Authors: Channing J. Paller, MD, and Emmanuel S. Antonarakis, MD
Clinical Advances in Hematology & Oncology
January 2013, Volume 11, Issue 1
Channing J. Paller, MD, and Emmanuel S. Antonarakis, MD
Drs. Paller and Antonarakis are Assistant Professors of Oncology at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, in Baltimore, Maryland.
Address correspondence to: Emmanuel S. Antonarakis, MD, Assistant Professor of Oncology, Prostate Cancer Research Program, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRB1-1M45, Baltimore, MD 21231; Phone: 443-287-0553; Fax: 410-614-8397; E-mail: [email protected]
Fewer than 12% of the 241,700 men expected to have been diagnosed with prostate cancer in the United States in 2012 will die from this disease.1 Many more patients will experience rising prostate-specific antigen (PSA) levels following local therapy, a condition known as biochemical recurrence (BCR; Figure 1). Physicians treating patients with BCR face a difficult set of decisions in attempting to delay the onset of metastatic disease and death while avoiding over-treating patients whose disease may never affect their overall survival or quality of life. In this generally healthy population, effective management requires that physicians evaluate PSA levels, as well as clinical and radiologic indicators, in order to balance the morbidity and efficacy of proposed treatments against the risks of metastatic progression.
Radical prostatectomy (RP), which is used in approximately 75,000 newly diagnosed prostate cancer cases each year (30% of those diagnosed),2 can cure appropriately-selected patients with localized disease, as can external-beam radiation therapy (RT) and brachytherapy, which are used in approximately 60,000 newly diagnosed cases (25% of those diagnosed).3 However, 20–40% of patients undergoing RP4,5 and 30–50% of patients undergoing RT will experience biochemical recurrence within 10 years.6 There is currently no consensus regarding optimal management of this disease state. Reasonable options include: 1)salvage radiation therapy, if progression has occurred after prostatectomy; 2) observation with close surveillance; 3) androgen deprivation therapy (ADT), either intermittent or continuous, initiated upon PSA recurrence or deferred until after clinical/radiographic progression; or 4) enrollment in investigational clinical trials.7
Not all patients with BCR prostate cancer have the same prognosis, and stratification of patients into appropriate risk groups is essential. One of the strongest predictors of metastasis and death is the PSA doubling time (PSADT), a mathematical determination of the length of time (in months) needed for the PSA level to double in a given patient. BCR patients with a PSADT greater than 9 months, for example, have a high probability of long-term, metastasis-free survival and overall survival.8 In addition, among patients with a slow PSADT, radiographic evidence of metastatic disease is likely to be discovered before patients experience clinical symptoms from their metastatic disease. Thus, the value of early ADT is unknown in this population, and research is needed to determine the optimal initiation point of ADT (early vs deferred and continuous vs intermittent) before physicians and patients can act with confidence. Similar questions about optimal treatment and best timing of treatment arise with other stratification factors, such as time-to-BCR, patient age and comorbidities, Gleason score, and pathologic stage. Therefore, multiple clinical factors must be taken into consideration when planning the optimal course of treatment for a particular patient with PSA-recurrent prostate cancer.
In recent years, the search for alternatives to chronic ADT for BCR prostate cancer patients has intensified. A wealth of clinical trials have focused on alternative (ie, non-castrating) hormonal agents, timing of conventional ADT, supplementing ADT with novel agents, or using hormone-sparing treatments in these patients (novel biologic agents, immunotherapies, natural products, and pharmaceuticals that have been approved by the FDA for other diseases but have demonstrated preclinical activity in hormone-sensitive prostate cancer). This review outlines the results of some of the pivotal trials that guide our practice, as well as relevant retrospective analyses describing the natural history of PSA-recurrent prostate cancer. We will conclude by discussing the status of several ongoing investigational trials focusing on treatment of patients with BCR prostate cancer.
Defining Biochemical Recurrence
Precision in defining BCR is important in order to identify patients at risk of disease progression, to determine the timing for additional treatment options (such as ADT), and to compare the efficacy of different treatments in the setting of clinical trials. Absent a common definition of BCR, predictions of metastatic progression and mortality would remain unreliable. Of note, the definition of PSA recurrence is dependent upon the type of local therapy received: prostatectomy or radiation therapy. To describe biochemical recurrence after RP, a panel of experts from the American Urological Association (AUA) evaluated 53 different definitions of BCR following RP observed in the literature, and recommended adoption of a single definition. This involved the presence of a PSA greater than 0.2 ng/mL measured 6–13 weeks after RP, followed by a confirmatory test showing a persistent PSA greater than 0.2 ng/mL.9 Ultra-sensitive PSA assays have recently improved detection levels down to 0.01 ng/mL, and may possibly lead to better treatment outcomes through earlier adoption of salvage radiation therapy following RP.10,11 However, false positives occurring because of trace amounts of PSA produced by residual benign prostatic tissue, along with uncertainty about whether ultra-low levels of PSA will be followed by continued PSA increases, have led practitioners to continue to rely on the AUA definition for determining when clinically-relevant biochemical recurrence has occurred after prostatectomy.
