Biochemical (Prostate-Specific Antigen) Relapse: An Oncologist's Perspective

OPTIMIZING TREATMENT FOR ADVANCED PROSTATE CANCER Biochemical (ProstateSpecific Antigen) Relapse: An Oncologist’s Perspective Mary-Ellen Taplin, MD University of Massachusetts Cancer Center, Worcester, MA Consensus has not been reached on the exact definition of biochemical relapse after prostatectomy; individual institution definitions of relapse after prostatectomy range from consecutively rising prostate-specific antigen (PSA) values of > 0.2 to > 0.6 ng/mL. PSA measurements after radiation are even less predictable. PSA level is a sensitive marker of occult prostate-cancer relapse and provides early notification of recurrence, but a PSA relapse does not equal a clinical relapse or death from prostate cancer. Data are reviewed from retrospective, single-institution trials that have clarified features of PSA relapse after both prostatectomy and radiation, such as the PSA doubling time and the time to the first PSA elevation, which are associated with clinical progression. Various options for treatment of biochemical relapse are also reviewed; these include hormone therapy, combined chemohormonal therapy, alternative medicine and dietary tactics, new agents, and future strategies, such as vaccination. Currently, there is no standard treatment for biochemical failure with proven benefit in terms of quality of life, time to metastases, or survival. Current options include observation for patients with long PSA doubling times or comorbid medical issues and standard or nontraditional hormone therapy or a clinical trial for men who desire early therapy or who have rapid PSA doubling times (< 10–12 months). Trials combining the early use of chemotherapy with hormone therapy are promising. Patients should be encouraged to enroll in clinical trials to help establish standards of care. [Rev Urol. 2003;5(suppl 3):S3-S13] © 2003 MedReviews, LLC Key words: Prostate cancer • Biochemical relapse • Prostate-specific antigen • Adjuvant chemohormonal therapy • Combined chemohormonal therapy • Prostatectomy • Radiation therapy ccording to the Surveillance, Epidemiology, and End Results (SEER) database, prostate cancer is the leading cancer diagnosis in American men and the second leading cause of cancer-related deaths.1 The use of prostatespecific antigen (PSA) levels for early diagnosis has led to a stage shift; approximately A VOL. 5 SUPPL. 3 2003 REVIEWS IN UROLOGY S3 Biochemical Relapse continued 85% of men are now diagnosed with localized disease.1 Projections for the year 2003 estimate 220,900 new cases and 28,900 deaths from prostate cancer in the United States.1 Prostate cancer is generally slow to progress; therefore, when treatment options are considered for any stage of prostate cancer, it is paramount to weigh life expectancy and therapeutic goals against the risk of morbidity from prostate cancer and possible interventions. Curative treatment options for localized prostate cancers include prostatectomy and radiation, administered either by external beam therapy or brachytherapy. It is estimated that 130,000 men are treated for cure each year in the United States. Despite early detection and improvements in surgical and radiation techniques, approximately 50,000 American men each year will experience a prostate-cancer relapse.2 Relapse is commonly asymptomatic and is detected as a rising PSA; it is thus described as a biochemical or serologic relapse. This review covers the standard and experimental approaches for the treatment of biochemical relapse of prostate cancer. Definition of Biochemical Relapse In the setting of organ-confined disease, it is generally expected that the PSA will be undetectable or at the assay-specified lowest level of detection after prostatectomy. The serum half-life of PSA is about 3.2 days, and, in most cases, undetectable levels should be reached by 4 weeks postoperatively. Consensus has not been reached on the exact definition of biochemical relapse after prostatectomy. Individual institutional definitions of relapse after prostatectomy range from consecutively rising PSA values of > 0.2 to > 0.6 ng/mL.3,4 PSA measurements after radiation are less S4 VOL. 5 SUPPL. 