This article addresses an increasingly common dilemma: the finding of a rising prostate-specific antigen (PSA) level in an asymptomatic patient following radical surgery or radiation therapy for prostate cancer. The incidence of prostate cancer has skyrocketed, and the number of men being treated with radiation or radical prosta-tectomy has similarly increased. The most common basis for the initial diagnosis of prostate cancer is an elevated PSA. For the patient who is already sensitized to PSA as a diagnostic marker, it is extremely distressing to learn that his PSA is rising following radical treatment. This is particularly true for the patient who has experienced a treatment-related adverse effect on quality of life. For the treating physician, this all-too common scenario is disappointing and even guilt-laden.
Waxman et al summarize the various management strategies that may be used in this scenario. The problem, of course, is that the evidence supporting the various therapeutic approaches is weak to nonexistent. The data quoted by the authors consist of retrospective reviews, often using surrogate end points.
The difficulty in this area is that the patient's and physician's desire to see the PSA return to normal or undetectable levels often drives the decision to treat, despite the fact that evidence of benefit may be lacking and evidence of harm (eg, long-term effects of androgen ablation) is clear. To date, there is no proof that any of the interventions used for patients with a rising PSA following radical treatment results in improved survival, compared to delayed therapy.
There are some indisputable facts. Failure of PSA to become undetectable after radical prostatectomy, or to reach a nadir of less than 1 ng/mL after radiation, generally means treatment failure. Adjuvant radiation improves local control in patients with positive margins after radical prostatectomy (according to phase II studies), but evidence of a survival benefit is lacking.
The issue of survival is being addressed in a randomized Southwest Oncology Group (SWOG) study that just successfully completed patient accrual. This study will likely answer this important question.
Following surgery, the time to biochemical failure is predictive of the pattern of relapse. Following radiation, the risk of relapse declines if patients' nadir PSA levels reach 1.0 ng/mL or less. In this group of patients, the relapse rate is 15%.
The definition of PSA failure has generally been based on the conventional PSA assay, which has a lower limit of detectability of 0.2 ng/mL. Use of the ultrasensitive PSA test results in the identification of relapsing patients 1 to 2 years earlier than occurs with the conventional assay.
Management Strategies for Biochemical Failure
The authors are very sanguine about the morbidity of salvage prostatectomy. Experienced surgeons are wary of this operation, as the risk-benefit ratio is poor. The rates of incontinence and positive margins are equivalent, on the order of 50% to 60%. A more conservative approach is warranted in all but the very unusual patient. Candidates for salvage prostatectomy should have a life expectancy of 20 years or more, have minimal or no pelvic fibrosis following radiation, and be prepared for a life of incontinence and impotence.
The authors make several references to the putative benefits of total androgen blockade compared to monotherapy. Since the Prostate Cancer Trialists Cooperative Group (PCTCG) meta-analysis of total androgen blockade published in the Lancet failed to demonstrate a conclusive benefit of total androgen blockade, a dogmatic statement regarding the benefits of combination therapy is not warranted. Although several studies have suggested an increased benefit in patients with minimal disease only, this conclusion is based solely on subset analysis. This type of analysis is useful for generating hypotheses for further studies but does not, by itself, constitute proof of benefit. Thus, the issue of total androgen blockade vs monotherapy remains an open one.
Androgen ablation, either early or delayed, is the option selected by most patients with biochemical failure after radical therapy. There are problems inherent in both the early and delayed strategies. These patients generally have a long survival. Early androgen ablation means many years of therapy, with the attendant expense and cumulative effects of prolonged androgen ablation, including loss of muscle mass, osteoporosis, and impotence. Delayed therapy means ongoing anxiety by the patient regarding his rising PSA, and concern by the physician that survival is being compromised by the lack of treatment.
Intermittent Androgen Ablation
It has been more than 10 years since the initial experience with intermittent therapy was fiest reported. It has proven to be a useful compromise between early and delayed approaches. It produces long-term local and systemic control with reduced morbidity. Patients resume sexual activity and normal energy levels during the off-treatment interval. While there is an unresolved issue of whether survival duration is equivalent, there are unequivocal quality-of-life benefits with this approach, as compared with continuous therapy.
We are currently initiating a phase III study of intermittent vs continuous androgen ablation for radiation failures associated with rising PSA.
Temporary Adjuvant Androgen Ablation
Another approach to improving the results of local therapy is the use of temporary adjuvant androgen ablation following radiation treatment. A recently presented landmark study, the European Organization for Research and Treatment of Cancer (EORTC) trial 92-02, compared radiation with or without 3 years of goserelin (Zoladex) injections beginning the day of the initial radiation dose plus 1 month of cyproterone acetate (Androcur) prior to radiation therapy. This study showed a clear overall survival benefit at 5 years (76% vs 54%) with the addition of adjuvant androgen ablation.
This study, which is the first to demonstrate a survival benefit of multimodality therapy, shows that the elusive goal of improved survival is attainable. Achieving this goal is likely a matter of identifying the optimal combinations and timing of the different modalities. This is analogous to the experience with combination therapy for testis cancer, in which many trials conducted over a period of 20 years were required to learn how different cytotoxic drugs and surgery could be optimally utilized together to maximize survival and minimize morbidity. Given the slow progression rate of prostate cancer, it may take even longer to prove the benefit of the analogous multimodality approach.
1. Lee WR, Hanlon AL, Hanks GE: PSA nadir following XRT for clinically localized prostate cancer. J Urol 156:459, 1996.
2. Yu H, Diamandis EP, Prestigiacomo AF, et al: Ultrasensitive PSA in the early detection of relapsing prostate cancer. Clin Chem 41(3):430-434, 1995.
3. Klotz L, Kerr H, Morse M, et al: Intermittent endocrine therapy for advanced prostate cancer. Cancer 58:2546-2551, 1986.