The definition of BCR following RT is more problematic. The AUA panel found 99 different definitions of BCR following RT, among which the American Society of Therapeutic Radiology and Oncology (ASTRO) definition was the most common. This was defined as the midpoint between PSA nadir and the first of 3 consecutive rises in PSA.9 Although the AUA recommends that the ASTRO definition be adopted, it has several weaknesses, including failure to use the PSA level at nadir as a risk factor and the requirement to backdate the time of biochemical recurrence. An alternative definition of “nadir +2 ng/mL” (Phoenix definition) has shown improved accuracy over ASTRO in predicting clinical failures.12-14 However, the nadir-based definition results in substantially lower estimates of BCR at 5 years, and substantially higher estimates of BCR at 10 years than the ASTRO definition.6 Pending more information on development of distant metastases and prostate-specific mortality, the AUA continues to recommend the ASTRO definition of BCR following RT.
Prognostic Factors in PSA-Recurrent Prostate Cancer
Pre- and post-treatment prognostic factors allow physicians to assign risk levels and use those risk groupings to help determine whether to start treatment immediately or to defer it. Pretreatment factors that have shown prognostic value include absolute baseline PSA, tumor stage (T-stage), and pathologic findings (including Gleason score, surgical margin status, and lymph node status). All of these parameters are prognostic of development of distant metastases and prostate-specific mortality, with Gleason score providing the greatest prognostic value with advanced T-stage and absolute PSA value also contributing to accuracy of prognosis.15 Gleason score continues to have prognostic value following local therapy but it is joined by other factors, of which PSADT is likely the most important prognostic factor for metastasis-free survival and overall survival.8 Time to biochemical recurrence has been shown to be a prognostic factor in some studies16,17 but not in others.8 In a landmark study, Pound and associates found that time to biochemical recurrence after RP was as effective as PSADT and Gleason score as a prognostic factor for metastasis.16 However, a recent multivariate analysis using updated information from these same patients showed that time to biochemical recurrence does not add measurably to the prognostic value of PSADT and Gleason score.8 Finally, changes in PSADT after initiation of therapy in the setting of clinical trials has also been shown to be prognostic of metastasis-free survival in patients with BCR disease following local therapy.7
PSA kinetics have long been known to be prognostic for metastasis-free survival, prostate cancer–specific survival, and overall survival. However, the exact cut-off points for defining high-risk disease have varied. In a study of 3,903 men who had undergone prostatectomy, PSADT less than 12 months corresponded with significantly increased risk of clinical failure.18 Another study of 8,669 patients with prostate cancer treated with surgery (5,918 patients) or radiation (2,751 patients) found that a PSADT of less than 3 months was significantly associated with prostate cancer–specific mortality.19 More recently, a series of 3 PSADT cut-off points have been chosen in defining 4 risk groups (<3 months vs 3–9 months vs 9–15 months vs >15 months).5,8 In addition, the number and timing of PSA measurements needed to accurately estimate PSADT has led to uncertainty about its reliability as a prognostic marker. In the authors’ opinion, 3 PSA measurements obtained 3 months apart is considered a reliable foundation for calculation of PSADT.
Finally, a retrospective study of patients with rising PSA following local therapy who were enrolled in 4 clinical trials of nonhormonal agents found that changes in PSADT after treatment initiation were prognostic for metastasis-free survival.7 Data on overall survival from this cohort are not yet mature. These data suggest that the onset of metastasis may be delayed if an experimental agent is capable of significantly lengthening the PSADT. If these preliminary findings are confirmed in prospective trials using metastasis-free survival as a primary endpoint, changes in PSADT could become a reasonable intermediate endpoint of future studies in this patient population.7
Diagnostic Evaluation After PSA Recurrence
No formal guidelines have been published defining the frequency of diagnostic evaluations for patients following BCR who choose to undergo surveillance rather than initiating early hormonal therapy. In the authors’ opinion, it is reasonable to monitor serum PSA every 3 months and to perform annual technetium-99 bone scans and bi-annual computed tomography (CT) scans in patients at high risk of metastatic progression as determined by PSA levels (≥5 ng/mL) and/or a rapid PSADT of 9 months or less. In one retrospective study describing the natural history of untreated PSA-recurrent prostate cancer after prostatectomy, it was observed that men with a PSADT of 9 months or less had a median metastasis-free survival of 2 years after biochemical recurrence.8 Another analysis from this same population reported that the median PSA value at the time of first radiographic metastasis was 31.4 ng/mL (interquartile range, 8.8–87.5 ng/mL).20 These figures may help to determine whether a particular patient might be at a more imminent risk of metastasis, allowing for more frequent PSA evaluations or imaging tests to be obtained at the treating physician’s discretion.
