Management of Rising Prostate-Specific Antigen after Treatment for Localized Prostate Cancer
A 60-year-old man had a screening prostate-specific antigen that was 7.0 ng/mL. The digital rectal exam was normal. A transrectal ultrasound and prostate biopsy revealed moderately well differentiated adenocarcinoma of the prostate, with a Gleason score of 7 (3 + 4). The bone scan and computed tomography (CT) scan of the abdomen and pelvis were negative for metastatic disease. The patient had a radical retropubic prostatectomy. The regional lymph nodes were negative, and the surgical margins were clear of prostate cancer, T1c disease. The postoperative PSA was undetectable, or less than 0.1 ng/mL 4 months after surgery. Three months later, his PSA was 0.2 ng/mL and a repeat PSA at 8 months and 9 months after surgery was 0.4 ng/mL and 0.7 ng/mL, respectively. He was asymptomatic except for occasional stress incontinence and erectile dysfunction. A Prostascint™ scan was positive for recurrence at the anastomotic site. The bone scan was negative.
Prostate cancer recurrence after initial localized treatment, detectable only by a rise in serum PSA level, is a common problem facing clinicians.1 A rising PSA can cause significant anxiety not only for the patient but also for his physician. Because PSA elevations can precede clinical disease by months or even years, the question of when and if to initiate therapy in these patients can be a dilemma. Treatment varies from watchful waiting to hormonal therapy using luteinizing hormone-releasing hormone (LHRH) agonists and/or anti-androgens, radiation therapy for patients with localized recurrence after radical prostatectomy, and salvage radical prostatectomy after failed radiation therapy. These are difficult decisions for physicians caring for patients with prostate cancer. This discussion focuses only on management for patients who have failed either surgery or radiation therapy for localized prostate cancer.
PSA elevation after radical prostatectomy
Prostate cancer recurrence generally occurs in 30-50% of patients within 10 years after radical prostatectomy and is first indicated by an increased serum value of PSA.2 Following a successful radical prostatectomy, all prostate tissue should be removed, and the PSA should be undetectable. If the PSA level begins to elevate after a radical prostatectomy, this usually signals failure of treatment. It is not always known why that happens, but some possibilities include a local recurrence possibly from prostate tissue left behind, implantation of cancer into the area of removal that occurred at the time of surgery, or possibly unrecognized early spread of the disease even when it was confined to the prostate. The biochemical recurrence is generally detected in months after radical prostatectomy as opposed to a clinical recurrence, which may take years to detect. Prostate-specific antigen is typically measured every 3 months during the first several years after surgery, and patients are examined at least twice a year. More recently, the PSA doubling time (PSADT) may be the most powerful predictor of disease progression.3 This study points out that PSA doubling time of less than 6 months suggests a higher probability of systemic disease, whereas PSA doubling time of more than 6 months indicates a higher probability of local relapse.4
Prostate-specific antigen doubling time allows for identification of patients at high risk for clinical relapse and death due to prostate carcinoma. Patients with a short PSADT—6 months or less—should be treated more aggressively than those with a longer PSADT. Detecting recurrence via diagnostic imaging is difficult. The location of recurrent disease after radical prostatectomy is important because it may include subsequent therapeutic decisions. Factors likely to predict local recurrence include positive surgical margins, a Gleason score of less than 7, PSA doubling time of more than 6 months, and PSA detectable more than 1 year after surgery. These patients are candidates for salvage radiotherapy. Early detection of recurrence after surgery has therapeutic implications, as it has been clearly shown that radiation treatment at lower PSAs is more effective compared to higher PSAs.5 I usually recommend salvage radiation therapy after radical prostatectomy if the patient has a life expectancy of at least 10 years.
Younger men or men with few comorbidities are the best candidates for radiation therapy with an elevated PSA after radical prostatectomy. Among the most important predictors for durable response to salvage radiation therapy in the post-prostatectomy PSA rise setting are Gleason score and PSA level. A person with both high Gleason scores (8-10) and elevated PSAs greater than 2 ng/mL has only a 12% chance of responding to radiation therapy.5 There is no evidence that the use of LHRH agonists in addition to radiation therapy improves time to evidence of metastases or improves survival. If a patient has a rising PSA after radical prostatectomy, my initial approach is to treat him early with radiation therapy to the prostatic bed. If that fails to result in an undetectable PSA, I institute early hormonal therapy using LHRH agonists with or without anti-androgens.
