The Effective Management of Biochemical Recurrence in Patients With Prostate Cancer

HORMONAL THERAPY AND PROSTATE CANCER The Effective Management of Biochemical Recurrence in Patients With Prostate Cancer David G. McLeod, MD Department of Urologic Oncology, Walter Reed Army Medical Center, Washington, DC; Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD; Center for Prostate Disease Research, Rockville, MD Prostate-specific antigen (PSA) testing has become the primary method of monitoring patients following definitive therapy for clinically localized prostate cancer. After surgery, an immediate detectable rise in PSA is correlated with subsequent local recurrence and/or metastasis. Following radiation therapy, biochemical failure is defined as 3 consecutive rises in PSA above the nadir. Treatment of postoperative or postradiation PSA recurrence involves several modalities, including luteinizing hormone– releasing hormone agonists. Although studies have demonstrated the advantages of early hormone therapy, they have not addressed at what PSA level treatment should begin. A better understanding of PSA’s kinetics will lead to a sense of when to begin treatment and when watchful waiting is the more appropriate course. [Rev Urol. 2005;7(suppl 5):S29-S36] © 2005 MedReviews, LLC Key words: Hormone therapy • Prostate cancer • Prostate-specific antigen recurrence • Radiation therapy • Radical prostatectomy rostate-specific antigen (PSA) is an androgen-regulated serine protease. This antigen is a member of the tissue kallikrein family of proteases and is located on chromosome 19q.13.4.1 Most of the secretory epithelial cells in the prostate are located in the peripheral zone and are the source of PSA production. The protease is subsequently released into the ejaculatory ducts from the acini. PSA thus becomes a portion of the seminal fluid and is the major protein P VOL. 7 SUPPL. 5 2005 REVIEWS IN UROLOGY S29 Management of Biochemical Recurrence continued Normal Cancer Active PSA Lumen inactive proPSA Secretory epithelium Basal cells Basement membrane Serum ACT free PSA ACT proPSA Bound PSA Bound PSA Figure 1. Disruption of the basal cell layer and basement membrane, allowing increased prostate-specific antigen (PSA) into the circulation. ACT,
1-antichymotrypsin. Reproduced with permission from Balk et al.7 in seminal fluid, which consists primarily of substrates semenogelin I and II.2 In prostate cancer, there is disruption of the basal cell layer and basement membrane, and this disruption is thought to allow increased PSA into the circulation (Figure 1). The first utility of PSA was in monitoring disease status in patients with prostate cancer; in the United States, it was approved for this indication by the Food and Drug Administration (FDA) in 1986. Pursuant to this use, and because of the fact that the PSA test is an inexpensive blood test that can be obtained with relative ease, its application led to its increasing role as a screening modality. In 1994, the FDA approved PSA as a screening tool, based in part on the seminal work of Catalona and colleagues.3 Nevertheless, the issue of “PSA screening” is still hotly debated, but patients increasingly expect this test to be afforded them—and at times demand it. The term PSA sometimes has been jokingly described as “patient-scaring antigen.” Indeed, there are some pa- S30 VOL. 7 SUPPL. 5 2005 tients whose reliance on the test could in a similar vein describe them as “PSA addicts,” as they would have the test as often as a physician would order it. The inescapable fact is that the number of PSA tests is increasing exponentially, and PSA’s role in screening is unlikely to decrease.4 However, the questions that arise concern the definition of recurrence and what, if anything, needs to be done at a given point at the first discernable rise. Before tackling the above-mentioned issues, it is relevant to review primary definitive treatments. The treatment modalities for clinically localized disease may be extremely vexing to patients. Consider the choices: radical prostatectomy, in which the approach may be retropubic, perineal, laparoscopic, or robotic; radiation therapy (intensitymodulated radiation therapy [IMRT], brachytherapy, or a combination of the two); cryotherapy; and the latest modality—high-intensity focused ultrasonography (HIFU). When one adds the use of neoadjuvant and adjuvant hormone therapy (HT) to radiation therapy, along with information from clinical trials using neoadjuvant and/or postoperative HT with or without chemotherapy, patients are faced with mounting informational challenges. Adding to this clinical milieu of options are the sources of information, which are legion. These sources range from the Internet, golfing The term PSA sometimes has been jokingly