Management of Biochemically Recurrent
Prostate Cancer After Local Therapy:
Evolving Standards of Care and New Directions
Channing J. Paller, MD, and Emmanuel S. Antonarakis, MD
Drs. Pal er and Antonarakis are Assistant Abstract: Among men treated with prostatectomy or radiation
Professors of Oncology at the Sidney therapy for localized prostate cancer, the state of an increasing pros- Kimmel Comprehensive Cancer Center at tate-specific antigen (PSA) level is known as biochemical recurrence Johns Hopkins, in Baltimore, Maryland. (BCR). BCR can be predictive of the development of subsequent distant metastases and ultimately death, but BCR often predates other signs of clinical progression by several years. Although patients Address correspondence to: may be concerned about their rising PSA levels, physicians attempt- Emmanuel S. Antonarakis, MD ing to address patient anxiety must inform them that BCR is not Assistant Professor of OncologyProstate Cancer Research Program typical y associated with imminent death from disease, and that the Sidney Kimmel Comprehensive Cancer natural history of biochemical progression may be prolonged. Misin- Center at Johns Hopkins terpretation of the significance of early changes in PSA may cause 1650 Orleans Street, CRB1-1M45 patients to receive androgen deprivation therapy (ADT) prematurely, Baltimore, MD 21231 especial y in settings where the disease is unlikely to impact survival. Phone: 443-287-0553 In addition, knowledge of the morbidities associated with ADT (hot Fax: 410-614-8397E-mail: eantona1@jhmi.edu flashes, impotence, sarcopenia, metabolic syndrome, bone loss, and increased risk of vascular disease) has accelerated the search for alternative treatment options for these patients. Clinical trials inves-tigating when and how to best use and supplement hormonal thera-pies in this patient population are under way, as are trials of novel nonhormonal targeted agents, immunotherapies, natural products, and other pharmaceuticals that have been approved by the US Food and Drug Administration (FDA) for other indications. This review will summarize the acceptable standards of care for the management of biochemical y recurrent prostate cancer, and wil also outline some novel experimental approaches for the treatment of this disease state. 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 deci- Prostate cancer, biochemical recurrence, PSA sions in attempting to delay the onset of metastatic disease and death while avoiding over-treating patients whose disease may Clinical metastases: castrate
Rising PSA:
Figure 1. Proportional prostate cancer clinical states model. The circles represent the proportional prevalence of each disease
state. Adapted from the prostate cancer clinical states model43 and the prostate cancer clinical states prevalence model.44 mCRPC=metastatic castration-resistant prostate cancer; PSA=prostate-specific antigen.
never affect their overall survival or quality of life. In experience clinical symptoms from their metastatic disease. this generally healthy population, effective management Thus, the value of early ADT is unknown in this popula- requires that physicians evaluate PSA levels, as well as tion, and research is needed to determine the optimal ini- clinical and radiologic indicators, in order to balance the tiation point of ADT (early vs deferred and continuous vs morbidity and efficacy of proposed treatments against intermittent) before physicians and patients can act with the risks of metastatic progression. confidence. Similar questions about optimal treatment and Radical prostatectomy (RP), which is used in approxi- best timing of treatment arise with other stratification fac- mately 75,000 newly diagnosed prostate cancer cases each tors, such as time-to-BCR, patient age and comorbidities, year (30% of those diagnosed),2 can cure appropriately- Gleason score, and pathologic stage. Therefore, multiple selected patients with localized disease, as can external- clinical factors must be taken into consideration when beam radiation therapy (RT) and brachytherapy, which planning the optimal course of treatment for a particular are used in approximately 60,000 newly diagnosed cases patient with PSA-recurrent prostate cancer.
(25% of those diagnosed).3 However, 20–40% of patients In recent years, the search for alternatives to chronic undergoing RP4,5 and 30–50% of patients undergoing RT ADT for BCR prostate cancer patients has intensified. will experience biochemical recurrence within 10 years.6 A wealth of clinical trials have focused on alternative (ie, There is currently no consensus regarding optimal manage- non-castrating) hormonal agents, timing of conventional ment of this disease state. Reasonable options include: 1) ADT, supplementing ADT with novel agents, or using salvage radiation therapy, if progression has occurred after hormone-sparing treatments in these patients (novel prostatectomy; 2) observation with close surveillance; 3) biologic agents, immunotherapies, natural products, and androgen deprivation therapy (ADT), either intermittent pharmaceuticals that have been approved by the FDA for or continuous, initiated upon PSA recurrence or deferred other diseases but have demonstrated preclinical activity until after clinical/radiographic progression; or 4) enroll- in hormone-sensitive prostate cancer). This review out- ment in investigational clinical trials.7 lines the results of some of the pivotal trials that guide our Not al patients with BCR prostate cancer have the practice, as well as relevant retrospective analyses describ- same prognosis, and stratification of patients into appro- ing the natural history of PSA-recurrent prostate cancer. priate risk groups is essential. One of the strongest pre- We will conclude by discussing the status of several ongo- dictors of metastasis and death is the PSA doubling time ing investigational trials focusing on treatment of patients (PSADT), a mathematical determination of the length of with BCR prostate cancer. time (in months) needed for the PSA level to double in a given patient. BCR patients with a PSADT greater than 9 Defining Biochemical Recurrence
