. The reference nadir is the lowest reading which is not followed by a subsequent fall. 2) Must be 2 consecutive rises above the reference nadir, at least 1 month apart. 3) PSA > 1.5 is required at any time after the reference nadir before PSA relapse can be scored. 4) Date of failure is midpoint between reference nadir and first post-true-nadir reading. 5) If true nadir is >=4, relapse is scored at that time and no further rises are needed. 6) Salvage therapy is considered a relapse.
** (Letter) "PSA relapse definitions--the Vancouver Rules show superior predictive power." Pickles et al. Int J Radiat Oncol Biol Phys. 1999 Feb 1;43(3):699-700.
* Horwitz, William Beaumont (1996) - Determined difference in therapeutic outcome was observed if different definitions of PSA failure are used.
** PMID 8948340 — "Assessing the variability of outcome for patients treated with localized prostate irradiation using different definitions of biochemical control." Horwitz et al. Int J Radiat Oncol Biol Phys. 1996 Oct 1;36(3):565-71.
* Fox Chase (1995) - 2 consecutive rises to a level > 1.5
** PMID 7531222 (1995)
** PMID 10701734 — "Scrutiny of the ASTRO consensus definition of biochemical failure in irradiated prostate cancer patients demonstrates its usefulness and robustness. American Society for Therapeutic Radiology and Oncology." Hanlon et al. Int J Radiat Oncol Biol Phys. 2000 Feb 1;46(3):559-66.
* Mass General - "Strict definition": after a nadir of <1 which occurs in 1 year, failure occurs if there are 2 consecutive rises. Failure is scored at the first increase. "Liberal definition": same as strict, but nadir only needs to be <4.
** PMID 7751173
* Memorial - After a nadir of <4, failure occurs if PSA rises above 4.
** PMID 7933238
* Stanford - Def#1: Def#2: 2 consecutive increases where 2nd was higher than normal and at least 20% above the nadir.
** PMID 7679756
* MDACC - 2 consecutive rises above nadir. Failure if increase by >1 or by a factor of 1.5.
** PMID 7533459
** PMID 7686443
* Houston criteria - absolute increase of 2 above the nadir
** ASTRO 2002 - criteria proposed
** PMID 12909209 — "Evaluation of the Houston biochemical relapse definition in men treated with prolonged neoadjuvant and adjuvant androgen ablation and assessment of follow-up lead-time bias." Pickles. Int J Radiat Oncol Biol Phys. 2003 Sep 1;57(1):11-8.
** Houston definition has improved predictive ability compared to ASTRO and Vancouver defs. Moreover, it does not violate the Cox propoprtional hazards test for patients treated both with and without androgen suppression.

#### Comparison of PSA failure definitions

* PMID 15711272 -- Definitions of biochemical failure that best predict clinical failure in patients with prostate cancer treated with external beam radiation alone: a multi-institutional pooled analysis. (Horwitz EM, J Urol. 2005)
** Pooled data on 4,839 patients with T1-2 prostate cancer treated with EBRT alone at 9 institutions
** Conclusion: "Defining BF as PSA greater than absolute nadir plus 2 ng/ml, dated at the call, PSA greater than current nadir plus 3 ng/ml, dated at the call, or 2 consecutive increases of at least 0.5 ng/ml, back dated, had higher sensitivity and specificity for DF alone or CF compared with the ASTRO definition."
* Taylor (Michigan) - Abstract — "Definitions of biochemical failure in prostate cancer following radiation therapy." Taylor JMG et al. Int J Radiat Oncol Biol Phys. 2001 Aug 1;50(5):1212-9.
** Single institution, 688 pts, 1987-96, all T stages, N0. Evaluated 10 definitions of biochemical failure.
** Favor Fox Chase Cancer Center method over ASTRO definition.
* Thames et al - Abstract — "Comparison of alternative biochemical failure definitions based on clinical outcome in 4839 prostate cancer patients treated by external beam radiotherapy between 1986 and 1995." Thames H et al. Int J Radiat Oncol Biol Phys. 2003 Nov 15;57(4):929-43.
** Used same pooled data set as Kuban et al, 2003 with 4839 pts and median f/u 6 years. Assessed 102 definitions of biochemical failure.
** Favors ASTRO definition but recognizes its bias from the backdating of PSA failures.

#### PSA failure after RT + hormonal therapy

These methods account for the expected rise in PSA after coming off hormonal therapy.
* Fox Chase modification of ASTRO definition (2005) - Uses the original ASTRO definition, with the following modifications: 1) If after an initial rise there is a decline in PSA, 2 further consecutive rises in PSA >0.1 are required for a failure. 2) If the PSA after 3 consecutive rises was unchanged but then declined, 2 further consecutive rises were also required.
** PMID 15817330 - "Biochemical failure and the temporal kinetics of prostate-specific antigen after radiation therapy with androgen deprivation." Buyyounouski MK et al. Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1291-8.
* EORTC (Bolla) - used PSA > 1.5 and 2 consecutive rises separated by >= 3 months (from PMID 12126818, 2002)
Comparisons:
* Fox Chase, 2005 (1991-98) - PMID 16169682 - "Defining biochemical failure after radiotherapy with and without androgen deprivation for prostate cancer." Buyyounouski MK et al. Int J Radiat Oncol Biol Phys. 2005 Dec 1;63(5):1455-62.
** Purpose: Compare 3 definitions of biochemical failure in pts treated with or without AD: ASTRO, modified ASTRO, and nadir plus 2 (Houston definition).
** Used same patient set as the other 2005 Fox Chase paper (see below).
** Conclusion: Nadir + 2 (Houston definition) is superior to the ASTRO and modified ASTRO definitions in predicting true failures.