described as “patient-scaring antigen.” Indeed, there are some patients whose reliance on the test could in a similar vein describe them as “PSA addicts,” as they would have the test as often as a physician would order it. Today, PSA as a surrogate endpoint to monitor disease progression is generally accepted as the primary method to monitor a patient following definitive therapy for clinically localized prostate cancer. It is important to remember, as mentioned earlier, that monitoring of disease status was the first approved use of PSA.5,6 Its use as a biomarker of response to therapy and as an early indicator of cancer recurrence is undeniable.7 REVIEWS IN UROLOGY partners, associates, friends, and family, to the sometimes biased views of different medical specialists and health care providers. Is it any surprise that a patient is frequently flummoxed by treatment decisions and that when a therapy decision is decided on, a therapy is rendered, and follow-up has begun, PSA levels frequently become a focal point in the lives of our patients? Of utmost importance is the failure of primary therapy, which not Management of Biochemical Recurrence infrequently challenges both patients and clinicians.8 The PSA issue is underscored by the fact that at the present time, approximately 35% of men who undergo prostatectomy will develop a detectable PSA recurrence within 10 years of their surgery.9 PSA Recurrence Following Surgery Surgical intervention for clinical localized disease is the treatment modality most often used in the United States. It has been recognized since the late 1980s that an immediate detectable postoperative PSA is a portent correlated with subsequent local recurrence and/or distant metastasis within 3 years.10 Lange and associates11 reported recurrence in all men with serum PSA  0.3 ng/mL. In their series, they found that in men with serum postoperative PSA levels  0.3 ng/mL, only 9% experienced tumor recurrence. Ultrasensitivity has extended the limits of PSA detectability to 0.001 ng/mL. In these assays, levels as low as 0.01 to 0.07 ng/mL may be an early signal of recurrence, a finding that was described more than a decade ago.12 However, the ultrasensitivity of PSA produced by residual cancerous and/or benign prostate cells, eg, a diagnosis of benign glands in the margins, may be vexing. Nonprostatic tissue, eg, primary gynecomastia and breast cancer and salivary duct and thyroid tumors, may produce minute amounts of PSA.13-15 Also, very low levels may be found in perianal and apocrine sweat glands.16,17 Nevertheless, in general, there is no appreciable source of serum PSA other than the prostate. With ultrasensitivity, what is the significance of slight fluctuations of hundreds or thousands of a percentage point? It is impossible to measure zero, and slight fluctuations will occur in different tests, eg, with vari- ous reagents, techniques of technicians performing assays, and laboratories. Practically speaking, these variations are de minimis, and an analogy can be given in which when one turns a radio dial to a nearby station, there is no static. However, when the dial is turned to a distant station, one can hear the station but is also aware of static or hissing in the background. When one tunes to a frequency in which there is no station, all he or she hears is the background static and hissing. When a laboratory technician is reading “hiss” or “background noises,” the result is usually reported in a value less than the minimum detectable value. Amling and associates18 showed that with thresholds of 0.2, 0.3, and 0.4 ng/mL, there is a risk of a contin- At the first time of detectability, a rise in PSA may be a harbinger of failure in some patients, but it is not necessarily equivalent to clinical failure or subsequent biochemical failure. What it can be though, as Kuban astutely pointed out, is an appropriate early endpoint for clinical trials. She made the provocative statement that no definition of PSA failure to date has become a surrogate for clinical progression or survival. Although she was speaking primarily from a post– initial radiation therapy standpoint, her observations are also valid when we critically look at biochemical failure after surgery, eg, with time of detectability after surgery and PSA doubling time (PSA-DT) being critical in any decision to embark on therapy. A decision to implement therapy, A decision to implement therapy, usually with some form of HT, must be carefully weighed against the implications of how such therapy will deleteriously impact quality of life. ual rise in PSA of 49%, 62%, and 72%, respectively, within 3 years. It was their feeling that a PSA level of  0.4 ng/mL or greater was the peak level to define a recurrence. On the other hand, some series use 0.2 ng/mL