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Management of Early-Stage Prostate Cancer
Neal Shore, MD
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Management of Biochemically Recurrent Prostate Cancer Following Local Therapy
Michael Kolodziej, MD, FACP
Participating Faculty: Prostate Cancer Management: Enhancing Cost-Effectiveness and Patient Outcomes
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Management of Biochemically Recurrent Prostate Cancer Following Local Therapy

Michael Kolodziej, MD, FACP
Localized therapy for prostate cancer is often curative; however, 20% to 30% of patients experience a recurrence. Men with biochemical recurrence (BCR) are typically identified following routine monitoring of prostatespecific antigen after treatment for localized disease. These patients exhibit no signs of prostate cancer. Initial evaluation attempts to determine whether the BCR is due to local recurrence or systemic disease. Depending on the type of initial local therapy, treatment options for local recurrence include salvage radiation therapy or salvage prostatectomy. If systemic recurrence is suspected, other options must balance the onset of metastatic disease with avoidance of overtreatment. The most common treatment is androgen deprivation therapy (ADT) via gonadotropinreleasing hormone agonists or antagonists. Because there are challenges associated with standard ADT, other treatment options are being investigated, including a number of natural products.

Am J Manag Care. 2014;20:S273-S281
Although local therapy for prostate cancer, such as radical prostatectomy or radiation, is curative for many patients, 20% to 30% experience a recurrence typically detected from a rise in serum prostate-specific antigen (PSA) levels.1-4 Five years after initial therapy, 15% of men experience this biochemical recurrence (BCR), while 20% to 40% of men exhibit BCR 10 years after radical prostatectomy1,5,6 and 30% to 50% after undergoing radiation treatment.7 Although both clinical features as well as pathological findings can predict the likelihood of biochemical relapse, once biochemical relapse occurs the patient is presumed to have recurrent prostate cancer.8 PSA is a sensitive and specific marker for prostate cancer. Monitoring for PSA levels after treatment of localized prostate cancer leads to the identification of men with a PSA-only (biochemical) recurrence, for which there are no symptoms or signs of locally recurrent or metastatic disease. The definition of PSA recurrence is dependent upon the type of initial local therapy received: radical prostatectomy or radiation therapy. Defining the optimal treatment plan for those who present with BCR represents a clinical challenge, because patients who exhibit a BCR often do not possess any other disease symptoms and may not develop metastatic disease for many years. An important question therefore exists in the medical community: should these men be further treated based solely on their PSA values? This review describes the definition of BCR, current and emerging strategies for the treatment of these patients, and alternative approaches.

Biochemical Recurrence

PSA Recurrence After Surgery

The PSA after radical prostatectomy should be undetectable. The timing for the drop in PSA has been well established,9 and the half-life of PSA in the serum post prostatectomy is 2 to 3 days.10,11 In some patients, residual prostatic tissue (for example, residual apical tissue post robotic prostatectomy) can lead to a measurable PSA after surgery; however, typically this low PSA remains stable over time. A detectable or rising PSA value is defined by the American Urological Association (AUA) as greater than 0.2 ng/mL after surgery with a second confirmatory level of greater than 0.2 ng/mL,12 although a cut point of 0.4 ng/mL may better predict the risk of metastatic relapse. When BCR is documented in post prostatectomy patients, the critical first patient evaluation step is to determine whether the recurrence is due to local recurrence or disseminated disease. Certain clinical features can help predict this distinction. For example, a PSA failure within 6 months of surgery is highly suggestive of metastatic disease,13,14 while patients with positive surgical margins are more likely to have locally recurrent disease.15 Interestingly, capsular involvement is not predictive of local recurrence.16 Invariably, radiographic evaluation includes CT imaging and bone scan, although these are often negative unless the PSA approximates 20.17

Radionuclide Imaging

For post prostatectomy patients suspected to harbor undetected cancer recurrence, radioimmunoscintigraphy (RIS) may help define the extent of disease. In this technique, radiolabeled monoclonal antibodies specifically bind to prostate-specific membrane antigen (PSMA), a protein expressed higher in malignant versus benign prostate cells. Rather than being dependent on a tumor size, RIS depends on the degree of biomarker expression (ie, PSMA).18 The radiopharmaceutical currently in clinical use is the 111In-capromab pendetide, ProstaScint, approved by the FDA in 1996 to detect distant metastasis in both high-risk patients with newly diagnosed prostate cancer and in patients with increasing PSA levels after radical prostatectomy. This monoclonal antibody specifically binds to the intracellular epitope of PSMA on prostatic epithelial cells, excluding secretory glycoproteins. When used after radical prostatectomy, ProstaScint has a sensitivity of 75% to 86% and a specificity of 47% to 86% in detecting local recurrence.18 There are conflicting data in the literature concerning the effective use of ProstaScint in determining the need for further therapy in the post prostatectomy setting. For instance, early studies reported that bone metastases cannot be detected by ProstaScint. Importantly, there is no observed difference in PFS in those with a positive scan versus a negative scan.18,19 Further, any positive predictive value of ProstaScint is low (27% to 50%), perhaps due to false-positive scans from postsurgical inflammation and vascular perturbations.18,20 Based on the currently published literature, ProstaScint scans should not be used in recommending salvage radiation therapy after radical prostatectomy.18-21