months, for example, have a high probability of long-term, metastasis-free survival and overal survival.8 In addition, Precision in defining BCR is important in order to identify among patients with a slow PSADT, radiographic evidence patients at risk of disease progression, to determine the of metastatic disease is likely to be discovered before patients timing for additional treatment options (such as ADT), and to compare the efficacy of different treatments in the tumor stage (T-stage), and pathologic findings (includ- setting of clinical trials. Absent a common definition of ing Gleason score, surgical margin status, and lymph BCR, predictions of metastatic progression and mortality node status). All of these parameters are prognostic of would remain unreliable. Of note, the definition of PSA development of distant metastases and prostate-specific recurrence is dependent upon the type of local therapy mortality, with Gleason score providing the greatest received: prostatectomy or radiation therapy. To describe prognostic value with advanced T-stage and absolute biochemical recurrence after RP, a panel of experts from PSA value also contributing to accuracy of prognosis.15 the American Urological Association (AUA) evaluated Gleason score continues to have prognostic value fol- 53 different definitions of BCR fol owing RP observed lowing local therapy but it is joined by other factors, of in the literature, and recommended adoption of a single which PSADT is likely the most important prognostic definition. This involved the presence of a PSA greater than factor for metastasis-free survival and overall survival.8 0.2 ng/mL measured 6–13 weeks after RP, fol owed by a Time to biochemical recurrence has been shown to be a confirmatory test showing a persistent PSA greater than prognostic factor in some studies16,17 but not in others.8 0.2 ng/mL.9 Ultra-sensitive PSA assays have recently In a landmark study, Pound and associates found that improved detection levels down to 0.01 ng/mL, and may time to biochemical recurrence after RP was as effective possibly lead to better treatment outcomes through earlier as PSADT and Gleason score as a prognostic factor for adoption of salvage radiation therapy fol owing RP.10,11 metastasis.16 However, a recent multivariate analysis However, false positives occurring because of trace amounts using updated information from these same patients of PSA produced by residual benign prostatic tissue, along showed that time to biochemical recurrence does not with uncertainty about whether ultra-low levels of PSA will add measurably to the prognostic value of PSADT and be fol owed by continued PSA increases, have led practitio- Gleason score.8 Finally, changes in PSADT after initia- ners to continue to rely on the AUA definition for deter- tion of therapy in the setting of clinical trials has also mining when clinical y-relevant biochemical recurrence has been shown to be prognostic of metastasis-free survival occurred after prostatectomy.
in patients with BCR disease following local therapy.7 The definition of BCR following RT is more prob- PSA kinetics have long been known to be prognos- lematic. The AUA panel found 99 different definitions of tic for metastasis-free survival, prostate cancer–specific BCR following RT, among which the American Society of survival, and overall survival. However, the exact cut-off Therapeutic Radiology and Oncology (ASTRO) defini- points for defining high-risk disease have varied. In a tion was the most common. This was defined as the mid- study of 3,903 men who had undergone prostatectomy, point between PSA nadir and the first of 3 consecutive PSADT less than 12 months corresponded with signifi- rises in PSA.9 Although the AUA recommends that the cantly increased risk of clinical failure.18 Another study of ASTRO definition be adopted, it has several weaknesses, 8,669 patients with prostate cancer treated with surgery including failure to use the PSA level at nadir as a risk (5,918 patients) or radiation (2,751 patients) found that a factor and the requirement to backdate the time of bio- PSADT of less than 3 months was significantly associated chemical recurrence. An alternative definition of "nadir with prostate cancer–specific mortality.19 More recently, +2 ng/mL" (Phoenix definition) has shown improved a series of 3 PSADT cut-off points have been chosen in accuracy over ASTRO in predicting clinical failures.12-14 defining 4 risk groups (<3 months vs 3–9 months vs 9–15 However, the nadir-based definition results in substan- months vs >15 months).5,8 In addition, the number and tially lower estimates of BCR at 5 years, and substantially timing of PSA measurements needed to accurately esti- higher estimates of BCR at 10 years than the ASTRO mate PSADT has led to uncertainty about its reliability definition.6 Pending more information on development as a prognostic marker. In the authors' opinion, 3 PSA of distant metastases and prostate-specific mortality, the measurements obtained 3 months apart is considered a AUA continues to recommend the ASTRO definition of reliable foundation for calculation of PSADT.
BCR following RT.