to indicate disease recurrence.19 At the Center for Prostate Disease Research, we use the criterion of 2 separate PSA values that are  0.2 ng/mL in postoperative patients as evidence of failure.20 It appears that this value is becoming a reasonable cut point. A recent European Consensus recommended the use of the value 0.2 ng/mL with one subsequent rise as the criterion for failure after radical prostatectomy.21 One important concept that should ensue from this discussion is the observation by Kuban and associates22 that biochemical failure is not a justification per se to initiate treatment. usually with some form of HT, must be carefully weighed against the implications of how such therapy will deleteriously impact quality of life. A detectable rise in PSA following definitive surgery must be juxtaposed with risk factors that include highgrade disease, extent of capsular penetration, surgical margins, seminal vesicle, nodal involvement, and/or PSA-DT. Every hormonal therapy administered for PSA-only recurrence after radical prostatectomy should take into account the above-mentioned variables, as they appear to be predictors of eventual metastases. Pound and colleagues23 illuminated what may be referred to as the natural history of progression of PSA following radical prostatectomy. They showed that on average, it takes 8 years from the time of a man’s first detectable PSA rise following radical VOL. 7 SUPPL. 5 2005 REVIEWS IN UROLOGY S31 Management of Biochemical Recurrence continued prostatectomy to the development of metastatic disease. A further elucidation of this frequent clinical dilemma was provided by D’Amico and colleagues,24 who recently showed that PSA-DT in patients treated with surgery or radiation is a valid endpoint for prostate cancer mortality. Novel neoadjuvant regimens with HT, with or without chemotherapeutic regimens, are undergoing investigation. To date, the literature suggests juvant radiation therapy? At the present time, these questions are legitimate but answers are unlikely to be forthcoming, as there are few clinical trials designed to illuminate these myriad questions. There is a major Southwest Oncology Group (SWOG) trial that may help answer the issue of delayed versus immediate radiation. In patients receiving delayed radiation therapy for rising PSAs, Forman and Velasco27 The role of salvage radiation for a PSA rise after radical prostatectomy remains controversial. It is only with randomized trials that the question of whether salvage radiotherapy can prevent distant metastases will be answered. S32 VOL. 7 SUPPL. 5 2005 demonstrated the utility of treating patients with 6600 cGy at levels  2 ng/mL (Figure 2). Would these patients benefit from chemotherapy with or without HT? Frequently, there is a balancing act among salvage radiotherapy, systemic treatment—usually involving HT—and continuing observation without intervention. Unfortunately, radiographic studies for PSA-only recurrence are not that reliable in the low PSA ranges, nor are computed tomography and bone scintigraphy. Positron emis- Figure 2. Cumulative disease-free survival after radiation therapy in stage T2/T3a-b patients. Reproduced with permission from Forman JD and Velasco J.27 Disease-free survival (%) that although surgical margins may be discernable as negative following neoadjuvant HT, subsequent PSA failures are not affected by neoadjuvant therapy.25 In an 8-month trial of neoadjuvant HT by Gleave and associates,26 the rate of PSA recurrence was proportional to the preoperative risk factors. Although it may seem intuitive that patients with high risk factors following surgery should be given a choice of therapy, in reality, the choice of treatment at this juncture is confusing. Success rates for salvage radiotherapy range from 10% to 50%, which leads to the conclusion that a great percentage of this cohort of patients may well have metastatic disease that is unrecognized. The role of salvage radiation for a PSA rise after radical prostatectomy remains controversial. It is only with randomized trials that the question of whether salvage radiotherapy can prevent distant metastases will be answered. The unanswerable questions, at least for now, are: Will survival be affected by radiation? Are these patients with occult disease at this juncture? Is there a role for HT before, during, or after ad- sion tomography (PET) is also unreliable in detecting local recurrence. Monoclonal antibody scanning with ProstaScint (Cytogen, Princeton, NJ) may aid in discerning patients who have recurrence only in the prostatic fossa. Hormonal therapy usually consists of luteinizing hormone–releasing hormone (LHRH) agonists. There are several LHRH agonists now on the US market as well as 1 gonadotropinreleasing hormone antagonist and 3 