Management of Biochemically Recurrent Prostate Cancer Following Local Therapy
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n REPORTS n Management of Biochemically Recurrent Prostate Cancer Following Local Therapy Michael Kolodziej, MD, FACP lthough local therapy for prostate cancer, such as radical prostatectomy or radiation, is curative for Abstract many patients, 20% to 30% experience a recurrence Localized therapy for prostate cancer is often typically detected from a rise in serum prostate-spe- curative; however, 20% to 30% of patients Acific antigen (PSA) levels.1-4 Five years after initial therapy, 15% of experience a recurrence. Men with biochemi- men experience this biochemical recurrence (BCR), while 20% to cal recurrence (BCR) are typically identified following routine monitoring of prostate- 40% of men exhibit BCR 10 years after radical prostatectomy1,5,6 specific antigen after treatment for localized 7 and 30% to 50% after undergoing radiation treatment. Although disease. These patients exhibit no signs of both clinical features as well as pathological findings can predict prostate cancer. Initial evaluation attempts the likelihood of biochemical relapse, once biochemical relapse to determine whether the BCR is due to local occurs the patient is presumed to have recurrent prostate can- recurrence or systemic disease. Depending cer.8 PSA is a sensitive and specific marker for prostate cancer. on the type of initial local therapy, treatment options for local recurrence include salvage Monitoring for PSA levels after treatment of localized prostate radiation therapy or salvage prostatectomy. cancer leads to the© Managedidentification Care of men& with a PSA-only (bio- If systemic recurrence is suspected, other chemical)Healthcare recurrence, Communications,for which there are no LL symptomsC or signs options must balance the onset of metastatic of locally recurrent or metastatic disease. The definition of PSA disease with avoidance of overtreatment. recurrence is dependent upon the type of initial local therapy The most common treatment is androgen deprivation therapy (ADT) via gonadotropin- received: radical prostatectomy or radiation therapy. Defining releasing hormone agonists or antagonists. the optimal treatment plan for those who present with BCR Because there are challenges associated with represents a clinical challenge, because patients who exhibit a standard ADT, other treatment options are BCR often do not possess any other disease symptoms and may being investigated, including a number of not develop metastatic disease for many years. An important natural products. question therefore exists in the medical community: should Am J Manag Care. 2014;20:S273-S281 these men be further treated based solely on their PSA values? This review describes the definition of BCR, current and emerg- ing 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 For author information and disclosures, see end of text. days.10,11 In some patients, residual prostatic tissue (for example, residual apical tissue post robotic prostatectomy) can lead to a VOL. 20, NO. 12 n THE AMERICAN JOURNAL OF MANAGED CARE n S273 Reports measurable PSA after surgery; however, typically this low and vascular perturbations.18,20 Based on the currently PSA remains stable over time. A detectable or rising PSA published literature, ProstaScint scans should not be used value is defined by the American Urological Association in recommending salvage radiation therapy after radical (AUA) as greater than 0.2 ng/mL after surgery with a prostatectomy.18-21 second confirmatory level of greater than 0.2 ng/mL,12 For potential improvements in radionuclide although a cut point of 0.4 ng/mL may better predict approaches to detect PSMA, additional strategies are the risk of metastatic relapse. When BCR is documented being explored. These include antibodies binding the in post prostatectomy patients, the critical first patient extracellular region of PSMA instead of the intracellular, evaluation step is to determine whether the recurrence is and radiolabeling with various compounds (89Zr and due to local recurrence or disseminated disease. Certain 64Cu have yielded positive results in mouse models).22-24 clinical features can help predict this distinction. For Aptamers is another class of radiopharmaceutical that example, a PSA failure within 6 months of surgery is has target specificity and affinity similar to that of highly suggestive of metastatic disease,13,14 while patients antibodies. Aptamers fold into a unique 3-dimensional with positive surgical margins are more likely to have conformation that is complementary to the surface of locally recurrent disease.15 Interestingly, capsular