3 2003 Table 1 The American Society for Therapeutic Radiology and Oncology (ASTRO) Consensus Panel Statement: Guidelines for Assessing Prostate-Specific Antigen (PSA) Levels After Radiation Therapy Definition of Biochemical Failure • Biochemical failure is not justification per se to initiate additional treatment. It is not equivalent to clinical failure. It is an appropriate early endpoint for clinical trials. • Three consecutive increases in PSA is a reasonable definition of biochemical failure after radiation therapy. For clinical trials, the date of failure should be the midpoint between the post-irradiation nadir PSA and the first of the three consecutive rises. • No definition of PSA failure has, as yet, been shown to be a surrogate for clinical progression or survival. • Nadir PSA is a strong prognostic factor, but no absolute level is a valid cut point for separating successful and unsuccessful treatments. Nadir PSA is similar in prognostic value to pretreatment prognostic variables. Reproduced with permission from American Society for Therapeutic Radiology and Oncology Consensus Panel.5 predictable. It generally takes between 12–42 months to achieve a nadir PSA after radiotherapy, and the nadir value in “cured" patients varies because of residual noncancerous prostate glands. The majority of men who achieve a durable PSA response attain nadir PSA values of < 1 ng/mL. The American Society for Therapeutic Radiology and Oncology (ASTRO) has published consensus panel guidelines for testing PSA levels following radiation therapy (Table 1).5 These guidelines define biochemical failure as three consecutive rises in PSA following radiotherapy with the date of failure being the midpoint between the PSA nadir and the first PSA rise. Although modifications have been suggested,6 these guidelines have standardized the reporting of outcomes after radiation. Natural History of Biochemical Relapse After Prostatectomy PSA is a sensitive marker of occult prostate-cancer relapse. Because of tumor heterogeneity, however, a PSA REVIEWS IN UROLOGY relapse does not equal a clinical relapse or death from prostate cancer. Our understanding of the natural history of PSA relapse is limited by the lack of multi-institutional prospective data. Retrospective, single-institution data are, however, available for relapse after both prostatectomy and radiation. These data have clarified features of PSA relapse such as the PSA doubling time and the time to the first PSA elevation, which are associated with clinical progression. Johns Hopkins’ investigators have given an excellent report on the natural history of biochemical failure, based on 1997 men who were treated with prostatectomy and did not receive adjuvant radiotherapy or hormone therapy for biochemical failure before documentation of distant metastases.7 Pound and colleagues7 described an 82% actuarial metastasis-free survival for the 1997 men 15 years after surgery. Of these 1997 men, 15% (n = 315) developed biochemical progression. Although the median time to failure of PSA was Biochemical Relapse Table 2 Hormonal Therapy Options for Patients with Biochemical Failure Hormone Therapy Advantage Disadvantage Approved by FDA Orchiectomy Cost effective Permanent; disfiguring NA LHRH agonist Reversible Expensive Yes CAB Reversible; possible small therapeutic advantage compared to LHRH alone Expensive; increased side effects Yes IAB Fewer side effects; lower cost Phase III studies ongoing NA Bicalutamide 150 mg once daily Noncastrating; improved energy, libido, potency Expensive; increased gynecomastia No Flutamide/finasteride Noncastrating; reduced side effects Increased gynecomastia No FDA, U.S. Food and Drug Administration; NA, not applicable; LHRH, luteinizing hormone-releasing hormone; CAB, combined androgen blockade; IAB, intermittent androgen blockade. 2.3 years, 4% of the patients developed recurrence after 10 years. Thirty-four percent developed metastatic disease within the study period. The median actuarial time to metastases was 8 years from the time of elevation of the PSA level. Once metastases were documented, the median actuarial time to death was 5 years. In survival analyses, the time to biochemical progression (P < .001), a Gleason score of 8–10 (P < .001), and a PSA doubling time of < 10 these data, however, give clinicians a framework with which to weigh the potential risk of disease against a patient’s overall health status. Hormone Therapy for Biochemical Relapse Hormone therapy for prostate cancer lowers serum testosterone to castrate levels or blocks the testosterone signaling pathway at the androgen receptor. Traditional options include orchiectomy, luteinizing hormone- A phase III trial demonstrated no survival benefit for the combination of antiandrogens with orchiectomy in men with metastatic prostate cancer. months (P < .001) were predictive of the probability of and time to the development of metastatic disease. In this study, an algorithm was constructed for estimating a man’s likelihood of remaining free of metastatic disease; because of the small numbers of men in each subgroup, however, the confidence intervals are wide.7 A longer follow-up and an increase in the number of men with higher-risk features will strengthen the algorithm; releasing hormone (LHRH) agonists, and estrogens (Table 2). The use of estrogen has declined because of thrombotic complications.8 The addition of an antiandrogen to orchiectomy