Salvage Radiation for PSA-Recurrent Prostate Cancer
Three large retrospective studies provide evidence that early salvage radiation therapy, delivered to patients with rapid PSADT, or while the PSA levels remain below 2.0 ng/mL, impacts survival of prostate cancer patients with BCR. A study at Duke University examined 519 patients who experienced BCR after prostatectomy, of which 219 patients received salvage radiation therapy. That study stratified the patients by PSADT (<6 months vs ≥6 months). Salvage radiation therapy significantly improved overall survival in both groups at a median follow-up of 11.3 years, with all-cause mortality hazard ratios (HR) for death of 0.53 and 0.52 for those with faster and slower PSADT, respectively.21
A second study of 635 patients with PSA-recurrence after prostatectomy at Johns Hopkins Hospital compared salvage radiation therapy (either alone or with ADT) against observation.22 In that study, salvage radiation was associated with a 3-fold increase in prostate-cancer specific survival after a median follow-up of 6 years after biochemical recurrence as compared with observation, but this improvement was limited to men with PSADT less than 6 months. Interestingly, salvage radiotherapy was still associated with significant improvement in prostate-specific survival when administered to patients with PSA above 2 ng/mL, only if those patients also had PSADT less than 6 months. No significant increase in prostate cancer–specific survival was seen in patients who were administered salvage radiation more than 2 years after PSA recurrence. In addition, ADT did not significantly improve prostate-cancer specific survival in this patient population.22 The greater impact of salvage radiation on prostate-specific survival in patients with PSADT less than 6 months was supported by an analysis of a subset of the Duke patients who had comorbidities at the time of PSA recurrence. Significant reduction in all-cause mortality was associated with salvage radiation in both patients with a PSADT less than 6 months (HR, 0.35; P=.042) and a PSADT greater than 6 months (HR, 0.60; P=.04), but the reduction in all-cause mortality was nearly 60% greater in the patients with PSADT less than 6 months.21
Although another large retrospective trial has not shown overall survival benefits from salvage radiation treatment after prostatectomy,23 the 2 studies described above provide adequate evidence that salvage radiation therapy may positively alter the progression of the disease when administered within 2 years of BCR and while the absolute PSA remains below 2 ng/mL (although even lower PSA values may further increase the chance of cure with salvage radiotherapy). The finding of improved prostate cancer–specific survival in men with PSADT less than 6 months is provocative (and perhaps counterintuitive), and should be confirmed by additional studies.
Hormonal Therapy For PSA-Recurrent Prostate Cancer
Selection of Hormonal Agents
Androgen deprivation therapy, either through chemical castration or, far more rarely, through orchiectomy, is one reasonable standard of care for BCR prostate cancer after maximal local therapy.24 Gonadotrophin-releasing hormone (GnRH) agonists, including leuprolide and goserelin, have been the primary medical castration therapies in the Western world. Recently, a GnRH antagonist, degarelix, has been gaining momentum in the first-line setting because clinical trial data suggest that it results in more rapid reduction of testosterone and marginally longer PSA progression-free survival intervals than leuprolide.25 In addition, patients on degarelix do not experience clinical flare and therefore do not require a short course of androgen receptor antagonists (such as bicalutamide or nilutamide) that are often prescribed for patients initiating leuprolide or goserelin. One potential disadvantage of degarelix is the requirement for monthly administration, since longer formulations of this compound do not exist at the present time. However, both GnRH agonists and antagonists remain reasonable options for initial hormonal treatment of patients with BCR prostate cancer.
Timing and Duration of ADT
Physicians wishing to treat BCR prostate cancer patients with ADT face 2 key timing questions: 1) whether to initiate ADT immediately upon PSA recurrence or to defer its use until after clinical/radiographic progression occurs, and 2) whether to use continuous administration of ADT or intermittent cyclic administration of ADT. As of December 2012, the American Society of Clinical Oncology (ASCO) had not provided definitive guidelines addressing either of these questions. We will review the relevant clinical trial data that may guide clinicians with respect to these 2 issues.
Immediate Versus Deferred ADT
When BCR patients experience clinical/radiographic metastatic disease, immediate initiation of ADT reduces further metastatic progression, improves pain (if present), and reduces the development of skeletal-related events (eg, pathological fracture and spinal cord compression). Immediate ADT in the metastatic setting also reduces prostate cancer–specific mortality, but does not necessarily improve overall survival (compared to initiating ADT at the time of symptomatic progression) because of increases in deaths from other causes.24,26 For nonmetastatic BCR patients, timing of ADT is controversial. Many men in the BCR setting choose to defer the initiation of hormonal therapy and prefer to allow their physician to monitor their PSA kinetics, bones scans, and CT scans on a regular basis. Two ongoing clinical trials are exploring the timing of ADT initiation after BCR following radiation, the Australian and New Zealand Timing of Androgen Deprivation trial (TOAD; NCT00110162) and the Canadian Early vs. Late Androgen Ablation Therapy trial (ELAAT; NCT0043975).