antiandrogens (Table 1). A fourth antiandrogen, cyproterone acetate, which has long been used in Europe, is being investigated in clinical trials in the United States to see whether the side effects of LHRH-induced hot flushes can be ameliorated by the concomitant use of this steroidal antiandrogen. Although androgen deprivation, primarily with LHRH therapy or—to a lesser extent—orchiectomy, is used primarily for demonstrable metastatic disease, there is still much discussion on the timing of such therapy in this advanced clinical setting. For example, a study by the Medical Research Council in the United Kingdom of 938 men with locally advanced and asymptomatic metastatic prostate cancer showed a small but statistically REVIEWS IN UROLOGY 100 90 80 70 60 50 40 30 20 10 0 Pretreatment PSA
2 ng/mL Pretreatment PSA  2 ng/mL 1 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 Time (mo) Management of Biochemical Recurrence Table 1 Available Hormonal Agents Brand Name Administration Chemical Name Manufacturer LHRH Agonists Eligard® (leuprolide acetate for injectable suspension) SQ injection Leuprolide acetate Sanofi-aventis Lupron Depot® (leuprolide acetate for depot suspension) IM injection Leuprolide acetate TAP Pharmaceuticals Inc. Trelstar Depot™ (injectable triptorelin pamoate) and Trelstar LA™ (triptorelin pamoate for injectable suspension) IM injection Triptorelin pamoate Watson Pharmaceuticals, Inc. Viadur® (leuprolide acetate implant) SQ implant Leuprolide acetate Bayer Corporation Pharmaceutical Division Zoladex® (goserelin acetate implant) SQ implant Goserelin acetate AstraZeneca Pharmaceuticals LP GnRH Antagonist Plenaxis™ (abarelix for injectable suspension) IM injection Abarelix Praecis Pharmaceuticals Inc. Oral Antiandrogens Casodex® (bicalutamide) 50 mg QD Bicalutamide AstraZeneca Pharmaceuticals LP Eulexin® (flutamide) 125 mg TID Flutamide Schering Corporation Nilandron® (nilutamide) 150 mg QD Nilutamide Sanofi-aventis All product information was obtained from product package inserts. IM, intramuscular; SQ, subcutaneous. significant survival advantage in those who received immediate HT versus men in the delayed-treatment group, in whom therapy was usually started for symptomatic progression of metastatic disease.28 In the delayed-treatment group, serious complications such spinal cord compression, pathological fracture, ureteral obstruction, and/or development of extraskeletal metastases were approximately twice as common as in the group receiving immediate HT. Also, patients with locally advanced prostate cancer but without demon- strable metastases had a survival benefit. As is true with all studies, there are problems with this trial. Critics are quick to point out that not all patients in the delayed-treatment arm received HT or other therapy. In addition, staging and treatment patterns were different from those in the United States during the study period. Nevertheless, this trial suggests that there are advantages to early hormonal therapy. Messing and associates29 published a smaller trial consisting of 98 patients. This prospective randomized study compared early versus delayed androgen therapy after radical prostatectomy and pelvic lymphadenectomy in patients with lymph node–positive prostate cancer. The researchers found that after 7 years, overall survival was significantly improved in the group of men with immediate androgen deprivation. The two trials mentioned above were conducted in men with locally advanced disease. In the latter trial, all patients had locally advanced disease, ie, lymph node involvement. Both trials demonstrated advantages of early HT, but they have not begun VOL. 7 SUPPL. 5 2005 REVIEWS IN UROLOGY S33 Management of Biochemical Recurrence continued to address the point at which PSA values should trigger HT, and no prospective trials to date have addressed this cauldron. PSA Recurrence Following Radiation With radiation therapy, various PSA endpoints have been used, because with this treatment modality, PSA values seldom reach the undetectable levels seen with prostatectomy. In the past, biochemical failure was defined by several markers, including the lowest posttreatment value (nadir), the time to achieve the PSA nadir, and whether PSA was continually rising after a period of stabilization. More recently, the Society for Therapeutic Radiology and Oncology (ASTRO) defined a radiation failure as 3 consecutive rises above the nadir.30 It is thought that 3 consecutive rises, as opposed to 2, guards against the error of a false biochemical rise following radiation therapy, which has been described by Hanlon and coinvestigators31 as a “bounce,” a phenomenon that is related to the pretreatment PSA and the radiation dose.31 As the Hanlon group pointed out, nearly one half of patients