or LHRH agonist treatment is termed “combined (or complete) androgen blockage" (CAB). The antiandrogens available in the U.S. are flutamide, bicalutamide, and nilutamide. A phase III trial demonstrated no survival benefit for the combination of antiandrogens with orchiectomy in men with metastatic prostate cancer.9 There may be some benefit to adding an antiandrogen to LHRH therapy, but studies have been conflicting, and meta-analyses have suggested that the overall benefit is likely small.10,11 The use of CAB is determined by cost and patient and physician preference. Newer methods of hormone therapy, which are noncastrating or are prescribed intermittently, have been developed in an attempt to reduce the side effects. Although these therapies have not yet been approved by the U.S. Food and Drug Administration as primary hormone therapy, if they prove effective, they may be used in men with minimal systemic disease who elect early hormone therapy. These therapies include bicalutamide (150 mg daily) as monotherapy, flutamide combined with finasteride, and intermittent androgen deprivation (IAD).12-14 Iversen and colleagues17 reported pooled results from two trials that randomized 1453 men with locally advanced or metastatic prostate cancer to bicalutamide (150 mg once VOL. 5 SUPPL. 3 2003 REVIEWS IN UROLOGY S5 Biochemical Relapse continued daily) versus either orchiectomy or LHRH monotherapy. There were reported advantages in sexual interest and physical capacity for the patients in the bicalutamide group, although the risk of gynecomastia was significantly increased. The survival outcome was similar for patients with locally advanced disease; castration, however, provided a 6-week survival advantage in patients with metastatic disease. Biochemical-fail- growth. There are animal models bearing prostate cancer that have supported this hypothesis, as well as models that have not shown an advantage to intermittent castration.16-18 A recent review by Dawson12 summarized the results of 11 nonrandomized clinical trials of IAD. In these studies, men with biochemical failure only had a shorter time to PSA nadir and a longer time off hormone therapy than men with Hormone therapy has proven palliative benefit in advanced prostate cancer. ure patients reflect the earliest stage of systemic disease, and the jury is still out on the relative effectiveness of bicalutamide monotherapy compared to castration in these patients. Finasteride (a 5-reductase inhibitor) and the antiandrogen flutamide have been combined as a form of noncastrating hormone therapy. Finasteride blocks the conversion of testosterone to the more active metabolite dihydrotestosterone, and flutamide blocks androgen-receptor signaling. This combination has been evaluated as early hormone therapy in patients with biochemical failure in several singleinstitution studies and in a Cancer and Leukemia Group B (CALGB) study.2 The combination induced PSA remissions in the majority of men. Similar to the disadvantages of bicalutamide monotherapy, however, breast tenderness and enlargement from peripheral conversion of testosterone to estrogen was a significant problem. At this point, a longer follow-up is needed to define the durability of responses and the relative side-effect profile compared to castration. It has been hypothesized that the use of IAD could delay the development of androgen independence by providing an environment of reduced selective pressure for autonomous S6 VOL. 5 SUPPL. 3 2003 advanced disease. Although formal quality of life (QOL) questionnaires were not always recorded, patients on intermittent therapy reported improvement in hot flashes, libido, potency, energy, and cognitive function; breast tenderness, gynecomastia, and weight gain did not usually improve. Several trials are prospectively evaluating IAD in advanced disease and biochemical-failure patients. The Southwest Oncology Group (SWOG)/Intergroup trial continues to enroll metastatic patients with the objective of comparing overall survival, treatment side effects, and physical and emotional function in each group. IAD versus continuous therapy is being evaluated in men with biochemical failure after external beam radiation therapy (XBRT) in Canada and in men with biochemical failure after prostatectomy by a German cancer association. The general use of IAD awaits the results of these phase III trials. Hormone therapy has proven palliative benefit in advanced prostate cancer. Until recently, there were no data that early versus delayed hormone therapy resulted in improvement in time to metastases or survival. The British Medical Research REVIEWS IN UROLOGY Council (MRC)19 has reported that early hormonal therapy delayed disease progression and improved survival in both cancer stage M0 and D2 patients. In this trial, death rates for