involve- the target, and their use has generated specific binding ment is not predictive of local recurrence.16 Invariably, to PSMA-positive cells in vitro.25 Additionally, low- radiographic evaluation includes CT imaging and bone molecular-weight PSMA inhibitors are showing promise scan, although these are often negative unless the PSA in early clinical studies.24,26 approximates 20.17 The role of other imaging modalities to define the site of recurrent disease is a rapidly evolving field. Radionuclide Imaging Initial results with FDG-PET imaging were extremely For post prostatectomy patients suspected to harbor disappointing. More recent trials using alternative radio- undetected cancer recurrence, radioimmunoscintigraphy labelled compounds including F18 and C11 Choline sug- (RIS) may help define the extent of disease. In this tech- gest improved sensitivity to detect both metastatic disease nique, radiolabeled monoclonal antibodies specifically in lymph nodes and bone. However, the positive predic- bind to prostate-specific membrane antigen (PSMA), tive value as defined by prolonged PSA-free survival a protein expressed higher in malignant versus benign after local salvage is not known. Further, the value in prostate cells. Rather than being dependent on a tumor patients with PSA values less than 1 ng/ml seems low.27 size, RIS depends on the degree of biomarker expres- Accordingly, in the setting of biochemical relapse, these sion (ie, PSMA).18 The radiopharmaceutical currently in modalities are considered investigational. clinical use is the 111In-capromab pendetide, ProstaScint, approved by the FDA in 1996 to detect distant metas- Salvage Radiation Therapy tasis in both high-risk patients with newly diagnosed The importance of forming a clinical judgment about prostate cancer and in patients with increasing PSA local versus systemic recurrence lies in the ability to sal- levels after radical prostatectomy. This monoclonal vage some surgical failures with radiation therapy. Large antibody specifically binds to the intracellular epitope of retrospective studies provide evidence that early salvage PSMA on prostatic epithelial cells, excluding secretory radiation therapy, delivered to patients with rapid PSA glycoproteins. When used after radical prostatectomy, doubling time (PSADT), or while the PSA levels remain ProstaScint has a sensitivity of 75% to 86% and a specific- below 2.0 ng/mL, influences survival of patients with ity of 47% to 86% in detecting local recurrence.18 There BCR.15,28 In a study carried out at Duke University, 519 are conflicting data in the literature concerning the patients29 were examined, and it was determined that effective use of ProstaScint in determining the need for salvage radiation therapy significantly (P = .02) improved further therapy in the post prostatectomy setting. For overall survival at a median follow-up of 11.3 years. instance, early studies reported that bone metastases can- A study at Johns Hopkins followed 635 patients28 and not be detected by ProstaScint. Importantly, there is no determined that salvage radiation therapy was associated observed difference in PFS in those with a positive scan with a 3-fold increase in prostate cancer–specific survival versus a negative scan.18,19 Further, any positive predic- after a median follow-up of 6 years after BCR compared tive value of ProstaScint is low (27% to 50%), perhaps due with observation alone. However, this improvement to false-positive scans from postsurgical inflammation was limited to men with a PSADT of less than 6 S274 n www.ajmc.com n DECEMBER 2014 Management of Biochemically Recurrent Prostate Cancer Following Local Therapy months. Interestingly, salvage radiation therapy was still fibrotic response to potentially curative radiotherapy, associated with significant improvement in prostate-spe- surgery is often not curative and is often associated with cific survival when administered to patients with a PSA severe toxicity including bladder and rectal injury that greater than 2 ng/mL, only if those patients also had a may require urinary or fecal diversion.35 Further, patients PSADT of less than 6 months. No significant increase in receiving salvage surgery have been shown to have a prostate cancer–specific survival was observed in patients higher probability of medical and surgical complications, who were administered salvage radiation therapy more including urinary tract infection, bladder neck contrac- than 2 years after PSA recurrence.28 It is important to ture, urinary retention, urinary fistula, abscess, and rectal note that the use of salvage radiation post prostatectomy injury. Also, approximately 75% of patients with salvage