For potential improvements in radionuclide approaches to detect PSMA, additional strategies are being explored. These include antibodies binding the extracellular region of PSMA instead of the intracellular, and radiolabeling with various compounds (89Zr and 64Cu have yielded positive results in mouse models).22-24 Aptamers is another class of radiopharmaceutical that has target specificity and affinity similar to that of antibodies. Aptamers fold into a unique 3-dimensional conformation that is complementary to the surface of the target, and their use has generated specific binding to PSMA-positive cells in vitro.25 Additionally, lowmolecular- weight PSMA inhibitors are showing promise in early clinical studies.24,26

The role of other imaging modalities to define the site of recurrent disease is a rapidly evolving field. Initial results with FDG-PET imaging were extremely disappointing. More recent trials using alternative radiolabelled compounds including F18 and C11 Choline suggest improved sensitivity to detect both metastatic disease in lymph nodes and bone. However, the positive predictive value as defined by prolonged PSA-free survival after local salvage is not known. Further, the value in patients with PSA values less than 1 ng/ml seems low.27 Accordingly, in the setting of biochemical relapse, these modalities are considered investigational.

Salvage Radiation Therapy

The importance of forming a clinical judgment about local versus systemic recurrence lies in the ability to salvage some surgical failures with radiation therapy. Large retrospective studies provide evidence that early salvage radiation therapy, delivered to patients with rapid PSA doubling time (PSADT), or while the PSA levels remain below 2.0 ng/mL, influences survival of patients with BCR.15,28 In a study carried out at Duke University, 519 patients29 were examined, and it was determined that salvage radiation therapy significantly (P = .02) improved overall survival at a median follow-up of 11.3 years. A study at Johns Hopkins followed 635 patients28 and determined that salvage radiation therapy was associated with a 3-fold increase in prostate cancer–specific survival after a median follow-up of 6 years after BCR compared with observation alone. However, this improvement was limited to men with a PSADT of less than 6 months. Interestingly, salvage radiation therapy was still associated with significant improvement in prostate-specific survival when administered to patients with a PSA greater than 2 ng/mL, only if those patients also had a PSADT of less than 6 months. No significant increase in prostate cancer–specific survival was observed in patients who were administered salvage radiation therapy more than 2 years after PSA recurrence.28 It is important to note that the use of salvage radiation post prostatectomy is associated with significantly higher rates of both acute and long-term toxicity, including gastrointestinal and genitourinary complications.30 In fact, impotence after salvage radiotherapy is almost universal.31 Given the aforementioned benefits and toxicities, the ultimate decision to proceed with salvage radiotherapy depends on the clinician’s judgment that the recurrence is localized to the prostatic fossa. It should be remembered that the studies cited did not employ the most current imaging modalities, and that as these improve the likelihood that disease is localized will also improve the outcomes for patients who are treated with salvage radiotherapy.

PSA Recurrence After Radiation

Following radiation treatment, the PSA levels typically do not fall to zero and the kinetics of PSA decline are different than that post prostatectomy.9 There have been several definitions offered to define BCR after radiation. One example is the Phoenix definition, which states that an increase in the PSA level by 2 ng/mL or more above the nadir constitutes BCR. The goal of the Phoenix definition is to predict clinical recurrence and progression rather than BCR alone. This approach results in substantially lower estimates of BCR at 5 years, and substantially higher estimates of BCR at 10 years compared with the traditional American Society for Radiation Oncology (ASTRO) definition. As with BCR after surgical relapse, an attempt is made to define probable local recurrence versus probable disseminated disease. In addition to the aforementioned imaging, Doppler ultrasound and ultrasound-guided biopsy of residual prostate tissue is occasionally pursued and can occasionally identify local recurrence; however, it is not a very sensitive or reliable approach.32

Surgical Salvage After Radiation

There has been extensive experience with salvage prostatectomy following radiation, but it is typically acknowledged that salvage radical prostatectomy is associated with a higher complication rate than this surgical approach without prior radiotherapy.33,34 Due to the fibrotic response to potentially curative radiotherapy, surgery is often not curative and is often associated with severe toxicity including bladder and rectal injury that may require urinary or fecal diversion.35 Further, patients receiving salvage surgery have been shown to have a higher probability of medical and surgical complications, including urinary tract infection, bladder neck contracture, urinary retention, urinary fistula, abscess, and rectal injury. Also, approximately 75% of patients with salvage prostatectomy experience impotence.34 For these reasons, this surgery should be only performed by highly skilled surgeons operating at centers of excellence with experience managing these patients. Other local modalities to treat local recurrence after radiation therapy, such as cryoablation, should be considered experimental.36

Efficacy and Limitations of Available Treatment Modalities

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