immediate hormone treatment for stages M0, MX, and M1 were 54%, 57%, and 76%, respectively, compared to 70%, 62%, and 80% for deferred therapy. Cancer-specific survival was highest in M0 patients who had immediate hormone therapy (P < .001). These results were complicated by the fact that 18% of the patients in the delayed treatment group never received hormone therapy before death, and patient-staging and follow-up were loosely defined. It is possible that the MRC M0 patients were actually more advanced than the typical biochemical failure patients in the United States today. Messing and associates20 reported improved survival and decreased risk of recurrence in patients with positive lymph nodes treated with early hormone therapy. In this Eastern Cooperative Oncology Group (ECOG) study, 100 men treated with radical prostatectomy who had microscopically positive lymph nodes were randomized to immediate hormone therapy or observation until progression (radiographic or clinical). After a median follow-up of 7.1 years, the prostate cancer-specific survival was 96% for immediate treatment versus 70% for delayed treatment. The progression-free survival was 86% for immediate hormone treatment versus 18% for delayed therapy. The editorial that accompanied this report discussed the pitfalls of the study, including the lower than projected accrual, the low cancer-specific survival in the observation patients, and the noncentralized Gleason scoring. The authors of the editorial concluded that the early use of hormone therapy should continue to be studied before Biochemical Relapse Table 3 Comparisons of Studies of Early Versus Delayed Hormone Therapy Author Disease Stage No. of Patients Median Follow-up MRC21 Locally advanced/D2 938 Messing et al.22 D1 Prostatectomy See et al.24 T1-4 Adjuvant or watchful waiting Conclusions Comments Not reported Prostate-related complications were reduced in early-treatment group 18% of patients in delayed hormonal treatment group never received therapy. Radiographic follow-up was sporadic 98 7.1 years Immediate hormone therapy with either orchiectomy or LHRH agonist reduced recurrence and improved survival Survival in the control group was lower than expected 8113 3.0 years 42% reduction in risk of objective progression for bicalutamide No difference in progression in the North American trial in which all patients received prostatectomy (80%) or radiotherapy (20%) MRC, (British) Medical Research Council; LHRH, luteinizing hormone-releasing hormone. being widely prescribed.21 See and colleagues22 have reported a large international effort to evaluate the effectiveness of bicalutamide (150 mg daily) as either adjuvant treatment to prostatectomy or radiotherapy or as initial hormone therapy without local therapy in men with localized prostate cancer. AstraZeneca Pharmaceuticals LP (Wilmington, DE) sponsored three separate, randomized, double-blind, placebo-controlled trials in North America, Scandinavia, and one with centers in Europe, South Africa, Australia, and Mexico which were designed to be analyzed together. With a median patient follow-up of 3.0 years, data were reported from 8113 patients; 4052 were randomized to bicalutamide, and 4,061 were randomized to placebo. The patient-treatment profiles differ significantly among the trials. In the North American trial, 100% of the patients were treated with prostatectomy or radiotherapy before randomization. In Europe and Scandinavia only 64% and 18%, respectively, received local therapy. The remaining patients were randomized either to bicalutamide or to placebo as part of “watchful waiting." No statistically significant endpoints have been reached in the North American trial. The other two trials demonstrated an improvement in objective progression (bone scan) in the bicalutamide group compared to controls. In the European trial, 181 patients in the bicalutamide group had objective clinical progression compared to 293 placebo patients (P << .0001); in the Scandinavian trial there were 99 events in the bicalutamide group compared to 179 in the placebo group (P << .0001). Survival differences can not yet be assessed. At this point, the U.S. FDA has not approved the use of bicalutamide as adjuvant therapy for prostate cancer. The AstraZeneca trials were designed prior to the present-day understanding of risk stratification for local prostate cancer, and 53% of the patients in the North American study had a Gleason score of ≤ 6. Given the favorable natural history of low-risk patients, it will take many years to reach the study endpoints of clinical progression and survival. The interim analysis supports the conclusion, based on the Scandinavian data, that the early use of bicalutamide in patients who do not have definitive local therapy reduces progression to metastatic disease. Results from MRC,19 Messing and associates,20 and See and colleagues22 suggest that early hormone therapy in M0, D1, and watchful waiting patients may be beneficial (Table 3).19,20,22 A survival benefit has not been conclu- VOL. 5 SUPPL. 