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Article Excerpt
Byline: STEPHEN J. FREEDLAND, MD, JUDD W. MOUL, MD, JOHN F. WARD, MD
ABSTRACT: Prostate-specific antigen (PSA) recurrence is the most common form of advanced prostate cancer. Salvage therapies may be effective even among some high-risk men, although long-term cancer control data are limited. The natural history of PSA recurrence is long but variable. The postrecurrence PSA doubling time can identify men at high risk for progression and death. Early hormonal therapy, possibly via combined androgen blockade, may reduce the risk of progression and improve cancer-specific survival among men with high-risk recurrence. Men with low-risk recurrences likely receive minimal benefit from aggressive early hormonal therapy and may actually be harmed.
KEY WORDS: castration, neoplasm, prostate, prostate-specific antigen, salvage therapy
Today, because of prostate-specific antigen (PSA) screening, prostate cancer in most patients is detected earlier and at younger ages than in the past. Despite this early detection and after definitive therapy, whether by radical prostatectomy (RP) or radiation therapy (RT), a biochemical recurrence will develop within 10 years of treatment in about 35% of men.1,2 With about 230,000 cases of prostate cancer diagnosed each year in the United States, it is estimated that a PSA-only recurrence develops in more than 50,000 men per year.3
Although the natural history of PSA recurrence can be long,4 recent studies have helped us stratify men for varying risk of clinical progression and prostate cancer death with ever-increasing accuracy.4-7 In this review, we discuss PSA recurrence after primary therapy. We focus on the definition of recurrence, the natural history and risk factors for progression, the role of salvage therapies aimed at cure or palliation, and the timing of these therapies. We also offer advice on how to incorporate this information into clinical practice.
PSA RECURRENCE DEFINED
During RP, essentially all PSA-producing cells should have been removed. Therefore, slight elevations in PSA levels are used to indicate cancer recurrence. The exact level that defines PSA recurrence is debated, however. In general, a PSA level higher than 0.4 or 0.2 ng/mL has been used in most studies.8,9
PSA levels do not fall to undetectable levels after RT as they do after RP. Rather, radiation induces a slow and not always steady decline in PSA level. The median time to PSA nadir is about 18 months-and possibly longer following brachytherapy. In addition, slight transient upswings in PSA levels (PSA bounce) are not uncommon. Therefore, defining recurrence in this setting is more challenging.
In 1997, the American Society for Therapeutic Radiology and Oncology (ASTRO) convened a consensus panel whose members defined recurrence after RT as 3 consecutive elevated PSA values after reaching a nadir, or a single elevated value significant enough to trigger the initiation of hormone therapy.10 The failure date is backdated to the midpoint between PSA nadir and the first of the 3 elevated PSA values. This backdating introduces a bias that overestimates the success at shorter follow-up times (not enough follow-up has occurred to document failure). Moreover, in long-term follow-up studies, the failures are backdated to an earlier point in time, resulting in a leveling of the Kaplan-Meier curve, in contrast to outcomes after RP in which PSA-free survival continues to decline over time.11
Because of the concerns mentioned above, ASTRO recently convened a new consensus panel that redefined recurrence: a PSA value higher than absolute nadir plus 2 ng/mL or a PSA value higher than absolute nadir plus 3 ng/mL.12 Both define the failure date as that when recurrence was met (ie, failure time is no longer backdated).
NATURAL HISTORY OF PSA RECURRENCE
The natural history of PSA recurrence can be quite long but varies. In a classic study at Johns Hopkins University, Pound and associates4 described 315 men with PSA failure following RP who did not receive hormonal therapy until the time of metastasis. The median time from PSA recurrence to metastasis was 8 years, and the median time from metastasis to death was 5 years.
In a recent follow-up study from Johns Hopkins that included a slightly larger cohort, the median time from PSA recurrence to prostate cancer death was not reached after 16 years of follow-up.6 However, prostate cancer deaths were seen as early as 1 year after PSA recurrence, although with very rare frequency. Thus, the natural history of recurrent prostate cancer is one of a slowly progressing disease, but in some men the progression can be quite rapid.
RISK FACTORS FOR CLINICAL PROGRESSION AND PROSTATE CANCER DEATH
Given this long but variable natural history, many investigators sought to identify risk factors to predict the likelihood of clinical progression and prostate cancer death. The variable that has most consistently been linked with adverse outcome is how fast the serum PSA level is rising, which is most commonly measured as PSA doubling time (PSADT).
Nearly 15 years ago, Carter and colleagues13 first demonstrated that changes in PSA levels over time could predict the likelihood of prostate cancer. Shortly thereafter, PSA kinetics were shown to predict the risk of distant versus local failure among men with PSA failure after RT14 and after RP.15 These initial observations were confirmed in later studies.4,7,16-19 A rapid PSADT has been linked not only to risk of metastasis but also to prostate cancer death.5-7,20 The association between PSADT and prostate cancer...
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