who experience biochemical bouncing are actually biochemically stable. There are different definitions of bouncing when brachytherapy is used as a single modality or in conjunction with IMRT. These criteria were defined by Cavanagh and colleagues32 and Critz and associates.33 The former group uses a temporary increase of  0.2 ng/mL and the latter, a temporary increase of  0.1 ng/mL. Prostate-specific antigen doubling time before radiation is the strongest predictor of subsequent biochemical failure ( 12 months) when one factors the variables of Gleason score, clinical stage, and radiology technique in a regression analysis. The center of prostate dose was the variable most closely related to PSA-DT. S34 VOL. 7 SUPPL. 5 2005 A PSA nadir  0.5 ng/mL within 2 years is a good prognostic sign as approximately 90% of these patients will remain free of recurrent disease. In postradiation failure, the issue of what treatment to initiate has all the same diagnostic and therapeutic dilemmas as those raised in patients who fail prostatectomy. Treatment options range from observation/ watchful waiting, salvage brachytherapy, salvage prostatectomy, salvage cryotherapy, and, of course, HT, either alone or in combination with the other options. Any attempt at salvage therapy must be tempered with realistic expectations on the part of patients and treating physicians. As with postoperative PSA rises, there are various comfort levels on the part of patients and physicians alike regarding when to treat postradiation PSA rises. Approximately one half to two thirds of patients may be cured with salvage prostatectomy.34,35 However, incontinence and impotency rates are much higher than with de novo prostatectomy, and rectal injury is not uncommon. Conclusions The treatment of PSA recurrence is a constantly changing enterprise as new options become available. Treatment plans need to be individualized because of the mutable nature of recurrence. We must consider comorbid illnesses and life expectancy along with important variables such as time from initial treatment and the increasing experience with PSA-DT. At present, there are no randomized trials studying biochemical recurrence; yet patients who experience this event are the group most commonly receiving hormonal therapy. Moul and coworkers36 recently published a retrospective analysis showing that of 1352 men, those with risk factors of Gleason score  7, a short PSA-DT ( 12 months), and pT3 disease delayed REVIEWS IN UROLOGY clinical metastasis by early administration of HT. A limitation of this study that has been freely admitted is that it is a retrospective study, and the question remains whether this finding will translate into a survival benefit. Although these are preliminary data, the study is a step on the road to discerning the appropriate time for HT intervention for a PSA recurrence following definitive therapy. In addition, a study by D’Amico and colleagues37 showed that an annual preoperative PSA velocity of  2.0 ng/mL was associated with a significantly shorter time to death from prostate cancer after radical prostatectomy. Well-known side effects of HT include hot flushes, decreased libido/potency, osteoporosis, weight gain, hair loss, and psychological effects with continuous therapy. Therefore, intermittent HT is being used with increasing frequency when patients are started on therapy for PSA recurrence alone, and two reports demonstrated that patients on intermittent HT do as well or better than those on continuous therapy.38,39 An interim analysis comparing intermittent androgen ablation to continuous androgen ablation in PSA recurrence following radical prostatectomy was presented at the 2004 American Urological Association.40 From the initial data, it appears there was a slightly higher progression, 8.3% compared with 6.4%, in the intermittent group; however, this study has not reached maturity. Prostate-specific antigen is usually the “trigger” in treatment decisions and is frequently the only criterion that we have to initiate and to monitor therapy. It should be remembered that even with its shortcomings, PSA remains the most efficacious marker available, both to evaluate therapy and to use as a screening tool. A better understanding of PSA’s kinetics, ie, doubling time and velocity, will Management of Biochemical Recurrence aid us in understanding which tumors to actively treat and which ones can be managed, at least in the near term, with watchful waiting. Timing and the pattern of recurrence will dictate therapy for the foreseeable future, but entered the arena of practical clinical practice. Therefore, PSA, with all its shortcomings, will continue to be the predominant diagnostic and prognostic marker for the foreseeable future. It should be remembered that even with its shortcomings, PSA remains the most efficacious marker available, both to evaluate therapy and to use as a screening tool. exact timing will still be a volatile issue. Prolific advances are being made in areas such as in-situ hybridization (ISH) and fluorescent ISH (FISH), semiquantitative real-time polymerase chain reaction assay, comparative genomic hybridization, and associated types of microarrays.41 However, these tools have not 2. 