3 2003 REVIEWS IN UROLOGY S7 Biochemical Relapse continued Table 4 Types of Solid Tumors and Estimated Benefits of Commonly Prescribed Adjuvant Therapies Type of Tumor Adjuvant Therapy Benefit Breast cancer: < age 50, node + CMF, CAF, AC, FEC Improved disease-free (35%) and overall survival (11%) at 10 years Breast cancer > age 50, node + CMF, CAF Improved disease-free (20%) and overall survival (3%) at 10 years Ovarian cancer (Ic-2) Carboplatin or cisplatin/Taxol 50% reduction in relapse Stomach/adenocarcinoma of gastroesophageal junction XRT + 5FU/lecovorin Improved median survival at 9 months Colon cancer: node + 5FU/lecovorin Improved survival by 22% Rectal cancer XRT + 5FU/lecovorin Improved overall survival by 29% Lung cancer — Approximately 5% benefit in overall survival in meta-analysis/standard of care evolving Melanoma: T4, node + High-dose interferon Improved survival by 40% Osteosarcoma Cisplatin-based Improved disease-free and overall survival Testis: resected stage II BEP Improved disease-free survival Bladder cancer: T3, node + Cisplatin-based Survival benefit unclear CMF, cyclophosphamide, methotrexate, and fluorouracil; CAF, cyclophosphamide, doxorubicin (Adriamycin), and fluorouracil; AC, doxorubicin (Adriamycin) and cyclophosphamide; FEC, fluoruracil, epirubicin, cyclophosphamide; XRT, external radiation therapy; FU, fluorouracil; BEP, bleomycin, etoposide, and cisplatin (Platinol). sively proved for biochemical-failure patients, and issues with the design of the trial and follow-up limit the conclusion that early hormone therapy should be recommended for all patients with biochemical failure. The toxicity of hormone therapy includes hot flashes, fatigue, wasting of muscles, breast tenderness and enlargement, reduced concentration, emotional lability, impotence and decreased libido, anemia, and osteoporosis. Toxicities will increase with prolonged use, and QOL must be considered when prescribing hormone therapy in asymptomatic men. Adjuvant Chemohormonal Therapy Randomized clinical trials have established standards for providing adjuvant therapy for many solid S8 VOL. 5 SUPPL. 3 2003 tumors. The power of data in support of adjuvant therapy varies across tumor types because of factors such as numbers of available patients, the patient’s age and motivation, and the organization of tumor-specific clinical the data are based on the results of approximately 35 years of randomized trials involving many thousands of women. The standard of care for woman with high-risk breast cancer is to treat them with adjuvant chemo- Worth noting is the fact that except for chemotherapy for testis cancer, none of the commonly prescribed adjuvant drug regimens are curative for advanced cancer. trialists. Table 4 outlines commonly prescribed chemotherapy regimens in solid tumors. Worth noting is the fact that except for chemotherapy for testis cancer, none of the commonly prescribed adjuvant drug regimens are curative for advanced cancer. Adjuvant therapy in breast cancer is perhaps our best model because REVIEWS IN UROLOGY therapy and/or 5 years of adjuvant hormone therapy.23 Prognostic features such as menopausal status, disease stage, Her-2/neu levels, estrogen and progesterone receptor expression, and tumor lymphatic and vascular invasion determine the type of adjuvant therapy. Data from meta-analyses demonstrate that in premenopausal Biochemical Relapse Biochemical failure patients Docetaxel 70 mg/m2 estramustine 10 mg/kg tid 5 days; repeat cycle every 21 days for 4 cycles Goserelin 10.8 mg bicalutamide 50 mg/daily; treat for 15 months PSA every 3 months Figure 1. Schema for phase II study of combined chemotherapy and hormone therapy for men with biochemical relapse. PSA, prostate-specific antigen. Data from Taplin et al.29 women combination chemotherapy reduces the annual risk of relapse by 35% and reduces the annual risk of mortality by 27%. In women age 50–69, these risks are reduced by 20% and 11%, respectively. The absolute increase in survival at 10 years for premenopausal women treated with adjuvant chemotherapy is 7%–11% and for postmenopausal women, 2%–3%. Adjuvant chemotherapy for breast cancer is usually started within 6 weeks of surgery. A debate remains regarding whether a sequential or combination approach should be used when combining chemotherapy with hormone therapy for estrogen receptor/progesterone receptor-positive patients. Using the preclinical Dunning rat model of prostate cancer, Isaacs24 demonstrated that the combination of chemotherapy (cyclophosphamide) and castration cured 30%–40% of animals, provided the combined treatment