ABSTRACT: Controversy exists over the optimal management of patients with an asymptomatic rising prostate-specific antigen (PSA) following definitive therapy for clinically localized prostate adenocarcinoma. Post-prostatectomy patients whose residual disease is felt to be confined to the area immediately adjacent to the prostatic bed may benefit from external-beam radiation therapy. Systemic recurrence may be managed with either watchful waiting or treated with hormone deprivation. Post-radiation therapy patients felt to have local disease progression may undergo salvage radical prostatectomy (if disease is clinically confined to the prostate gland) or cryotherapy (although this is still considered "experimental"). Patients who are not candidates for salvage therapy can be managed with watchful waiting or hormone deprivation. For patients in whom definitive therapy has failed, treatment should be individualized according to pathologic stage (if post-prostatectomy), rate of PSA progression, surgical candidacy status (if post-radiation therapy), and attitudes and expectations of the physician and patient. [ONCOLOGY 11(4):457-465, 1997]

Introduction

A denocarcinoma of the prostate is the most common malignancy in men and the second most common cause of cancer deaths in North American males.[1,2] Definitive therapy for clinically-localized adenocarcinoma of the prostate (stages T1 and T2) is either radical prostatectomy or radiation therapy. Prostate-specific antigen (PSA) was first described by Wang et al in 1979.[3] Prostate-specific antigen has enzymatic activity and is produced by the prostate and periurethral glands in men.[4] Following radical prostatectomy, serum PSA should decrease to an undetectable level if all prostatic tissue has been removed. Several investigators have described the relationship between postoperative PSA and the subsequent risk of disease recurrence.[5,6]

Rising PSA Post-Prostatectomy

Post-prostatectomy PSA is a sensitive indicator of disease, and its elevation often precedes clinically-recurrent disease by months to years.[7] Pathologic stage has been shown to correlate with the risk of residual disease, progression, and survival.[8-10] In some series, as many as 50% of patients undergoing radical prostatectomy have been found to have extracapsular extension on final pathologic staging.

Not all tumors that are pathologic stage T3 have the same risk of local recurrence and/or progression. Among patients found to be margin-positive by pathologic staging, Coetzee et al have suggested a difference in local disease recurrence between patients whose PSA drops to an undetectable level postoperatively and those whose PSA does not become undetectable.[11] They feel that patients who are margin-positive (C2) but who attain an undetectable PSA postoperatively, followed by a delayed increase in PSA, have possibly only a local recurrence in the prostatic fossa, whereas patients whose PSA does not fall to undetectable levels postoperatively most likely have microscopic metastases.

In addition to PSA and digital rectal examination, transrectal ultrasound is useful in detecting local recurrence following radical prostatectomy.[12] Prostate-specific antigen failure rates following radical prostatectomy for pathologically organ-confined disease range from 9% to 14%.[5,13,14] Upon review of these results, several investigators have found the presence of unconfined disease that was overlooked by histopathologic examination.[14-16]

Adjuvant Radiation Therapy

The primary question to be addressed is whether PSA failure following radical prostatectomy represents local recurrence, and thus, is amenable to treatment with adjuvant radiation therapy. Klein has concluded that PSA failure patients post-prostatectomy who have low Gleason grade, low initial PSA, and low PSA velocity after surgery, are more likely to benefit from adjuvant radiation. He also found that such patients who have negative margins are likely to have metastatic disease.[17]

Several studies have shown a poor long-term response to adjuvant radiation in patients who never achieve undetectable PSA levels following radical prostatectomy.[9,18] Studies that support the use of adjuvant radiation therapy for PSA failure cite improved local control of disease and up to 53% success in reaching undetectable PSA levels; however, this does not translate into an improvement in the incidence of distant metastasis or overall survival.[19-21]

The timing of salvage radiation following PSA failure has also been investigated. The potential cure rate after waiting for the PSA level to rise before initiating salvage radiation is £ 33%.[22] Serum PSA concentrations are reduced to the undetectable range in 30% to 80% of men treated with salvage radiation therapy. However, in 30% to 60% of men who respond to radiation therapy, the serum PSA concentration will rise again within 2 years.[23]

New methods to help determine local vs distant recurrence include reverse-transcriptase polymerase chain reaction (PCR) and Prosta-scint (a monoclonal antibody to cell membrane PSA).[24]

Androgen Deprivation Therapy

Data suggest that patients whose PSA fails to normalize initially after radical prostatectomy are likely to have distant metastases, whereas those who develop a delayed (more than 18 months) rise in PSA are likely to have a local recurrence.[25] Watchful waiting is one option for the management of patients with PSA failure following radical prostatectomy who are not felt to have a local recurrence.

The decision as to when such a patient would benefit from androgen-deprivation therapy remains controversial. The mainstay of therapy for advanced metastatic prostate cancer has been either bilateral scrotal orchiectomy, estrogen therapy, or androgen blockade. However, in the last 5 years, the definition and treatment of "advanced prostate cancer" have undergone a metamorphosis. Advanced adenocarcinoma of the prostate now not only includes stage D2 (M1 disease) but also an increasing PSA level after radical prostatectomy or other definitive local therapy.

FIGURE 1
Progression-Free Survival

FIGURE 2
Same Subset, Overall Survival

It has been established that a substantial survival benefit is enjoyed by those with minimal metastatic disease who are treated with combined androgen blockade.[reference 26 and Figure1 and Figure 2] Androgen deprivation therapy decreases PSA levels initially in nearly all men. Among men with stage D2 disease, only 9% still have undetectable serum PSA levels after 2 years. Also, 72% of men who have a good initial response (within the first 6 months) experience increases in serum PSA within the second 6 months following therapy.[27]

Novel Therapeutic Approaches

Some patients whose PSA rises after definitive local therapy (with radical prostatectomy, radiation therapy, or cryotherapy) and their physicians are apprehensive about using standard androgen deprivation therapy. In such patients, novel therapeutic approaches have been investigated. In several studies, Fleshner and Trachtenberg have shown durable decreases in PSA levels using the combination of finasteride (Proscar) and flutamide (Eulexin) in patients with advanced prostate cancer.[28] It is not known whether this combination will affect time to progression or overall outcome in these patients.

Summary

In summary, a PSA that does not fall to an undetectable level following radical prostatectomy has been associated with metastatic disease, whereas a PSA level that initially drops to an undetectable level and later begins rising is possibly associated with local recurrence. Patients whose PSA does not fall to an undetectable level following radical prostatectomy are unlikely to be cured by adjuvant radiation therapy. Patients whose PSA nadir is undetectable following radical prostatectomy and then subsequently becomes detectable should undergo restaging. If, after restaging, these patients are felt to have local recurrence, they may benefit from adjuvant radiation therapy.

Controversy exists over the efficacy of early vs delayed hormonal therapy for an asymptomatic rising PSA following radical prostatectomy. Combined androgen therapy has shown both increased time to progression and survival when compared with bilateral orchiectomy or a luteinizing hormone-releasing hormone (LHRH) agonist alone.

Finally, novel therapies have been proposed to lower PSA while decreasing side effects usually associated with standard androgen deprivation therapy. However, a survival advantage of such therapies has yet to be demonstrated.