3. 5. 6. 7. 8. 9. References 1. 4. Yousef GM, Diamandis EP. The new human tissue kallikrein gene family: structure function, and association to disease. Endocr Rev. 2001;22: 184-204. Lilja H, Oldbring J, Rannevik G, Laurell CB. Seminal vesicle–secreted proteins and their reactions during gelation and liquefaction of human semen. J Clin Invest. 1987;80:281-285. Catalona WL, Smith DS, Ratliff, TL, et al. Measurements of prostate-specific antigen in serum as screening for prostate cancer. N Engl J Med. 1991;324:1156-1161. 10. 11. Fitzpatrick JM. PSA screening for prostate cancer—a review of the evidence. Urol News. 2004;9:6-8. Lange PH, Ercole CJ, Lightner DJ, et al. The value of serum prostate specific antigen determinations before and after radical prostatectomy. J Urol. 1989;141:873-879. Frazier HA, Robertson JE, Humphrey PA, Paulson DF. Is prostate specific antigen of clinical importance in evaluating outcome after radical prostatectomy. J Urol. 1993;149:516-518. Balk SP, Ko Yoo-Joung, Bubley GL. Biology of prostate-specific antigen. J Clin Urol. 2003;2: 383-391. Moul JW. Prostate-specific antigen only progression of prostate cancer. J Urol. 2000;163:16321642. Pound CR, Partin AW, Epstein JI, et al. Prostate specific antigen after anatomic radical retropubic prostatectomy: patterns of recurrence and cancer control. Urol Clin North Am. 1997;24: 395-406. Osterling JE, Chan DW, Epstein JI, et al. Prostate specific antigen in the preoperative and postoperative evaluation of localized prostate cancer treated with radical prostatectomy. J Urol. 1988; 139:766-772. Lange PH, Ercole CJ, Lightner DJ, et al. The value of serum prostate specific antigen determinations before and after radical prostatectomy. J Urol. 1989;141:873-879. Main Points • The number of prostate-specific antigen (PSA) tests is increasing exponentially, and PSA’s role in screening is unlikely to decrease. PSA as a surrogate endpoint to monitor disease progression is generally accepted as the primary method to monitor a patient following definitive therapy for clinically localized prostate cancer. • Approximately 35% of men who undergo prostatectomy will develop a detectable PSA recurrence within 10 years of their surgery. • One important concept is the observation by Kuban and associates that biochemical failure is not a justification per se to initiate treatment. At the first time of detectability, a rise in PSA may be a harbinger of failure in some patients, but it is not necessarily equivalent to clinical failure or subsequent biochemical failure. • A detectable rise in PSA following definitive surgery must be juxtaposed with risk factors that include high-grade disease, extent of capsular penetration, surgical margins, seminal vesicle, nodal involvement, and/or PSA doubling time (PSA-DT), as these variable appear to be predictors of eventual metastases. • Two trials demonstrated advantages of early hormone therapy (HT) but have not addressed at what point PSA values should trigger HT, and no prospective trials to date have focused on this question. • PSA-DT before radiation is the strongest predictor of subsequent biochemical failure ( 12 months) when one factors the variables of Gleason score, clinical stage, and radiology technique in a regression analysis. • Approximately one half to two thirds of patients who have postradiation biochemical failure may be cured with sal- vage prostatectomy. However, incontinence and impotency rates are much higher than with de novo prostatectomy, and rectal injury is not uncommon. • Well-known side effects of HT include hot flushes, decreased libido/potency, osteoporosis, weight gain, hair loss, and psychological effects with continuous therapy. Therefore, intermittent HT is being used with increasing frequency when patients are started on therapy for PSA recurrence alone, and studies have shown that patients on intermittent HT do as well or better than those on continuous therapy. VOL. 7 SUPPL. 5 2005 REVIEWS IN UROLOGY S35 Management of Biochemical Recurrence continued 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. S36 Prestigiacomo AF, Stamey TA. A comparison of 4 ultrasensitive prostate-specific antigen assays for early detection of residual cancer after radical prostatectomy. J Urol. 1994;152(5 pt 1):15151519. Gatalica Z, Norris BA, Kovatich AJ. Immunohistochemical localization of prostate-specific antigen in ductal epithelium of male breast. Potential diagnostic pitfall in patients with gynecomastia. Appl Immunohistochem Mol Morphol. 