was given at the time the tumors were small. Until recently, clinical trials evaluating adjuvant chemotherapy in prostate cancer were hindered by the lack of drugs with proven benefit in advanced disease. Mitoxantrone, an anthracycline, and prednisone have been approved for hormone-refractory prostate cancer (HRPC), based on improvements in QOL endpoints such as pain control.25,26 More recently, the combination of estramustine and a taxane has demonstrated significant clinical effectiveness. Taxane/estramustine regimens have had high PSA and measurable-disease response rates of 65%–80% and 30%, respectively, in phase I-II clinical trials.27,28 The median patient survival in the CALGB phase II trial of estramustine and docetaxel (Taxotere®, Aventis Pharmaceuticals, Bridgwater, NJ) was 21 months; this result compared favorably to a median survival of 11 months in a phase II trial of mitoxantrone and prednisone in contemporary hormone-refractory patients.27 An Intergroup phase III trial of estramustine/docetaxel versus mitoxantrone/prednisone has been completed, and survival data will follow. Given the favorable response rates in HRPC, it is logical to evaluate the effectiveness of chemotherapy in earlier disease settings such as neoadjuvant, adjuvant, and biochemical failure. The prognostic nomograms discussed above allow stratification of patients into lowrisk, intermediate-risk, and high-risk groups, and risk stratification can be factored into a clinical trial design. An Intergroup adjuvant trial of 2 years of hormone therapy, with or without 6 months of mitoxantrone and prednisone, for high-risk patients opened to accrual in 1999. This trial is targeted to accrue 1360 patients to have the power to detect a 30% increase in median survival improvement for 6 months of treatment with adjuvant mitoxantrone. The results of this and other trials will determine the efficacy of adjuvant chemotherapy in prostate cancer in the coming years. Combined Chemohormonal Therapy for Biochemical Failure A study of combined chemohormonal therapy for biochemical relapse is ongoing at the University of Massachusetts/Lahey Clinic/Dartmouth/ Beth Israel Deaconess Medical Center.29 To date, 47 of the targeted 61 patients have entered this phase II trial of estramustine and docetaxel and combined androgen blockade (CAB). The study endpoints include feasibility, toxicity, PSA response rates, time to biochemical and clinical progression, and time to next treatment. Treatment consists of four cycles of docetaxel, 70 mg/m2 given intravenously on day 2 of a 21-day cycle, and oral estramustine 10 mg/kg divided tid days 1–5 (Figure 1). After completion of chemotherapy, the patients receive 15 months of hormone therapy with goserelin and bicalutamide. Currently, 29 patients have completed 18 months of protocol therapy; 15 of these patients have been off hormone therapy for 12 or more months with a median followup of 29 months since enrollment. The characteristics of the enrolled patients include an average age of 63 years; 34 men with prior prostatectomy; 13 men with primary radiotherapy; 38% with Gleason score > 7; and a mean pre-enrollment PSA of 7.40 ng/mL (Table 5). The majority of the patients completed protocol chemotherapy and hormone therapy. VOL. 5 SUPPL. 3 2003 REVIEWS IN UROLOGY S9 Biochemical Relapse continued The doses of chemotherapy were reduced for thrombosis in 4 patients and elevated liver function tests in 2 patients. The doses of bicalutamide or goserelin were also reduced because of breast enlargement in 2 patients.29 After completion of four cycles of estramustine and docetaxel, 78% of patients had an undetectable PSA; 92% had an undetectable PSA during or after completion of hormone therapy; and 4 patients did not achieve an undetectable PSA. With a median follow-up of 1 year since the completion of hormone therapy 76% of the men continue to have an undetectable PSA, and the majority of these men are no longer castrate. Four of the men have started other therapy since the completion of protocol therapy for a rising PSA level (3 are receiving an LHRH agonist, and 1 is taking diethylstilbestrol [DES]). Two men have died from the second development of primary gastrointestinal tumors that presented while they were on the hormonetherapy segment of the trial. Toxicity included a 38% rate of grade 3/4 neutropenia with no documented infections, and a 9% rate of thrombosis (2, deep vein thrombosis; 1, minor cerebrovascular accident). A total of 90% of the men had castrate levels of testosterone after four cycles of estramustine and docetaxel.31 The contribution of cytotoxic versus hormonal effects of this regimen in early-stage patients is not presently known. The long-term consequences of this approach on the natural history of biochemical failure await investigation in the phase III setting. These preliminary data prove that chemohormonal therapy for men with biochemical failure is feasible, well-tolerated, and provides a high PSA response rate (92%), which is durable in 76% of patients off hormone therapy for at least 1 year. S10 VOL. 5 SUPPL. 