Finally, a retrospective study of patients with rising PSA following local therapy who were enrolled in 4 clini- Prognostic Factors in PSA-Recurrent Prostate
cal trials of nonhormonal agents found that changes in PSADT after treatment initiation were prognostic for metastasis-free survival.7 Data on overall survival from Pre- and post-treatment prognostic factors allow physi- this cohort are not yet mature. These data suggest that cians to assign risk levels and use those risk groupings the onset of metastasis may be delayed if an experimental to help determine whether to start treatment imme- agent is capable of significantly lengthening the PSADT. diately or to defer it. Pretreatment factors that have If these preliminary findings are confirmed in prospective shown prognostic value include absolute baseline PSA, trials using metastasis-free survival as a primary endpoint, changes in PSADT could become a reasonable intermedi- 2 ng/mL, only if those patients also had PSADT less than ate endpoint of future studies in this patient population.7 6 months. No significant increase in prostate cancer–specific survival was seen in patients who were administered salvage Diagnostic Evaluation After PSA Recurrence
radiation more than 2 years after PSA recurrence. In addition, ADT did not significantly improve prostate-cancer specific No formal guidelines have been published defining the survival in this patient population.22 The greater impact of frequency of diagnostic evaluations for patients following salvage radiation on prostate-specific survival in patients with BCR who choose to undergo surveillance rather than ini- PSADT less than 6 months was supported by an analysis of a tiating early hormonal therapy. In the authors' opinion, subset of the Duke patients who had comorbidities at the time it is reasonable to monitor serum PSA every 3 months of PSA recurrence. Significant reduction in al -cause mortal- and to perform annual technetium-99 bone scans and bi- ity was associated with salvage radiation in both patients annual computed tomography (CT) scans in patients at with a PSADT less than 6 months (HR, 0.35; P=.042) and high risk of metastatic progression as determined by PSA a PSADT greater than 6 months (HR, 0.60; P=.04), but the levels (≥5 ng/mL) and/or a rapid PSADT of 9 months reduction in al -cause mortality was nearly 60% greater in the or less. In one retrospective study describing the natural patients with PSADT less than 6 months.21 history of untreated PSA-recurrent prostate cancer after Although another large retrospective trial has not prostatectomy, it was observed that men with a PSADT shown overall survival benefits from salvage radiation of 9 months or less had a median metastasis-free survival treatment after prostatectomy,23 the 2 studies described of 2 years after biochemical recurrence.8 Another analy- above provide adequate evidence that salvage radiation sis from this same population reported that the median therapy may positively alter the progression of the disease PSA value at the time of first radiographic metastasis was when administered within 2 years of BCR and while the 31.4 ng/mL (interquartile range, 8.8–87.5 ng/mL).20 absolute PSA remains below 2 ng/mL (although even These figures may help to determine whether a particular lower PSA values may further increase the chance of patient might be at a more imminent risk of metastasis, cure with salvage radiotherapy). The finding of improved allowing for more frequent PSA evaluations or imaging prostate cancer–specific survival in men with PSADT less tests to be obtained at the treating physician's discretion. than 6 months is provocative (and perhaps counterintui- tive), and should be confirmed by additional studies. Salvage Radiation for PSA-Recurrent Prostate
Hormonal Therapy For PSA-Recurrent Prostate
Three large retrospective studies provide evidence that early salvage radiation therapy, delivered to patients with rapid Selection of Hormonal Agents
PSADT, or while the PSA levels remain below 2.0 ng/mL, Androgen deprivation therapy, either through chemical impacts survival of prostate cancer patients with BCR. A castration or, far more rarely, through orchiectomy, is study at Duke University examined 519 patients who expe- one reasonable standard of care for BCR prostate cancer rienced BCR after prostatectomy, of which 219 patients after maximal local therapy.24 Gonadotrophin-releasing received salvage radiation therapy. That study stratified the hormone (GnRH) agonists, including leuprolide and patients by PSADT (<6 months vs ≥6 months). Salvage goserelin, have been the primary medical castration thera- radiation therapy significantly improved overal survival pies in the Western world. Recently, a GnRH antagonist, in both groups at a median fol ow-up of 11.3 years, with degarelix, has been gaining momentum in the first-line al -cause mortality hazard ratios (HR) for death of 0.53 and setting because clinical trial data suggest that it results in 0.52 for those with faster and slower PSADT, respectively.21 more rapid reduction of testosterone and marginally lon- A second study of 635 patients with PSA-recurrence ger PSA progression-free survival intervals than leupro- after prostatectomy at Johns Hopkins Hospital compared lide.25 In addition, patients on degarelix do not experience salvage radiation therapy (either alone or with ADT) clinical flare and therefore do not require a short course against observation.22 In that study, salvage radiation of androgen receptor antagonists (such as bicalutamide or was associated with a 3-fold increase in prostate-cancer nilutamide) that are often prescribed for patients initiat- specific survival after a median fol ow-up of 6 years after ing leuprolide or goserelin. One potential disadvantage of biochemical recurrence as compared with observation, but degarelix is the requirement for monthly administration, this improvement was limited to men with PSADT less since longer formulations of this compound do not exist than 6 months. Interestingly, salvage radiotherapy was still at the present time. However, both GnRH agonists and associated with significant improvement in prostate-specific antagonists remain reasonable options for initial hor- survival when administered to patients with PSA above monal treatment of patients with BCR prostate cancer.
Timing and Duration of ADT
that BCR patients with PSADT 15 months or greater Physicians wishing to treat BCR prostate cancer patients often enjoy prolonged progression-free survival.8 At with ADT face 2 key timing questions: 1) whether to the authors' institution, given the lack of a clear overall initiate ADT immediately upon PSA recurrence or to survival advantage with the use of immediate ADT, it is defer its use until after clinical/radiographic progression generally recommended to defer ADT in patients at low occurs, and 2) whether to use continuous administra- risk of metastatic progression (eg, PSADT >9 months; tion of ADT or intermittent cyclic administration of absolute PSA <10 ng/mL), while early initiation of ADT ADT. As of December 2012, the American Society of remains a reasonable choice for those at high risk of Clinical Oncology (ASCO) had not provided definitive developing metastatic disease (eg, PSADT <6 months; guidelines addressing either of these questions. We will absolute PSA >20 ng/mL).
review the relevant clinical trial data that may guide clinicians with respect to these 2 issues.