Until results of these studies are available, uncertainty about the overall survival benefits of immediate ADT initiation, combined with serious adverse effects and quality-of-life issues that may accompany ADT treatment, has led many patients to defer ADT initiation and to opt instead for observation. Their choice to defer ADT is supported by a recently published retrospective review of surgical patients in a single institution,8 and confirmed by a second study in an independent patient population.27 These studies reported median metastasis-free survival intervals of 10 years among men with BCR following prostatectomy, even in the absence of ADT and salvage radiation. In addition, another retrospective analysis of BCR prostate cancer patients found that PSADT rose approximately 4 months over 5 years, even without ADT or other therapies, in patients whose PSADT was greater than 15 months at the beginning of the period.28 These data support earlier findings that BCR patients with PSADT 15 months or greater often enjoy prolonged progression-free survival.8 At the authors’ institution, given the lack of a clear overall survival advantage with the use of immediate ADT, it is generally recommended to defer ADT in patients at low risk of metastatic progression (eg, PSADT >9 months; absolute PSA <10 ng/mL), while early initiation of ADT remains a reasonable choice for those at high risk of developing metastatic disease (eg, PSADT <6 months; absolute PSA >20 ng/mL).
Continuous Versus Intermittent ADT
Once the decision to use ADT has been made, a second controversial decision for BCR prostate cancer patients is whether to use intermittent or continuous administration of androgen deprivation. Intermittent androgen deprivation (IAD) is a cyclic process in which induction treatment continues until maximal PSA response. ADT is then temporarily withdrawn until serum PSA levels rise to a predetermined level, agreed upon by patient and physician (often between 4 and 10 ng/mL), at which point ADT is reinitiated. IAD can allow testosterone levels to recover during each off-treatment cycle, lessening sexual dysfunction and loss of bone mass often associated with continuous androgen deprivation.29 The lower cost and improved quality of life, combined with noninferiority of IAD in overall survival, have led many patients to choose IAD for treatment of BCR prostate cancer.
Two large phase III trials have attempted to determine whether IAD was noninferior to continuous androgen deprivation (CAD) in patients with recurrent prostate cancer. In an international trial involving 1,386 men with BCR following radiation therapy (with or without prior prostatectomy), patients were randomized into CAD or IAD arms. The IAD group received 8 months of hormonal therapy followed by treatment withdrawal until PSA reached 10 ng/mL or higher during the off-treatment period. After a median follow-up of 6.9 years, the endpoint of overall survival was shown to be noninferior for IAD compared to CAD (8.8 years vs 9.1 years, HR, 1.02; 95% confidence interval [CI], 0.86–1.21). Prostate cancer–related deaths were greater in the IAD group (122 vs 97 deaths), while non-prostate deaths were lower in the IAD group (134 vs 146 deaths). In addition, men in the IAD arm reported reduced hot flashes, although no other differences in adverse effects were reported.29 Based on the results of this large and well-conducted study, the authors now view intermittent ADT as a very reasonable standard of care for the management of patients with BCR prostate cancer.
A second phase III trial studied 626 southern European patients with locally advanced prostate cancer (some had also developed metastatic disease) and found no difference in overall survival between the IAD and CAD arms, because the reduction in prostate cancer–specific deaths in the CAD arm was offset by a larger number of deaths from cardiovascular disease in the CAD arm. Patients in the IAD arm reported better sexual function, although there was no significant difference in reported quality of life between the treatment arms.30 Thus, the benefit of avoiding prostate cancer–related death using CAD is balanced by the benefit of avoiding death from other causes, such as cardiovascular disease, using IAD. The risks and benefits must be weighed in each patient, paying particular attention to cardiovascular disease history and risk factors for metabolic syndrome.
Experimental Approaches For PSA-Recurrent Prostate Cancer
The current treatment landscape for prostate cancer patients experiencing biochemical recurrence offers no ideal systemic approach. Benefits of early initiation of continuous ADT or intermittent ADT are offset by the risk of osteopenia and cardiovascular disease, in addition to the bothersome and common side effects, including hot flashes and erectile dysfunction. Patients with slower PSADT, for whom ADT may not be immediately indicated, face years of anxiety and often seek treatments that delay PSA progression and development of metastases. To this end, researchers are investigating 3 approaches to complement or replace those described earlier in this review for the management of BCR patients: 1) the use of novel agents or vaccination approaches to enhance and/or supplement ADT; 2) the use of pharmaceutical agents or combinations of agents that may already be approved by the US FDA for treatment of other diseases and have demonstrated preclinical activity against hormone-sensitive prostate cancer; and 3) the use of natural products that have shown preclinical activity against hormone-sensitive prostate cancer. Table 1 shows a selected list of completed or ongoing clinical trials investigating a number of such therapeutic strategies in patients with BCR, nonmetastatic prostate cancer.