3 2003 Table 5 Patient Characteristics and Preliminary Results for 47 Patients with Biochemical Failure Treated with Combined Chemohormonal Therapy Patient Characteristics Preliminary Results No. of patients entered/No. expected 47/61 Mean age 63 years Prior prostatectomy 34 patients Prior radiotherapy 13 patients Gleason score > 7 38% Mean PSA at enrollment 7.40 ng/mL Completed 18 months of therapy 29 patients Off hormone therapy minimum of 12 months 15 patients Undetectable PSA after chemotherapy alone 76% Undetectable PSA after chemohormonal therapy 92% Undetectable PSA off therapy (median follow-up 29 months) 76% Castrate level of testosterone after chemotherapy 90% Neutropenia grade 3 or 4 38% Thrombosis 9% PSA, prostate-specific antigen. Data from Taplin et al.31 Other novel approaches include the use of new chemotherapy agents, such as the epothilone analogues, priming chemotherapy with testosterone replacement, and combining commonly prescribed chemotherapy with new compounds, such as growth-factor and receptor tyrosine kinase inhibitors. Future Directions Patients with biochemical failure are a favorable group in which to investigate novel therapeutics because, in general, they have few comorbid medical problems, they are motivated, they have a long life-expectancy compared to patients with other recurrent solid tumors, and their PSA provides a surrogate endpoint with which to test clinical hypotheses. A comprehensive discussion of all ongoing clinical trials for biochem- REVIEWS IN UROLOGY ical failure is beyond the scope of this review, but several concepts will be discussed. Goluboff and colleagues30 have reported the results of a multicenter, randomized, double-blind, placebocontrolled study of exisulind (250 mg bid) in patients with biochemical failure after prostatectomy. Another trial showed that, in prostate cancer cell lines, exisulind induces apoptosis and activation of protein kinase G by cyclic guanosine monophosphate phosphodiesterase.31 This trial demonstrated a significant suppression in the rate of rise of PSA (37% lower; P = .017) for exisulind compared to placebo. The effect was most profound for high-risk patients. Ongoing clinical trials are also evaluating the efficacy of the cyclooxygenase-1 (COX-1) inhibitor, celecoxib, in men with biochemical Biochemical Relapse failure. Celecoxib has been shown to reduce the number of adenomatous colorectal polyps in patients with familial adenomatous polyposis, and in vitro can reduce the growth of prostate cancer. Vaccination is another strategy that is actively being explored in prostate-cancer patients with biochemical failure.32 Vaccinations as therapeutics have not yet proven effective and are not routinely prescribed for treatment of any type of tumor. The aim of a vaccination approach is to induce tumor-specific immunity that is dependent on an appropriate tumor-specific antigen, effective antigen presentation, and generation of an immune response. Early vaccine strategies relied on whole tumor cells or tumor-cell fragments to elicit an immune response. Newer approaches rely on the expression of recombinant or synthetic tumor antigens.33 Approaches to prostate-cancer vaccination include granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting autologous prostate tumor cells,34 prostate acid phosphatase or PSApulsed dendritic cells,35 carbohydrate and glycoprotein (MUC-1 and MUC2 mucin)-based vaccines,32 and engi- neered fowlpox/vaccinia vaccines.36 In a phase I study, 42 men with androgen-independent prostate cancer were treated with a recombinant vaccinia PSA vaccine.36 Of these, 38 patients completed the second vaccine cycle, and 26 completed the planned three cycles. There were no objective tumor responses, but immunologic responses were demonstrated by an increase in the propor- approaches, given the minimal tumor burden and reliable tumor marker. It is hoped that significant advances will be made in cancer vaccine therapy in the future. GM-CSF alone has recently been shown to have activity in a phase II trial in men with biochemical failure.38 Thirty patients with PSA levels between 0.4–6.0 ng/mL were treated with subcutaneous GM-CSF 250 Biochemical-failure patients are ideal for applying vaccination approaches, given the minimal tumor burden and reliable tumor marker. tion of PSA-specific T cells that could lyse PSA-expression tumor cells in vitro. Patients came off the study because of the progression of disease. In order to augment the immune response, this strategy has been modified by combining a vaccinia vector