Continuous Versus Intermittent ADT
Once the decision to use ADT has been made, a second Immediate Versus Deferred ADT
controversial decision for BCR prostate cancer patients When BCR patients experience clinical/radiographic is whether to use intermittent or continuous adminis- metastatic disease, immediate initiation of ADT reduces tration of androgen deprivation. Intermittent androgen further metastatic progression, improves pain (if pres- deprivation (IAD) is a cyclic process in which induction ent), and reduces the development of skeletal-related treatment continues until maximal PSA response. ADT is events (eg, pathological fracture and spinal cord com- then temporarily withdrawn until serum PSA levels rise to pression). Immediate ADT in the metastatic setting a predetermined level, agreed upon by patient and physi- also reduces prostate cancer–specific mortality, but does cian (often between 4 and 10 ng/mL), at which point not necessarily improve overall survival (compared to ADT is reinitiated. IAD can allow testosterone levels to initiating ADT at the time of symptomatic progression) recover during each off-treatment cycle, lessening sexual because of increases in deaths from other causes.24,26 For dysfunction and loss of bone mass often associated with nonmetastatic BCR patients, timing of ADT is contro- continuous androgen deprivation.29 The lower cost and versial. Many men in the BCR setting choose to defer improved quality of life, combined with noninferiority of the initiation of hormonal therapy and prefer to allow IAD in overall survival, have led many patients to choose their physician to monitor their PSA kinetics, bones IAD for treatment of BCR prostate cancer.
scans, and CT scans on a regular basis. Two ongoing Two large phase III trials have attempted to deter- clinical trials are exploring the timing of ADT initia- mine whether IAD was noninferior to continuous tion after BCR following radiation, the Australian and androgen deprivation (CAD) in patients with recurrent New Zealand Timing of Androgen Deprivation trial prostate cancer. In an international trial involving 1,386 (TOAD; NCT00110162) and the Canadian Early men with BCR following radiation therapy (with or vs. Late Androgen Ablation Therapy trial (ELAAT; without prior prostatectomy), patients were random- ized into CAD or IAD arms. The IAD group received Until results of these studies are available, uncer- 8 months of hormonal therapy followed by treatment tainty about the overall survival benefits of immediate withdrawal until PSA reached 10 ng/mL or higher dur- ADT initiation, combined with serious adverse effects ing the off-treatment period. After a median follow-up and quality-of-life issues that may accompany ADT of 6.9 years, the endpoint of overall survival was shown treatment, has led many patients to defer ADT initiation to be noninferior for IAD compared to CAD (8.8 years and to opt instead for observation. Their choice to defer vs 9.1 years, HR, 1.02; 95% confidence interval [CI], ADT is supported by a recently published retrospective 0.86–1.21). Prostate cancer–related deaths were greater review of surgical patients in a single institution,8 and in the IAD group (122 vs 97 deaths), while non-prostate confirmed by a second study in an independent patient deaths were lower in the IAD group (134 vs 146 deaths). population.27 These studies reported median metastasis- In addition, men in the IAD arm reported reduced hot free survival intervals of 10 years among men with BCR flashes, although no other differences in adverse effects following prostatectomy, even in the absence of ADT were reported.29 Based on the results of this large and and salvage radiation. In addition, another retrospec- well-conducted study, the authors now view intermit- tive analysis of BCR prostate cancer patients found tent ADT as a very reasonable standard of care for the that PSADT rose approximately 4 months over 5 years, management of patients with BCR prostate cancer.
even without ADT or other therapies, in patients whose A second phase III trial studied 626 southern PSADT was greater than 15 months at the beginning European patients with locally advanced prostate can- of the period.28 These data support earlier findings cer (some had also developed metastatic disease) and Table 1. Selected Completed and Ongoing Clinical Trials for Patients With PSA-Recurrent Prostate Cancer After Local Therapy
Trials of ADT Plus Additional Experimental Agents
Sequencing of sipuleucel-T and ADT in men with non- metastatic biochemically-recurrent prostate cancerADT with or without bevacizumab for PSA-recurrent prostate Ongoing cancer after definitive local therapyOral thalidomide versus placebo in addition to ADT in Trend toward increased PSADT with III - NCT00004635 patients with stage D0 androgen-dependent prostate cancer thalidomide versus placebo45 Bicalutamide with or without MK-2206 (Akt inhibitor) in patients with previously treated prostate cancerBicalutamide and RO4929097 in patients with previously treated prostate cancerTremelimumab (CTLA4-blocking antibody) plus short-term Significant prolongation of PSADT was I - NCT00702923 bicalutamide in patients with stage D0 prostate cancer observed in 18% of patients46 Trials of Other Nonhormonal Pharmaceuticals
