Rising PSA After Local Therapy Failure:
Immediate vs. Deferred Treatment

JUDD W. MOUL, MD, FACS,
LTC(P), MC, USA
Urology Service
Department of Surgery
Walter Reed Army Medical Center
Washington, DC

Center for Prostate Disease Research
Department of Surgery
Uniformed Bethesda, Maryland

ABSTRACT

Patients whose only sign of recurrence after local therapy for prostate cancer is a rising prostate-specific antigen level (PSA-only recurrence) have become more common. We have developed two models to predict PSA-only recurrence after radical prostatectomy, one using traditional factors (race, sigmoidal transformation of PSA, postoperative Gleason sum, and organ confinement)and a secondusing traditional clinical andpathologic variables combined with molecular biomarker levels. Treatment options for patients with PSA-only recurrence include observation, radiation therapy for patients who have undergone surgery, salvage surgery or cryotherapy for patients who have received radiotherapy, and traditional or nontraditional hormonal therapy. Radiation for PSA-only recurrence is likely to benefit men who have no adverse pathology, a low PSA level at recurrence, and PSA recurrence after the first year.

Salvage radicalprostatectomy and clyotherapypose a relatively high risk of incontinence and other morbidity and should be reserved for carefully selected patients with a high likelihood of organ-confined disease. Hormonal therapy is probably the single most beneficial treatmentfor PSA­only recurrence. Nontraditional low-dose oral hormonal therapy and intermittent hormonaltherapy aregaining inpopularity, although their long-term efficacy is unknown. More clinical trials are needed to fine-tune prognostic models and to determine the best treatments, alone or in combination, for PSA-only recurrence.

The "prostate-specific antigen (PSA)-era" (1988 to present) has dramatically altered the epidemiology of prostate cancer in the United States and in many other industrialized countries.[ 1] Although the prevalence of prostate cancer has fallen somewhat since its peak in the early 1990s, the American Cancer Society still estimates that approximately 179,000 new cases will be diagnosed in 1999.

An unprecedented stage migration has accompanied this large shift in incidence. The Surveillance, Epidemiology and End Results (SEER) Program of the National Cancer Institute noted a 52% decline in the rate of distant metastatic (stage D) prostate cancer between 1990 and 1994.[3] At the same time, the rate of diagnosis of localized disease skyrocketed. Our Department of Defense Center for Prostate Disease Research database at Walter Reed Army Medical Center (WRAMC) found that the incidence of localized prostate cancer (stages A and B) increased from approximately 50% of cases in 1988 to more than 75% of cases by 1996.

Along with this change in stage distribution has come a change in treatment patterns. The SEER program found that rates of radical prostatectomy rose from 17.4 cases per 100,000 in 1988 to 54.6 cases per 100,000 in 1992.[31 By 1992, 36.6% of patients with locoregional disease underwent radical prostatectomy, and 32.3% received radiation therapy.

Furthermore, there has been a shift in the age-adjusted rates of these treatments. Most notably, there was a threeto fourfold rise in the rate of radical prostatectomy in men 45 to 59 years old, and a two-to threefold rise in men 60 to 69 years of age. Rates of radiation therapy also increased one-to twofold in 45- to 79-year-old men.

In the late 1990s, clinicians are now seeing the effects of the boom in the diagnosis and localized treatment of prostate cancer of the early 1990s. A large number of generally younger men who were treated for clinically localized prostate cancer have experienced a recurrence of their disease. Figure I illustrates the problem clinicians are facing.

With more than 50,000 men per year developing a PSA-only recurrence (in­dicated only by an elevated PSA level, as will be discussed in the next section), it is obvious that this is a key issue for urologists, radiation oncologists, medi­cal oncologists, and, perhaps most im­portantly, the patient and his family.

Assessment of PSA-Only Recurrence After Prostatectomy

The PSA level at which to define treat­ment failure after radical prostatectomy varies in the literature. Some series have used any detectable level; others, a single value > 0.4 or 0.5 ng/mL; and still oth­ers, two consecutive values >= 0.2 ng/mL, At our hospital, employing the Abbott IMx assay, we use the criterion of two values >= 0.2 ng/mL, or any single value >= 0.5 ng/mL.

In clinical practice, it generally is quite obvious when radical prostatecto­my patients develop a PSA-only re­currence because their PSA becomes detectable and continues to rise. The use of an ultrasensitive PSA assay may result in the identification of relapsing patients I to 2 years earlier than can be achieved with a conventional assay.

The timing of the rise in PSA level after surgery also is important. Patients whose PSA never falls to an undetect­able level in the postoperative period generally are considered to have sys­temic disease. However, some of these men who do not attain an undetectable PSA after surgery do respond to salvage radiation to the prostatic bed. This suggests that systemic disease is not universal in this setting. Likewise, a PSA level that rises rapidly during the postoperative period may be indicative of metastatic disease. Patients whose PSA level remains undetectable for long periods (I to 4 years) and then gradual­ly rises are considered to have local disease recurrence.

After Radiation Therapy

Until recently, the definition of PSA­only recurrence after radiation therapy was widely debated. In 1997, the American Society for Therapeutic Radiology and Oncology (ASTRO) convened a consensus panel to determine guidelines for PSA-only recurrence (biochemical failure) after radiation therapy.[4] The panel agreed on the following four guidelines:

1. Biochemical failure is not a justi­fication per se to initiate additional treatment. It is not equivalent to clinical failure. Biochemical failure is, however, an appropriate early end point for clinical trials.
   


2. Three consecutive increases in PSA level3 provide a reasonable definition of biochemical failure after radia­tion therapy. For clinical trials, the date of failure should be the midpoint between the postirradiation nadir PSA level and the first of three consecutive rises.
   


3. As yet, no definition of PSA-only recurrence has been shown to be a surrogate for clinical progression or survival.
   


4. Nadir PSA level is a strong prognostic factor, but no absolute level is a valid cut-off point for identifying successful and unsuccessful treatments. Nadir PSA level is similar in prognos­tic value to pretreatment prognostic variables.
   

Prediction of PSA-0nly Recurrence

Because early adjuvant therapy may be beneficial to patients with localized disease in whom treatment is destined to fail, many studies have evaluated a variety of prognostic variables in an attempt to identify individuals who are at high risk of disease recurrence after surgery. The following variables have shown a significant correlation with PSA-only recuffence[5-151: pretreatment PSA level; prostatic acid phos­phatase level; prostatectomy specimen Gleason sum; pathologic stage; tumor volume; endorectal coil magnetic resonance imaging results; DNA ploidy; race; and, more recently, molecular biomarkers, such as p53, bcl-2, and Ki­67. Recently, some investigators have combined prognostic variables into models or equations that can be used to predict the likelihood of recurrence.