Selected Trials of ADT Plus Additional Experimental Agents
The effectiveness of sipuleucel-T (Provenge, Dendreon), the first immunotherapy approved for the treatment of metastatic castration-resistant prostate cancer, is being evaluated in BCR patients who have not yet received hormonal therapy to determine whether administration at an earlier disease state will improve antitumor immune responses and clinical outcomes. It has been suggested that the effectiveness of the vaccine may be enhanced by ADT-induced, T-cell–mediated responses that target prostate cancer cells.31 Preclinical research in animal models demonstrated ADT enhancement of immunotherapy efficacy,32,33 and human studies combining hormonal therapy with immunotherapy confirmed the additive effect.34 A randomized phase II trial is seeking to determine the optimal sequencing for ADT and sipuleucel-T (NCT01431391) in men with PSA-recurrent prostate cancer.
Bevacizumab (Avastin, Genentech/Roche), an anti-angiogenesis monoclonal antibody approved in the United States for multiple tumor types (but not prostate cancer), inhibits vascular endothelial growth factor (VEGF), a major mediator to angiogenesis. ADT induces an 80% reduction in VEGF content in hormone-sensitive prostate cancer cells.35 In LNCaP xenograft studies, VEGF inhibition combined with ADT demonstrates an increase in tumor necrosis, when compared with either ADT alone or VEGF inhibition alone.36 A randomized phase II trial is evaluating the effect on time-to-PSA-progression when adding bevacizumab to 6 months of ADT in BCR patients (NCT00776594). In this trial, all patients receive a short course of ADT, and two-thirds also receive 8 doses of intravenous bevacizumab, administered 3 weeks apart.
Reciprocal negative feedback between the androgen receptor and PI3-kinase/Akt/mTOR pathways enables combined pathway inhibition that results in profound apoptosis in preclinical prostate cancer models.37 In this model, inhibition of the PI3-kinase pathway alone induces overactivation of the androgen receptor pathway, while inhibition of the androgen receptor alone promotes overactivation of the PI3-kinase/Akt/mTOR pathway. Following from this preclinical work, a translational randomized phase II study is combining MK-2206 (an Akt inhibitor) with the anti-androgen bicalutamide in patients with BCR prostate cancer (NCT01251861). During the first 12 weeks of the study, patients are randomized to receive either MK-2206 or to undergo observation. Thereafter, bicalutamide is added to both study arms and continued until evidence of PSA progression.
Selected Trials of Other Nonhormonal Agents
More than 20 clinical trials have been launched in BCR patients, evaluating agents previously approved by the FDA for other diseases that may show benefit in prostate cancer (Table 1). Although many of these trials have been completed, none have resulted in further evaluation in phase III trials. Among the agents that have completed testing are celecoxib (Celebrex, Pfizer), rosiglitazone (Avandia, GlaxoSmithKline), imatinib (Gleevec, Novartis), vitamin D derivatives, lenalidomide (Revlimid, Celgene), lapatinib (Tykerb, GlaxoSmithKline), fenretinide, ATN-224, and the pTVG-HP vaccine. One trial (using celecoxib) was halted early because of excessive cardiovascular toxicities. Other trials completed their accrual but found little or no benefit from the experimental drug, with observed PSADT increases that were not much larger than the increases found in BCR patients who were managed with observation/placebo.28 Most of the trials were of insufficient duration to measure accepted clinical outcomes, such as radiologic evidence of metastases or survival. It should be emphasized that PSADT changes alone do not provide sufficient justification for major investments in phase III trials, especially in light of side effects and costs associated with many of the compounds being tested for this relatively healthy population.
Selected Trials of Natural Products
A large proportion of patients with BCR prostate cancer who are concerned about their rising PSA but also want to avoid the side effects of ADT and other pharmaceuticals are actively self-medicating with natural products in an attempt to lower their PSA. However, there is little documented evidence that these products are effective and they may not be safe in the quantities or formulations being sold, despite having been consumed for decades by thousands of people in their natural plant forms. A series of clinical trials seeking to evaluate the safety and efficacy of natural products, including pomegranate juice and extract, muscadine grape skin extract, Chinese grass seed oil, acai berry, and brassica vegetables (eg, broccoli), are now under way. Preclinical rationale supporting these studies focuses on inhibition of nuclear factor-κB and Akt (pomegranate products,38 muscadine grape skin extract,39 acai berry,40 and brassica vegetables41). To date, 2 pomegranate trials have been published and both demonstrated significant improvement in PSADT.38,42 However, these trials are difficult to interpret in the absence of a placebo comparator group. To this end, placebo-controlled trials are now under way for pomegranate (NCT00336934), brassica vegetables (NCT00607932), and muscadine grape skin extract (NCT01317199) in order to compare changes in PSA kinetics between the active treatment arm and the placebo arm.
