The Role of PSA in the Radiotherapy of Prostate Cancer

Dr. Roach initiates his discussion with the relevant statementthat how we detect, stage, and treat carcinoma of the prostate,as well as subsequently evaluate treatment efficacy, has foreverbeen dramatically altered by the availability of prostate specificantigen (PSA), which has been labeled "the most useful tumormarker available" [1]. However, as Dr. Roach also notes,new information and insights generate new questions and uncertaintiesabout the best applications of this valuable tumor marker. Someof the uncertainties are discussed in his review and include,but are not limited to:

1) different monoclonal/polyclonal assay methodologies (in theUnited States there are 5 different PSA assays available to thephysician and in Europe there are now 36 different assays);

2) no universally accepted reference standard;

3) variable physician-assigned intermediate PSA end points (asan example, the "undetectable" PSA level after surgeryhas ranged from equal to or less than 0.1 ng/mL to equal to orless than 0.6 ng/mL and after definitive irradiation, from 0.5ng/mL to 4.0 ng/mL); and

4) biologic variations (eg, an individual's serum PSA level willvacillate within short periods and is determined by varying contributionsfrom benign prostatic hypertrophy and such other prostatic perturbationsas infection, infarct, and basement membrane permeability associatedwith aging, in addition to the parameter of primary interest,cancer volume).

The Cancer- and Organ-Specificity of PSA

Major efforts have been directed toward increasing the cancerspecificity of PSA and thereby reducing the number of false-positiveresults. These include age-specific reference ranges, PSA density,PSA velocity, and, most recently, free-to-total PSA ratios. Whileurologists await the validated free-to-total PSA ratio cut-offpoints to hopefully increase the specificity of early cancer detection,radiation oncologists will analyze post-radiation free-to-totalratios to identify patients whose PSA falls to levels betweenundetectable and normal, who may experience a favorable prognosis.Will there be a subgroup of patients with a detectable PSA afterexternal-beam radiation therapy who, by virtue of their high ratioof free to total PSA, will fare more favorably than a subgroupwith the same total PSA level but a low ratio?

Although increasing the specificity of PSA for cancer detectionis a major objective, ample information is simultaneously appearingto challenge the validity of the prostate organ-specific labelwe have attached to this 30-kd protease. Prostate-specific antigenhas been found in breast tissue, both normal and cancerous, aswell as in the ovary, endometrium, colon, liver, and kidney [2].It appears that any organ with hormone-receptor activity can expressPSA with appropriate ligand stimulation [2].

Dr. Roach appropriately emphasizes the importance of PSA as apretreatment stratification/ prognostic factor. Several serieshave demonstrated the prognostic value of PSA and, with multivariateanalysis [3,4], have identified it as the most important prognosticpretreatment variable. Our analysis of pretreatment PSA distributionin selected contemporary surgical and radiation series treatingstage T1/T2 prostate cancer clearly demonstrated a statisticallymore favorable distribution in the surgical series [3]. Basedon this less favorable PSA tumor mix within the same tumor stage,it is anticipated that the outcome of the radiation series alsowill be less favorable.

Treatment-Intensification Strategies

The high failure rate by PSA criteria after radiation [5], theidentification of PSA failure in a relatively short time intervalof 12 to 24 months after radiation, and the recognition that pretreatmentPSA levels more than 10 ng/mL, and certainly more than 20 ng/mL,predict for a significant subsequent PSA failure rate have promptedimplementation of treatment-intensification strategies. Thesehave included neoadjuvant or adjuvant androgen deprivation ora combination of both with radiation therapy, conformal radiationtherapy with dose escalation, and wide-field radiation therapyto include the pelvic nodes. Some of these modifications are addressedin the author's Table 2, which describes the multiarm RTOG protocol9413. Other strategies combine brachytherapy, radiation sensitizers,hyperthermia, neutrons, or protons with traditional photon therapy.