PSA elevation after radiation therapy
Radiation therapy is commonly employed to treat localized prostate cancer. Because the prostate remains in situ and can be a source of PSA production from the remaining epithelial cells of the prostate, there exists a great deal of debate in describing what constitutes failure. After radiation therapy, PSA typically declines. Following successful external beam radiation or seed implants, the patients who remain free of disease have an almost undetectable PSA level, typically below 1.0 ng/mL. There seems to be little argument that once the PSA begins to rise from a baseline level (called nadir level) that this constitutes failure. Until recently, the definition of PSA-only 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.6,7 The panel agreed on the following guideline: Three consecutive increases in PSA levels provide a reasonable definition of biochemical failure after radiation therapy.
Once it is established that the PSA is rising, it is usually advisable to search for disease beyond the prostate. This may include a Prostascint scan. A Prostascint scan is performed after injecting a monoclonal antibody that detects prostate-specific membrane antigen linked to a radioactive substance. A positive Prostascint scan suggests the presence of a local recurrence of prostate cancer. These tests help determine whether the cancer represents a local recurrence, a distant event (usually in bone or lymph nodes), or a combination of both. In some cases, a biopsy at the level of the urethrovesical anastomosis is performed following either radiation or radical prostatectomy.
Salvage prostatectomy is sometimes performed after unsuccessful radiation treatment if the cancer is still localized to the prostate gland. Success is only 10-64% using salvage prostatectomy after radiation therapy. The risk of complications after salvage surgery is very high: 10 times that of men who have not had radiation. For example, urinary incontinence after salvage prostatectomy is often untreatable with medications, collagen implants, or other standard treatment measures. Salvage cryosurgery may be effective in certain patients who fail external beam radiotherapy. The best candidates are those with localized prostate cancer and PSA levels below 10 ng/mL. Salvage prostatectomy offers a chance to cure some patients who fail radiation therapy. The keys to selecting these patients are by evaluating the stage and grade of the cancer, their longevity, quality-of-life concerns, and overall health. Unfortunately, the majority of patients who were potent before undergoing this procedure are impotent afterward. This is due to the fact that there is an extensive amount of reaction around the prostate, and it is difficult to do a nerve-sparing procedure after radiation therapy.
There is also a risk of incontinence, and, even in patients who are ultimately not incontinent, it takes months before control of the urine returns. In managing patients who have a rising PSA level following radiation therapy, the decision to use salvage local treatment is often a tough sell. The criteria for candidates for salvage prostatectomy include patients for whom surgery was initially an option; this includes patients with early-stage disease (TI-2), low-grade Gleason scores (< 8), and low PSA levels (< 15 ng/mL). In addition, at the time of salvage therapy, patients should be young enough to tolerate and benefit from the procedure. Given that the average age of irradiated patients is 66 years, the average time to treatment failure is 3 years, and more than 50% of patients are not operative candidates at the time of original surgery, it is not surprising that so few patients are candidates for salvage local treatment. More importantly, however, many patients who initially were candidates for surgery, but who chose to undergo radiation therapy instead, did so to minimize the risks associated with surgery (ie, incontinence and impotence). If patients wished to avoid these risks initially, it is unlikely that many would accept a 40% rate of incontinence with salvage prostatectomy when they declined the option because of a 4% risk!
Patients with rising PSA after either radiation therapy or radical prostatectomy can be effectively managed. Many patients who have been treated for prostate cancer are frequently uncomfortable having their PSA drawn, watching it rise, and not having any additional therapeutic treatment strategies. There are evidence-based data that suggest that early treatment is the best approach for patients with biochemical relapse before they develop clinical evidence of disease.
OUTCOME OF THE CASE PATIENT
The patient was referred to a radiation oncologist who performed salvage radiation therapy to the prostatic bed. His post-radiation PSA has nadired at 0.2 ng/mL for 12 months. His erectile dysfunction was treated with penile rehabilitation with sildenafil 25 mg per day, and 100 mg on demand. His mild urinary stress incontinence was controlled with Kegel exercises and occasional use of a Cunningham clamp that he only used in “social” situations where he wanted to ensure continence.