Although the treatment landscape for patients with BCR prostate cancer remains challenging, new research is helping to identify patient populations suitable for specific therapies. Clinical trials of pharmaceutical agents, vaccines, and natural products, as well as new approaches to timing and combining hormonal treatments, are currently ongoing. In addition, several trials are now stratifying their patient populations into different risk categories based on the natural history of their disease as well as their age and comorbidities. As more stratified evidence emerges, physicians and their patients may look forward to a time when they can choose treatment strategies that delay the onset of metastatic lesions while avoiding or minimizing the costs and side effects associated with ADT.
The ultimate goal in treating patients with BCR prostate cancer is to identify a safe and effective nonhormonal therapy that is able to delay metastasis and death without the need for pharmacologic castration. An alternative attractive strategy would be one in which a limited course of androgen deprivation (eg, 6 or 12 months) is given together with an additional hormonal or nonhormonal agent in an attempt to eradicate micrometastatic disease before the development of clinical/radiographic metastases. However, designing these types of clinical trials is challenging. For example, if investigating a nonhormonal agent for patients with BCR prostate cancer, the time to first metastasis and time to death are very prolonged, even if selecting only high-risk patients (those with PSADT <6 months). In addition, time to metastasis will be affected by subsequent treatments (including hormonal treatments) that patients may opt to receive if they come off study due to further rises in their PSA. Finally, metastasis-free survival has not been shown to be associated with overall survival in patients with PSA-recurrent prostate cancer, so it is unclear whether it could be used as a surrogate endpoint without adequate follow-up for overall survival. Even more questionable is the significance of treatment-induced changes in PSA kinetics as they relate to metastasis-free survival and overall survival.
Rather than focusing on noncastrating approaches, an alternative strategy would be to investigate the efficacy of short-course androgen suppression combined with other nonhormonal (eg, immunotherapies, antiangiogenics) or novel hormonal agents. A potential relevant endpoint in this setting could be the achievement of an undetectable PSA after a finite course of ADT and after testosterone levels have recovered to the noncastrate range. An undetectable PSA after testosterone recovery in this setting could be interpreted as a “cure” for these patients, although the significance of this has not been tested or validated. With an ever increasing range of novel hormonal agents, the question has emerged as to whether a short course of more complete/maximal androgen signaling inhibition (androgen annihilation) may be able to eradicate micrometastatic disease in this setting. Trials are currently being designed to test this intriguing hypothesis.
1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American Cancer Society; 2012.
2. Burkhardt JH, Litwin MS, Rose CM, et al. Comparing the costs of radiation therapy and radical prostatectomy for the initial treatment of early-stage prostate cancer. J Clin Oncol. 2002;20:2869-2875.
3. Shipley WU, Thames HD, Sandler HM, et al. Radiation therapy for clinically localized prostate cancer: a multi-institutional pooled analysis. JAMA. 1999;281:1598-1604.
4. Roehl KA, Han M, Ramos CG, Antenor JA, Catalona WJ. Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results. J Urol. 2004;172:910-914.
5. Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA. 2005;294:433-439.
6. Kupelian PA, Mahadevan A, Reddy CA, Reuther AM, Klein EA. Use of different definitions of biochemical failure after external beam radiotherapy changes conclusions about relative treatment efficacy for localized prostate cancer. Urology. 2006;68:593-598.
7. Antonarakis ES, Zahurak ML, Lin J, Keizman D, Carducci MA, Eisenberger MA. Changes in PSA kinetics predict metastasis-free survival in men with PSA-recurrent prostate cancer treated with nonhormonal agents: combined analysis of 4 phase II trials. Cancer. 2012;118:1533-1542.
8. Antonarakis ES, Feng Z, Trock BJ, et al. The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up. BJU Int. 2012;109:32-39.
9. Cookson MS, Aus G, Burnett AL, et al. Variation in the definition of biochemical recurrence in patients treated for localized prostate cancer: the American Urological Association Prostate Guidelines for Localized Prostate Cancer Update Panel report and recommendations for a standard in the reporting of surgical outcomes. J Urol. 2007;177:540-545.
10. Terai A, Matsui Y, Yoshimura K, Arai Y, Dodo Y. Salvage radiotherapy for biochemical recurrence after radical prostatectomy. BJU Int. 2005;96:1009-1013.
11. Kinoshita H, Kamoto T, Nishiyama H, Nakamura E, Matsuda T, Ogawa O. Prostate specific antigen nadir determined using ultra-sensitive prostate specific antigen as a predictor of biochemical progression after radical prostatectomy in Japanese males. Int J Urol. 2007;14:930-934.
12. Kestin LL, Vicini FA, Martinez AA. Practical application of biochemical failure definitions: what to do and when to do it. Int J Radiat Oncol Biol Phys. 2002;53:304-315.
13. Horwitz EM, Thames HD, Kuban DA, et al. Definitions of biochemical failure that best predict clinical failure in patients with prostate cancer treated with external beam radiation alone: a multi-institutional pooled analysis. J Urol. 2005;173:797-802.