All of these strategies key initially on achieving a low PSA nadiras an intermediate end point. However, this focus should not detractfrom the practical reality that many patients remain clinicallywell not only during their post-treatment PSA nadir but also duringits subsequent rise. The lead time between a detectable PSA andclinical failure for patients with clinical stage B2 in our serieswas 54 months [5]. Clearly, for patients in the eighth decadeof life, irradiation can often provide freedom from clinical progressionfor their anticipated life span.

Defining the Appropriate Post-Radiation PSA

Nevertheless, a major effort has been directed toward definingthe appropriate PSA level to expect after external-beam radiationtherapy. Indeed, this is an important effort, not only as oneyardstick for assessing the relative merits of new therapies,but also to standardize reporting of results from different institutions.A consensus conference to address this important issue will beheld this fall under the auspices of the American Society forTherapeutic and Radiation Oncology (ASTRO).

Over the past several years, the nadir PSA level acceptable toradiation oncologists after external-beam radiation therapy oflocalized prostate cancer has decreased from a PSA of equal toor less than 4.0 ng/mL to equal to or less than 2.0 ng/mL [6]to equal to or less than 1.5 ng/mL [7] to equal to or less than1.0 ng/mL [8], and, most recently, to equal to or less than 0.5ng/mL [9]. The intermediate- and long-term biomarker (PSA) progression-freeoutcomes of any series will understandably vary according to whichlevel has been used as an acceptable post-radiation nadir. Thecohort with the best prognosis are patients who have a PSA ofequal to or less than 0.5 ng/mL [9]. These patients have beendescribed as meeting the criteria of a bloodless prostatectomy.The group most likely to reach the nadir of equal to or less than0.5 ng/mL are those with a pretreatment PSA of equal to or lessthan 4.0 ng/mL. (In our Eastern Virginia Medical School series,only 13% of patients had a pretreatment PSA at or below this level).

This finding raises an interesting paradox; namely, the most favorabletreatment outcomes are seen among patients in whom our best tumormarker has not indicated the presence of tumor. Presumably, thesepatients were diagnosed based on an abnormal digital rectal examination,generally considered to be very insensitive to the presence oftumor or the extent of tumor volume. This serves as a reminderthat, while biomarkers are in the process of evolution, testing,and application, physicians involved in the detection, treatment,and care of patients with prostate cancer need to practice andmaintain their clinical skills.

References:

1. Oesterling JE: Prostate-specific antigen: A critical assessmentof the most useful tumor marker for adenocarcinoma of the prostate.J Urol 145:907, 1991.

2. Diamandis EP, Yu H: Editorial: New biological functions ofprostate-specific antigen?

J Clin Endocrinol Metab 80(5):1515, 1995.

3. Kuban D, El-Mahdi A, Schellhammer P: Prostate-specific antigenfor pretreatment prediction and posttreatment evaluation of outcomeafter definitive irradiation for prostate cancer. Int J RadiatOncol Biol Phys 32(2):307, 1995.

4. Zagars G: Serum PSA as a tumor marker for patients undergoingdefinitive radiation therapy. Urol Clin North Am 20:737, 1993.

5. Schellhammer P, El-Mahdi A, Wright G, et al: Prostate-specificantigen to determine progression-free survival after radiationtherapy for localized carcinoma of the prostate. Urology 42:13,1993.

6. Geist RW: Reference range for prostate-specific antigen levelsafter external beam radiation therapy for adenocarcinoma of theprostate. Urology 45(6):1016, 1995.

7. Hanks G, Perez C, Kozar M, et al: PSA confirmation of cureat 10 years of T1b, T2, N0, M0 prostate cancer patients treatedin RTOG protocol 7706 with external beam irradiation. Int J RadiatOncol Biol Phys 30:289, 1994.

8. Kavadi V, Zagars G, Pollack A: Serum prostate-specific antigenafter radiation therapy for clinically localized prostate cancer:Prognostic implications. Int J Radiat Oncol Biol Phys 30(2):279,1994.

9. Tibbs M, Zietman A, Dallow KC, et al: Biochemical outcome followingexternal beam radiation for T1-2 prostate carcinoma: The importanceof achieving an undetectable nadir PSA. Int J Radiat Oncol BiolPhys 32(suppl 1):230, 1995.