Celecoxib versus placebo in patients with BCR prostate cancer Despite significant improvements in PSA II - NCT00136487 velocity with celecoxib, study terminated early due to cardiovascular concerns47 Celecoxib in treating patients with relapsed prostate cancer Significant slowing in PSADT with following radiation therapy or radical prostatectomy celecoxib at 3, 6, and 12 months48 Rosiglitazone versus placebo for androgen-dependent recurrent No increase in PSADT or time-to- PSA-progression with rosiglitazone vs Disulfiram in patients with recurrent prostate cancer as evidenced by a rising PSAValproic acid in treating patients with progressive nonmeta- static prostate cancerAtorvastatin and celecoxib for patients with rising PSA levels after local therapy for prostate cancerImatinib in prostate cancer patients with rising PSA following Median PSA did not decrease radical prostatectomy significantly and trial was halted early due to toxicities50 Calcitriol in treating patients with a rising PSA level following Significant but smal increase in PSADT II - NCT00004043 local therapy for prostate cancer from baseline (7.8 to 10.3 months)51 Calcifediol for patients with PSA-recurrent prostate cancer 80% of patients had increases in Study of 2 different doses of lenalidomide in biochemically- Significant dose-dependent improve- I/II - NCT00348595 ment in PSA slope53 Hydroxychloroquine in treating patients with rising PSA levels Ongoing after local therapy for prostate cancerLapatinib for patients with PSA-recurrent prostate cancer No PSA responses but significant reduc- tion in mean PSA slope (log PSA/mo)54 Sulforaphane in treating patients with PSA-recurrent pros- tate cancerpTVG-HP (prostatic acid phosphatase DNA-plasmid vaccine) Significant but smal increase in PSADT I - NCT00582140 in patients with recurrent prostate cancer from baseline (6.5 to 8.5 months)55 Fenretinide in patients with BCR, hormone-naïve prostate Did not meet primary endpoint of Trials of Other Nonhormonal Pharmaceuticals
Sipuleucel-T versus placebo for the treatment of hormone- Sipuleucel-T patients had a 48% III - NCT00779402 sensitive PSA-recurrent prostate cancer increase in PSADT 57 Metformin with simvastatin for patients with BCR prostate carcinomaATN-224 (copper/zinc superoxide dismutase inhibitor) at Significant mean PSA slope decrease 2 dose levels in patients with PSA-recurrent prostate cancer (P=.006) and mean PSADT increase (P=.032) in the low-dose arm only 58 Trials of Nonhormonal Natural Products
Pomegranate juice in treating patients with PSA-recurrent pros- Significant increase in median tate cancer (single-arm study) PSADT from baseline (11.5–28.7 POMx capsules (pomegranate extract) in patients with PSA- Significant 6-month PSADT recurrent prostate cancer: 18-month dose-finding study improvement from baseline, no dose Pomegranate extract versus placebo in treating patients with rising PSA after surgery or radiation therapyTwo doses of MPX capsules (muscadine grape skin extract) on I/II - NCT01317199 rising PSA levels in patients following local therapy for pros- tate cancer (placebo-controlled trial)Acai juice in prostate cancer patients with rising PSA after local Ongoing therapy (single-arm study)Kanglaite (Chinese grass seed oil) gelcaps in PSA-recurrent I/II - NCT01483586 prostate cancer (dose-finding study)Brassica vegetable diet or indole-3-carbinol pills for patients with PSA recurrence after prostatectomy (2-arm study)Combination herbal therapy (vitamins D and E, selenium, green tea extract, saw palmetto, lycopene, soy derivatives) for PSA recurrence after local therapy (single-arm study) found no difference in overall survival between the ideal systemic approach. Benefits of early initiation of IAD and CAD arms, because the reduction in prostate continuous ADT or intermittent ADT are offset by cancer–specific deaths in the CAD arm was offset by a the risk of osteopenia and cardiovascular disease, in larger number of deaths from cardiovascular disease in addition to the bothersome and common side effects, the CAD arm. Patients in the IAD arm reported better including hot flashes and erectile dysfunction. Patients sexual function, although there was no significant dif- with slower PSADT, for whom ADT may not be imme- ference in reported quality of life between the treatment diately indicated, face years of anxiety and often seek arms.30 Thus, the benefit of avoiding prostate cancer– treatments that delay PSA progression and develop- related death using CAD is balanced by the benefit of ment of metastases. To this end, researchers are inves- avoiding death from other causes, such as cardiovascu- tigating 3 approaches to complement or replace those lar disease, using IAD. The risks and benefits must be described earlier in this review for the management of weighed in each patient, paying particular attention to BCR patients: 1) the use of novel agents or vaccination cardiovascular disease history and risk factors for meta- approaches to enhance and/or supplement ADT; 2) the bolic syndrome.
use of pharmaceutical agents or combinations of agents that may already be approved by the US FDA for treat- Experimental Approaches For PSA-Recurrent
ment of other diseases and have demonstrated preclini- cal activity against hormone-sensitive prostate cancer; and 3) the use of natural products that have shown The current treatment landscape for prostate cancer preclinical activity against hormone-sensitive prostate patients experiencing biochemical recurrence offers no cancer. Table 1 shows a selected list of completed or ongoing clinical trials investigating a number of such Selected Trials of Other Nonhormonal Agents
therapeutic strategies in patients with BCR, nonmeta- More than 20 clinical trials have been launched in static prostate cancer.