14. Kuban DA, Levy L, Potters L, et al. Comparison of biochemical failure definitions for permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys. 2006;65:1487-1493.
15. Pierorazio PM, Ross AE, Lin BM, et al. Preoperative characteristics of high-Gleason disease predictive of favourable pathological and clinical outcomes at radical prostatectomy. BJU Int. 2012;110:1122-1128.
16. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA. 1999;281:1591-1597.
17. Buyyounouski MK, Hanlon AL, Horwitz EM, Pollack A. Interval to biochemical failure highly prognostic for distant metastasis and prostate cancer-specific mortality after radiotherapy. Int J Radiat Oncol Biol Phys. 2008;70:59-66.
18. Ward JF, Blute ML, Slezak J, Bergstralh EJ, Zincke H. The long-term clinical impact of biochemical recurrence of prostate cancer 5 or more years after radical prostatectomy. J Urol. 2003;170:1872-1876.
19. D’Amico AV, Moul JW, Carroll PR, Sun L, Lubeck D, Chen MH. Surrogate end point for prostate cancer-specific mortality after radical prostatectomy or radiation therapy. J Natl Cancer Inst. 2003;95:1376-1383.
20. Antonarakis E, Keizman D, Carducci M, Eisenberger M. The effect of PSA doubling time (PSADT) and Gleason score on the PSA at the time of first metastasis in men with biochemical recurrence after prostatectomy. J Clin Oncol (ASCO Annual Meeting Abstracts). 2011;29: Abstract 16.
21. Cotter SE, Chen MH, Moul JW, et al. Salvage radiation in men after prostate-specific antigen failure and the risk of death. Cancer. 2011;117:3925-3932.
22. Trock BJ, Han M, Freedland SJ, et al. Prostate cancer-specific survival following salvage radiotherapy vs observation in men with biochemical recurrence after radical prostatectomy. JAMA. 2008;299:2760-2769.
23. Boorjian SA, Karnes RJ, Crispen PL, Rangel LJ, Bergstralh EJ, Blute ML. Radiation therapy after radical prostatectomy: impact on metastasis and survival. J Urol. 2009;182:2708-2714.
24. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an American Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25:1596-1605.
25. Crawford ED, Tombal B, Miller K, et al. A phase III extension trial with a 1-arm crossover from leuprolide to degarelix: comparison of gonadotropin-releasing hormone agonist and antagonist effect on prostate cancer. J Urol. 2011;186:889-897.
26. Immediate versus deferred treatment for advanced prostate cancer: initial results of the Medical Research Council Trial: the Medical Research Council prostate cancer working party investigators. Br J Urol. 1997;79:235.
27. Antonarakis ES, Chen Y, Elsamanoudi SI, et al. Long-term overall survival and metastasis-free survival for men with prostate-specific antigen-recurrent prostate cancer after prostatectomy: analysis of the Center for Prostate Disease Research National Database. BJU Int. 2011;108:378-385.
28. Paller C, Xie S, Olatoye D, et al. The effect of PSA frequency and duration on PSA doubling time (PSADT) calculations in men with biochemically recurrent prostate cancer after definitive local therapy. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012; 30: Abstract 99246.
29. Crook JM, O’Callaghan CJ, Duncan G, et al. Intermittent androgen suppression for rising PSA level after radiotherapy. N Engl J Med. 2012;367:895-903.
30. Calais da Silva FE, Bono AV, Whelan P, et al. Intermittent androgen deprivation for locally advanced and metastatic prostate cancer: results from a randomised phase 3 study of the South European Uroncological Group. Eur Urol. 2009;55:1269-1277.
31. Mercader M, Bodner BK, Moser MT, et al. T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer. Proc Natl Acad Sci U S A. 2001;98:14565-14570.
32. Koh YT, Gray A, Higgins SA, Hubby B, Kast WM. Androgen ablation augments prostate cancer vaccine immunogenicity only when applied after immunization. Prostate. 2009;69:571-584.
33. Drake CG, Doody AD, Mihalyo MA, et al. Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen. Cancer Cell. 2005;7:239-249.
34. Madan RA, Gulley JL, Schlom J, et al. Analysis of overall survival in patients with nonmetastatic castration-resistant prostate cancer treated with vaccine, nilutamide, and combination therapy. Clin Cancer Res. 2008;14:4526-4531.
35. Stewart RJ, Panigrahy D, Flynn E, Folkman J. Vascular endothelial growth factor expression and tumor angiogenesis are regulated by androgens in hormone responsive human prostate carcinoma: evidence for androgen dependent destabilization of vascular endothelial growth factor transcripts. J Urol. 2001;165:688-693.
36. Nicholson B, Gulding K, Conaway M, Wedge SR, Theodorescu D. Combination antiangiogenic and androgen deprivation therapy for prostate cancer: a promising therapeutic approach. Clin Cancer Res. 2004;10:8728-8734.
37. Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell. 2011;19:575-586.