### Definition of PSA Failure Post-Radical Prostatectomy

Therapeutic goal of Radical prostatectomy is removal of prostatic and neoplastic tissue, so post-RP PSA level is undetectable, that is under 0.2 ng/ml (evaluated 30-45 days after surgery). Standard practice is to define post-RP biochemical failure as a PSA level exceeding 0.2 ng/mL on at least two successive evaluations or exceeding 0.4 ng/mL on a single evaluation. By contrast, patients who never achieve undetectable levels and/or whose PSA rises very rapidly following surgery likely have metastatic disease.
* PMID 10799151 - "Prostate specific antigen only progression of prostate cancer." J Urol 2000 Jun;163(6):1632-42 Moul JW
The use of very low PSA thresholds risks overtreating patients whose PSA level is detectable due to residual benign prostatic tissue. For example, one recent report demonstrated that a single PSA elevation of less than 0.4 ng/mL after radical prostatectomy is associated with subsequent stable, nonprogressing disease in up to 50% of patients.
* PMID 11257657 - "Defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point?" Amling et al. J Urol. 2001 Apr;165(4):1146-51.
* 2006; Johns Hopkins (1985-2004) PMID 16921049 -- "Defining biochemical recurrence of prostate cancer after radical prostatectomy: a proposal for a standardized definition." (Stephenson AJ, J Clin Oncol. 2006 Aug 20;24(24):3973-8.)
** Conclusion: "BCR defined as a PSA value of at least 0.4 ng/mL followed by another increase best explains the development of distant metastasis among 10 candidate definitions, after controlling for clinical variables and the use of secondary therapy. On the basis of this evidence, we propose that this definition be adopted as the standard for reporting the outcome of RP."

## PSA kinetics
### Post-treatment PSA Bounce

* PMID 15936550 -- PSA bounces after neoadjuvant androgen deprivation and external beam radiation: Impact on definitions of failure. (Zietman AL, Int J Radiat Oncol Biol Phys. 2005)
** Conclusion: "A substantial proportion of patients treated by EBRT with neoadjuvant deprivation experienced a PSA bounce. A large percentage of these bounces scored as biochemical failure according to the ASTRO definition. The Nadir-plus-three definition is less vulnerable to this bias."
* PMID 12377320 -- Using the magnitude of PSA bounce after MRI-guided prostate brachytherapy to distinguish recurrence, benign precipitating factors, and idiopathic bounce. (Das P, Int J Radiat Oncol Biol Phys. 2002)
** Results: +0.6ng/ml idiopathic bounce vs. +1.2ng/ml for ejaculation (p=0.003), instrumentation (p=0.007), proctitis (p<0.0001) and biopsy-proven local recurrence (p=0.006)
** Conclusion:"In patients treated with MRI-guided prostate brachytherapy, recent ejaculation, instrumentation, or ongoing radiation proctitis can cause a transient increase in PSA, the magnitude of which is significantly higher than that for idiopathic PSA bounce, but is similar to that in patients with recurrent disease."

### After hormonal therapy + RT

* Fox Chase, 2005 (1991-98) - PMID 15817330 - "Biochemical failure and the temporal kinetics of prostate-specific antigen after radiation therapy with androgen deprivation." Buyyounouski MK et al. Int J Radiat Oncol Biol Phys. 2005 Apr 1;61(5):1291-8.
** Purpose: 1) describe the PSA kinetics after RT alone, RT + short term androgen deprivation (STAD, 3-12 months), and RT + long-term AD (LTAD, 1-3 yrs). 2) show the potential rise of PSA after withdrawal of AD. 3) Test the ASTRO definition in this setting. This paper provides a graphic representation of PSA kinetics.
** Retrospecitive. 688 men with localized prostate cancer treated with 3D-CRT, without AD or with STAD (82) or LTAD (20). Minimum of 4 yrs f/u. Mean dose 74 Gy (ICRU dose). Biochemical failure used ASTRO definion as well as modified ASTRO definition (see section above). PSA obtained q6months.
** Median f/u 5-6 years. For those without biochemical failure, the PSA after STAD remains relatively constant, and after LTAD, PSA rises steadily towards 1. Between 22% and 29% of pts who had a failure by the ASTRO criteria subsequently had a fall in the PSA and were not classified as BF by the revised definition.

## Surrogate Endpoints

* Post-treatment PSA-DT
** ASCO Abstract. Surrogate Endpoint for Prostate Cancer-specific Survival: Validation from an Analysis of Radiation Therapy Oncology Group Protocol 92-02. Valicenti et al.
*** Conclusion:Post-treatment PSA-DT <12 months met all of Prentice’s criteria for surrogacy. For the first time, this was accomplished for a prospectively studied patient population, and justifies strong consideration for PSA-DT< 12 months as a surrogate endpoint for prostate cancer mortality.
* PMID 13130113 Full text - "Surrogate End Point for Prostate Cancer–Specific Mortality After Radical Prostatectomy or Radiation Therapy." D'Amico et al Journal of the National Cancer Institute, Vol. 95, No. 18, 1376-1383, September 17, 2003
** A post-treatment PSA-DT of less than 3 months and the specific value of the post-treatment PSA-DT when it is 3 months or more appear to be surrogate end points for prostate cancer-specific mortality after surgery or radiation therapy.

## References

* 1 2 Klein, Eric (ed.)(2004). Management of Prostate Cancer. Google books link
* ↑ PMID 17372918