BCR patients, evaluating agents previously approved by the FDA for other diseases that may show benefit Selected Trials of ADT Plus Additional Experimental
in prostate cancer (Table 1). Although many of these trials have been completed, none have resulted in further The effectiveness of sipuleucel-T (Provenge, Dendreon), evaluation in phase III trials. Among the agents that the first immunotherapy approved for the treatment of have completed testing are celecoxib (Celebrex, Pfizer), metastatic castration-resistant prostate cancer, is being eval- rosiglitazone (Avandia, GlaxoSmithKline), imatinib uated in BCR patients who have not yet received hormonal (Gleevec, Novartis), vitamin D derivatives, lenalidomide therapy to determine whether administration at an earlier (Revlimid, Celgene), lapatinib (Tykerb, GlaxoSmith- disease state wil improve antitumor immune responses and Kline), fenretinide, ATN-224, and the pTVG-HP vac- clinical outcomes. It has been suggested that the effective- cine. One trial (using celecoxib) was halted early because ness of the vaccine may be enhanced by ADT-induced, of excessive cardiovascular toxicities. Other trials com- T-cel –mediated responses that target prostate cancer cel s.31 pleted their accrual but found little or no benefit from Preclinical research in animal models demonstrated ADT the experimental drug, with observed PSADT increases enhancement of immunotherapy efficacy,32,33 and human that were not much larger than the increases found in studies combining hormonal therapy with immunotherapy BCR patients who were managed with observation/ confirmed the additive effect.34 A randomized phase II trial placebo.28 Most of the trials were of insufficient duration is seeking to determine the optimal sequencing for ADT to measure accepted clinical outcomes, such as radio- and sipuleucel-T (NCT01431391) in men with PSA- logic evidence of metastases or survival. It should be recurrent prostate cancer. emphasized that PSADT changes alone do not provide Bevacizumab (Avastin, Genentech/Roche), an anti- sufficient justification for major investments in phase III angiogenesis monoclonal antibody approved in the United trials, especially in light of side effects and costs associ- States for multiple tumor types (but not prostate cancer), ated with many of the compounds being tested for this inhibits vascular endothelial growth factor (VEGF), a major relatively healthy population.
mediator to angiogenesis. ADT induces an 80% reduction in VEGF content in hormone-sensitive prostate cancer Selected Trials of Natural Products
cel s.35 In LNCaP xenograft studies, VEGF inhibition com- A large proportion of patients with BCR prostate cancer bined with ADT demonstrates an increase in tumor necrosis, who are concerned about their rising PSA but also want when compared with either ADT alone or VEGF inhibition to avoid the side effects of ADT and other pharmaceuti- alone.36 A randomized phase II trial is evaluating the effect cals are actively self-medicating with natural products in on time-to-PSA-progression when adding bevacizumab to an attempt to lower their PSA. However, there is little 6 months of ADT in BCR patients (NCT00776594). In documented evidence that these products are effective this trial, al patients receive a short course of ADT, and and they may not be safe in the quantities or formulations two-thirds also receive 8 doses of intravenous bevacizumab, being sold, despite having been consumed for decades by administered 3 weeks apart.
thousands of people in their natural plant forms. Reciprocal negative feedback between the androgen A series of clinical trials seeking to evaluate the safety and receptor and PI3-kinase/Akt/mTOR pathways enables efficacy of natural products, including pomegranate juice and combined pathway inhibition that results in profound extract, muscadine grape skin extract, Chinese grass seed oil, apoptosis in preclinical prostate cancer models.37 In acai berry, and brassica vegetables (eg, broccoli), are now under this model, inhibition of the PI3-kinase pathway alone way. Preclinical rationale supporting these studies focuses induces overactivation of the androgen receptor pathway, on inhibition of nuclear factor-κB and Akt (pomegranate while inhibition of the androgen receptor alone promotes products,38 muscadine grape skin extract,39 acai berry,40 and overactivation of the PI3-kinase/Akt/mTOR pathway. brassica vegetables41). To date, 2 pomegranate trials have been Following from this preclinical work, a translational ran- published and both demonstrated significant improvement domized phase II study is combining MK-2206 (an Akt in PSADT.38,42 However, these trials are difficult to interpret inhibitor) with the anti-androgen bicalutamide in patients in the absence of a placebo comparator group. To this end, with BCR prostate cancer (NCT01251861). During placebo-control ed trials are now under way for pomegranate the first 12 weeks of the study, patients are randomized (NCT00336934), brassica vegetables (NCT00607932), and to receive either MK-2206 or to undergo observation. muscadine grape skin extract (NCT01317199) in order to Thereafter, bicalutamide is added to both study arms and compare changes in PSA kinetics between the active treat- continued until evidence of PSA progression.
ment arm and the placebo arm.
a short course of more complete/maximal androgen sig- naling inhibition (androgen annihilation) may be able to Although the treatment landscape for patients with BCR eradicate micrometastatic disease in this setting. Trials are prostate cancer remains chal enging, new research is help- currently being designed to test this intriguing hypothesis.
ing to identify  patient  populations  suitable for  specific therapies. Clinical trials of pharmaceutical agents, vaccines, and natural products, as wel as new approaches to tim- ing and combining hormonal treatments, are currently 1. American Cancer Society. Cancer Facts & Figures 2012. Atlanta: American ongoing. In addition, several trials are now stratifying their Cancer Society; 2012.
2. Burkhardt JH, Litwin MS, Rose CM, et al. Comparing the costs of radiation patient populations into different risk categories based on therapy and radical prostatectomy for the initial treatment of early-stage prostate the natural history of their disease as wel as their age and cancer. J Clin Oncol. 2002;20:2869-2875.
comorbidities. As more stratified evidence emerges, physi- 3. Shipley WU, Thames HD, Sandler HM, et al. Radiation therapy for clinical y local-ized prostate cancer: a multi-institutional pooled analysis. JAMA. 1999;281:1598-1604.
cians and their patients may look forward to a time when 4. Roehl KA, Han M, Ramos CG, Antenor JA, Catalona WJ. Cancer progression they can choose treatment strategies that delay the onset of and survival rates following anatomical radical retropubic prostatectomy in 3,478 metastatic lesions while avoiding or minimizing the costs consecutive patients: long-term results. J Urol. 2004;172:910-914.
5. Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer- and side effects associated with ADT. specific mortality following biochemical recurrence after radical prostatectomy. The ultimate goal in treating patients with BCR pros- tate cancer is to identify a safe and effective nonhormonal 6. Kupelian PA, Mahadevan A, Reddy CA, Reuther AM, Klein EA. Use of different definitions of biochemical failure after external beam radiotherapy changes conclusions therapy that is able to delay metastasis and death without about relative treatment efficacy for localized prostate cancer. Urology. 2006;68:593-598.
the need for pharmacologic castration. An alternative 7. Antonarakis ES, Zahurak ML, Lin J, Keizman D, Carducci MA, Eisenberger attractive strategy would be one in which a limited course MA. Changes in PSA kinetics predict metastasis-free survival in men with PSA-recurrent prostate cancer treated with nonhormonal agents: combined analysis of of androgen deprivation (eg, 6 or 12 months) is given 4 phase II trials. Cancer. 2012;118:1533-1542.
together with an additional hormonal or nonhormonal 8. Antonarakis ES, Feng Z, Trock BJ, et al. The natural history of metastatic pro- agent in an attempt to eradicate micrometastatic disease gression in men with prostate-specific antigen recurrence after radical prostatec-tomy: long-term follow-up. BJU Int. 2012;109:32-39.
before the development of clinical/radiographic metastases. 9. Cookson MS, Aus G, Burnett AL, et al. Variation in the definition of biochemi- However, designing these types of clinical trials is chal eng- cal recurrence in patients treated for localized prostate cancer: the American Uro- ing. For example, if investigating a nonhormonal agent for logical Association Prostate Guidelines for Localized Prostate Cancer Update Panel report and recommendations for a standard in the reporting of surgical outcomes. patients with BCR prostate cancer, the time to first metas- J Urol. 2007;177:540-545.
tasis and time to death are very prolonged, even if selecting 10. Terai A, Matsui Y, Yoshimura K, Arai Y, Dodo Y. Salvage radiotherapy for only high-risk patients (those with PSADT <6 months). In biochemical recurrence after radical prostatectomy. BJU Int. 2005;96:1009-1013.
11. Kinoshita H, Kamoto T, Nishiyama H, Nakamura E, Matsuda T, Ogawa O. addition, time to metastasis wil be affected by subsequent Prostate specific antigen nadir determined using ultra-sensitive prostate specific treatments (including hormonal treatments) that patients antigen as a predictor of biochemical progression after radical prostatectomy in may opt to receive if they come off study due to further Japanese males. Int J Urol. 2007;14:930-934.
12. Kestin LL, Vicini FA, Martinez AA. Practical application of biochemical rises in their PSA. Final y, metastasis-free survival has not failure definitions: what to do and when to do it. Int J Radiat Oncol Biol Phys. been shown to be associated with overal survival in patients with PSA-recurrent prostate cancer, so it is unclear whether 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 it could be used as a surrogate endpoint without adequate beam radiation alone: a multi-institutional pooled analysis. J Urol. 2005;173:797-802.
fol ow-up for overal survival. Even more questionable is the 14. Kuban DA, Levy L, Potters L, et al. Comparison of biochemical failure definitions significance of treatment-induced changes in PSA kinetics 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- as they relate to metastasis-free survival and overal survival.
Gleason disease predictive of favourable pathological and clinical outcomes at Rather than focusing on noncastrating approaches, radical prostatectomy. BJU Int. 2012;110:1122-1128.
an alternative strategy would be to investigate the efficacy 16. Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. of short-course androgen suppression combined with other nonhormonal (eg, immunotherapies, antiangio- 17. Buyyounouski MK, Hanlon AL, Horwitz EM, Pollack A. Interval to biochem- genics) or novel hormonal agents. A potential relevant ical failure highly prognostic for distant metastasis and prostate cancer-specific mortality after radiotherapy. Int J Radiat Oncol Biol Phys. 2008;70:59-66.
endpoint in this setting could be the achievement of an 18. Ward JF, Blute ML, Slezak J, Bergstralh EJ, Zincke H. The long-term clinical undetectable PSA after a finite course of ADT and after impact of biochemical recurrence of prostate cancer 5 or more years after radical testosterone levels have recovered to the noncastrate prostatectomy. J Urol. 2003;170:1872-1876.
19. D'Amico AV, Moul JW, Carroll PR, Sun L, Lubeck D, Chen MH. Surrogate range. An undetectable PSA after testosterone recovery end point for prostate cancer-specific mortality after radical prostatectomy or in this setting could be interpreted as a "cure" for these radiation therapy. J Natl Cancer Inst. 2003;95:1376-1383.
patients, although the significance of this has not been 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 metas- tested or validated. With an ever increasing range of novel tasis in men with biochemical recurrence after prostatectomy. J Clin Oncol (ASCO hormonal agents, the question has emerged as to whether Annual Meeting Abstracts). 2011;29: Abstract 16.
21. Cotter SE, Chen MH, Moul JW, et al. Salvage radiation in men after prostate- 40. Poulose SM, Fisher DR, Larson J, et al. Anthocyanin-rich acai (Euterpe olera- specific antigen failure and the risk of death. Cancer. 2011;117:3925-3932.
cea Mart.) fruit pulp fractions attenuate inflammatory stress signaling in mouse 22. Trock BJ, Han M, Freedland SJ, et al. Prostate cancer-specific survival follow- brain BV-2 microglial cells. J Agric Food Chem. 2012;60:1084-1093.
ing salvage radiotherapy vs observation in men with biochemical recurrence after 41. Aggarwal BB, Ichikawa H. Molecular targets and anticancer potential of radical prostatectomy. JAMA. 2008;299:2760-2769.
indole-3-carbinol and its derivatives. Cell Cycle. 2005;4:1201-1215.