38. Pantuck AJ, Leppert JT, Zomorodian N, et al. Phase II study of pomegranate juice for men with rising prostate-specific antigen following surgery or radiation for prostate cancer. Clin Cancer Res. 2006;12:4018-4026.
39. Hudson TS, Hartle DK, Hursting SD, et al. Inhibition of prostate cancer growth by muscadine grape skin extract and resveratrol through distinct mechanisms. Cancer Res. 2007;67:8396-8405.
40. Poulose SM, Fisher DR, Larson J, et al. Anthocyanin-rich acai (Euterpe oleracea Mart.) fruit pulp fractions attenuate inflammatory stress signaling in mouse brain BV-2 microglial cells. J Agric Food Chem. 2012;60:1084-1093.
41. Aggarwal BB, Ichikawa H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle. 2005;4:1201-1215.
42. Paller C, Ye X, Wozniak P, et al. A randomized phase II study of pomegranate extract for men with rising prostate-specific antigen following initial therapy for localized prostate cancer. Prostate Cancer Prostic Dis. 2012. [Epub ahead of print]
43. Scher HI, Morris MJ, Basch E, Heller G. End points and outcomes in castration-resistant prostate cancer: from clinical trials to clinical practice. J Clin Oncol. 2011;29:3695-3704.
44. Solo K, Mehra M, Dhawan R, Valant J, Scher H. Prevalence of prostate cancer (PC) clinical states (CS) in the United States: estimates using a dynamic progression model. J Clin Oncol (ASCO Annual Meeting Abstracts). 2009;27: Abstract 4637.
45. Figg WD, Hussain MH, Gulley JL, et al. A double-blind randomized crossover study of oral thalidomide versus placebo for androgen dependent prostate cancer treated with intermittent androgen ablation. J Urol. 2009;181:1104-1113.
46. McNeel DG, Smith HA, Eickhoff JC, et al. Phase I trial of tremelimumab in combination with short-term androgen deprivation in patients with PSA-recurrent prostate cancer. Cancer Immunol Immunother. 2012;61:1137-1147.
47. Smith MR, Manola J, Kaufman DS, Oh WK, Bubley GJ, Kantoff PW. Celecoxib versus placebo for men with prostate cancer and a rising serum prostate-specific antigen after radical prostatectomy and/or radiation therapy. J Clin Oncol. 2006;24:2723-2728.
48. Pruthi R, Derksen E. A phase II trial of celecoxib in PSA recurrent prostate cancer after definitive radiation therapy or radical prostatectomy. J Clin Oncol (ASCO Annual Meeting Abstracts). 2004;22: Abstract 14S.
49. Smith MR, Manola J, Kaufman DS, et al. Rosiglitazone versus placebo for men with prostate carcinoma and a rising serum prostate-specific antigen level after radical prostatectomy and/or radiation therapy. Cancer. 2004;101:1569-1574.
50. Lin AM, Rini BI, Weinberg V, et al. A phase II trial of imatinib mesylate in patients with biochemical relapse of prostate cancer after definitive local therapy. BJU Int. 2006;98:763-769.
51. Beer TM, Lemmon D, Lowe BA, Henner WD. High-dose weekly oral calcitriol in patients with a rising PSA after prostatectomy or radiation for prostate carcinoma. Cancer. 2003;97:1217-1224.
52. Abdel-Wahab M, Schwartz G, Howard G, et al. Calcifediol in recurrent prostate cancer-A phase II trial. Proc Am Soc Clin Oncol. 2003;22:1708.
53. Keizman D, Zahurak M, Sinibaldi V, et al. Lenalidomide in nonmetastatic biochemically relapsed prostate cancer: results of a phase I/II double-blinded, randomized study. Clin Cancer Res. 2010;16:5269-5276.
54. Liu G, Chen YH, Kolesar J, et al. Eastern Cooperative Oncology Group phase II trial of lapatinib in men with biochemically relapsed, androgen dependent prostate cancer. Urol Oncol. 2011. [epub ahead of print]
55. McNeel DG, Dunphy EJ, Davies JG, et al. Safety and immunological efficacy of a DNA vaccine encoding prostatic acid phosphatase in patients with stage D0 prostate cancer. J Clin Oncol. 2009;27:4047-4054.
56. Cheung E, Pinski J, Dorff T, et al. Oral fenretinide in biochemically recurrent prostate cancer: a California cancer consortium phase II trial. Clin Genitourin Cancer. 2009;7:43-50.
57. Beer TM, Bernstein GT, Corman JM, et al. Randomized trial of autologous cellular immunotherapy with sipuleucel-T in androgen-dependent prostate cancer. Clin Cancer Res. 2011;17:4558-4567.
58. Lin J, Zahurak M, Beer TM, et al. A non-comparative randomized phase II study of 2 doses of ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with biochemically recurrent hormone-naive prostate cancer. Urol Oncol. 2011. [epub ahead of print]