2000;2:158-161. Fan CY, Wang J, Barnes EL. Expression of androgen receptor and prostatic specific markers in salivary duct carcinoma: an immunohistochemical analysis of 13 cases and review of the literature. Am J Surg Pathol. 2000;24:579586. Carder PJ, Speirs V, Ramsdale J, Lansdown MR. Expression of prostate specific antigen in male breast cancer. J Clin Pathol. 2005;58:69-71. Howorth DJ, Aronson ID, Diamandis EP. Immunobiochemical localization of prostatespecific antigen in benign and malignant breast tissues. Br J Cancer. 1977;75:1646-1651. Lovgren J, Valtonen-Andre C, Marshall K, et al. Measurement of prostate-specific antigen and human glandular kallikrein 2 in different body fluids. J Androl. 1999;20:348-355. Amling CL, Bergstralh EJ, Blute ML, et al. Defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point? J Urol. 2001;165:1146-1151. Han M, Partin AW, Pound CR, et al. Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. Urol Clin North Am. 2001;28: 555-563. Moul JW. Early hormonal therapy for PSA-only recurrence of prostate cancer as an independent predictor of delayed clinical metastasis. Am J Clin Rev. 2004;2:531-541. Boccon-Gibod L, Djavan WB, Hammerer P, et al. Management of prostate-specific antigen relapse in prostate cancer: a European consensus. Int J VOL. 7 SUPPL. 5 2005 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. Clin Pract. 2004;58:381-390. Kuban DA, Thames HD, Levy LB. PSA after radiation for prostate cancer. Oncology. 2004;18: 595-604. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:1591-1597. D’Amico AV, Moul JW, Carroll PR, et al. Prostate specific antigen doubling time as a surrogate end point for cancer specific mortality following radical prostatectomy or radiation therapy. J Urol. 2004;172:542-547. Meng MV, Grossfield GD, Carroll PR, et al. Neoadjuvant strategies for prostate cancer prior to radical prostatectomy. Semin Urol Oncol. 2002;20:10-18. Gleave ME, La Bianca SE, Goldenberg SL, et al. Long-term neoadjuvant hormone therapy prior to radical prostatectomy: evaluation of risk for biochemical recurrence at 5-year follow-up. Urology. 2000;56:289-294. Forman JD, Velasco J. Therapeutic radiation in patients with a rising post-prostatectomy PSA level. Oncology. 1998;12:33-39. The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council trial. Br J Urol. 1997;79:235-246. Messing EM, Manola J, Sarosdy M, et al. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 1999;341:17811788. Cox J, Grigon D, Kaplan L, et al. Consensus statement: guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys. 1997; 45:886-891. Hanlon AL, Pinover WH, Horwitz EM, Hanks GE. Patterns and fate of PSA bouncing following 3D-CRT. Int J Radiat Oncol Biol Phys. 2001;50: 845-849. REVIEWS IN UROLOGY 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. Cavanagh W, Blasco J, Grimm P, et al. Transient elevation of serum prostate-specific antigen following (125)I (103)Pd brachytherapy for localized prostate cancer. Semin Urol Oncol. 2000;18:160-165. Critz F, Williams W, Benton J, et al. Prostate specific antigen bounce after radioactive seed implantation followed by external beam radiation for prostate cancer. J Urol. 2000;163: 1085-1089. Pisters LL. Salvage radical prostatectomy: refinement of an effective procedure. Semin Radiat Oncol. 2003;13:166-174. Touma NJ, Izawa JI, Chin JL. Current status of local salvage therapies following radiation failure for prostate cancer. J Urol. 2005;173: 373-379. Moul JW, Wu H, Sun L, et al. Early versus delayed hormonal therapy for prostate specific antigen only recurrence of prostate cancer after radical prostatectomy. J Urol. 2004;171:1141-1147. D’Amico AV, Shen M, Roehl KA, et al. Preoperative PSA velocity and the risk of death from prostate cancer after radical prostatectomy. N Engl J Med. 2004;351:125-135. de Leval J, Boca P, Yousef E, et al. Intermittent versus continuous total androgen blockade in the treatment of patients with advanced hormone-naive prostate cancer: results of a prospective randomized multicenter trial. Clin Prostate Cancer. 2002;1:163-171. Lane TM, Answell W, Farrugia D, et al. Longterm outcomes in patients with prostate cancer managed with intermittent androgen suppression. Urol Int. 2004;73:117-122. Tunn U, Kurek R, Maubach L. Intermittent is as effective as continuous androgen deprivation in patients with PSA-relapse after radical prostatectomy (RP). Paper presented at: Annual Meeting of American Urological Association; May 8-13, 2004; San Francisco, CA. Abstract 5590. Johnson LA, Lynch WL. Geonomic research and prostate cancer: what does it offer us? Br J Urol. 2005;95:163-169.