carrying costimulatory molecules and modified PSA as a boost, followed by vaccine priming with a fowlpox vector together with GM-CSF as a costimulatory factor.37 This vaccine strategy is being tested in a multicenter, randomized (placebo), phase II trial. Biochemical-failure patients are ideal for applying vaccination mg/m2/d on days 1–14 of a 28-day cycle. Although only 10% of the patients had a 50% reduction in PSA, there was an increase in the PSA doubling time for 26 patients. The therapy was well-tolerated and had an average duration of treatment of 16.5 cycles (range, 5.0–33.0 cycles). There was no measurement of antiprostate immunity, and because PSA was the primary endpoint, no conclusions could be made regarding the mechanism of GM-CSF modulation of PSA. Further investigation of GMCSF and other immune stimulatory cytokines, either alone or in combi- Main Points • There is no consensus on the exact definition of biochemical relapse after prostatectomy, and classification of consecutively rising prostate-specific antigen (PSA) values that indicate relapse varies considerably. PSA measurements after radiation therapy are even less predictable. • PSA level is a sensitive marker of occult prostate-cancer relapse and provides early notification of recurrence. • Single-institution, retrospective trials have clarified features of PSA relapse after both prostatectomy and radiation, such as the PSA doubling time and the time to the first PSA elevation, both of which are associated with clinical progression. • Currently, there is no standard treatment for biochemical failure with proven benefit in terms of quality of life, time to metastases, or survival. • Current options include observation for patients with long PSA doubling times or comorbid medical issues, and standard or nontraditional hormone therapy or a clinical trial for men who desire early therapy or who have rapid PSA doubling times. • Trials combining the early use of chemotherapy with hormone therapy are promising. Patients should be encouraged to enroll in clinical trials to help establish standards of care. VOL. 5 SUPPL. 3 2003 REVIEWS IN UROLOGY S11 Biochemical Relapse continued nation, is warranted. Alternative/complementary medicine and dietary tactics are popular.39 A common question asked at the time of biochemical failure is “How can I change my diet, and what supplements can I take to make my PSA go down?" Many patients with a history of prostate cancer take a host of supplements, with or without a physician’s involvement. Although many complementary approaches have demonstrated in vitro activity against prostate cancer cell lines, there are no proven clinical benefits in terms of QOL, time to progression, or survival. Supplements in common use include vitamin E, selenium, genistein, soy extracts, lycopenes, green tea concentrates, and saw palmetto. Several institutions have evaluated the effects of diet on biochemicalfailure patients. A study by Carmody and coworkers, reported in Saxe and associates,40 explored the results of a well-known, mindfulness-based, stress-reduction program with a low saturated fat, high-fiber, plant-based diet to determine its effect on men with biochemical failure. All patients experienced a weight loss and a lowering of blood pressure and cholesterol; there was also an increase in the PSA doubling time in 8 out of 10 men, and 3 men had a decrease in absolute PSA.40 The results are being confirmed in a larger trial. or survival. If microscopic systemic disease is suspected, the options include observation for patients with long PSA doubling times or comorbid medical issues. For men who desire early therapy or who have rapid PSA doubling times (< 10–12 months), the therapeutic options include standard or nontraditional hormone therapy or a clinical trial. Trials combining the early use of chemotherapy with hormone therapy are promising. Patients should be encouraged to enroll in clinical trials when possible to help establish standards of care. References 1. 2. 3. 4. 5. 6. 7. Conclusions There are approximately 280,000 new cases of prostate cancer each year in the United States, and despite definitive local therapy there are about 50,000 cases of biochemical failure each year. PSA provides early notification of recurrence and directs the patient’s and physician’s attention to the next therapeutic step. Currently, there is no standard treatment for biochemical failure with proven benefit in terms of QOL, time to metastases, S12 VOL. 5 SUPPL. 3 2003 8. 9. 10. 11. 12. 13. REVIEWS IN UROLOGY Jemal A, Thomas A, Murray T, Thun M. Cancer statistics, 2002. CA Cancer J Clin. 2002;52:23–47. Moul JW. Prostate specific antigen only progression of prostate cancer. J Urol. 2000;163:1632–1642. Pound CR, Partin AW, Epstein J, Walsh PC. 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