23. Boorjian SA, Karnes RJ, Crispen PL, Rangel LJ, Bergstralh EJ, Blute ML. 42. Pal er C, Ye X, Wozniak P, et al. A randomized phase II study of pomegran- Radiation therapy after radical prostatectomy: impact on metastasis and survival. ate extract for men with rising prostate-specific antigen fol owing initial therapy for J Urol. 2009;182:2708-2714.
localized prostate cancer. Prostate Cancer Prostic Dis. 2012. [Epub ahead of print] 24. Loblaw DA, Virgo KS, Nam R, et al. Initial hormonal management of androgen- 43. Scher HI, Morris MJ, Basch E, Heller G. End points and outcomes in castra- sensitive metastatic, recurrent, or progressive prostate cancer: 2006 update of an Ameri- tion-resistant prostate cancer: from clinical trials to clinical practice. J Clin Oncol. can Society of Clinical Oncology practice guideline. J Clin Oncol. 2007;25:1596-1605.
25. Crawford ED, Tombal B, Mil er K, et al. A phase III extension trial with a 1-arm 44. Solo K, Mehra M, Dhawan R, Valant J, Scher H. Prevalence of prostate cancer crossover from leuprolide to degarelix: comparison of gonadotropin-releasing hormone (PC) clinical states (CS) in the United States: estimates using a dynamic progression agonist and antagonist effect on prostate cancer. J Urol. 2011;186:889-897.
model. J Clin Oncol (ASCO Annual Meeting Abstracts). 2009;27: Abstract 4637.
26. Immediate versus deferred treatment for advanced prostate cancer: initial 45. Figg WD, Hussain MH, Gul ey JL, et al. A double-blind randomized crossover study results of the Medical Research Council Trial: the Medical Research Council pros- of oral thalidomide versus placebo for androgen dependent prostate cancer treated with tate cancer working party investigators. Br J Urol. 1997;79:235.
intermittent androgen ablation. J Urol. 2009;181:1104-1113.
27. Antonarakis ES, Chen Y, Elsamanoudi SI, et al. Long-term overall survival and 46. McNeel DG, Smith HA, Eickhoff JC, et al. Phase I trial of tremelimumab metastasis-free survival for men with prostate-specific antigen-recurrent prostate in combination with short-term androgen deprivation in patients with PSA- cancer after prostatectomy: analysis of the Center for Prostate Disease Research recurrent prostate cancer. Cancer Immunol Immunother. 2012;61:1137-1147.
National Database. BJU Int. 2011;108:378-385.
47. Smith MR, Manola J, Kaufman DS, Oh WK, Bubley GJ, Kantoff PW. Cele- 28. Pal er C, Xie S, Olatoye D, et al. The effect of PSA frequency and duration on PSA coxib versus placebo for men with prostate cancer and a rising serum prostate- doubling time (PSADT) calculations in men with biochemical y recurrent prostate specific antigen after radical prostatectomy and/or radiation therapy. J Clin Oncol. cancer after definitive local therapy. J Clin Oncol (ASCO Annual Meeting Abstracts). 2012; 30: Abstract 99246.
48. Pruthi R, Derksen E. A phase II trial of celecoxib in PSA recurrent prostate 29. Crook JM, O'Cal aghan CJ, Duncan G, et al. Intermittent androgen suppression cancer after definitive radiation therapy or radical prostatectomy. J Clin Oncol for rising PSA level after radiotherapy. N Engl J Med. 2012;367:895-903. (ASCO Annual Meeting Abstracts). 2004;22: Abstract 14S.
30. Calais da Silva FE, Bono AV, Whelan P, et al. Intermittent androgen deprivation 49. Smith MR, Manola J, Kaufman DS, et al. Rosiglitazone versus placebo for men for local y advanced and metastatic prostate cancer: results from a randomised phase with prostate carcinoma and a rising serum prostate-specific antigen level after 3 study of the South European Uroncological Group. Eur Urol. 2009;55:1269-1277.
radical prostatectomy and/or radiation therapy. Cancer. 2004;101:1569-1574.
31. Mercader M, Bodner BK, Moser MT, et al. T cell infiltration of the prostate 50. Lin AM, Rini BI, Weinberg V, et al. A phase II trial of imatinib mesylate in induced by androgen withdrawal in patients with prostate cancer. Proc Natl Acad patients with biochemical relapse of prostate cancer after definitive local therapy. Sci U S A. 2001;98:14565-14570.
BJU Int. 2006;98:763-769.
32. Koh YT, Gray A, Higgins SA, Hubby B, Kast WM. Androgen ablation aug- 51. Beer TM, Lemmon D, Lowe BA, Henner WD. High-dose weekly oral cal- ments prostate cancer vaccine immunogenicity only when applied after immuniza- citriol in patients with a rising PSA after prostatectomy or radiation for prostate tion. Prostate. 2009;69:571-584.
carcinoma. Cancer. 2003;97:1217-1224.
33. Drake CG, Doody AD, Mihalyo MA, et al. Androgen ablation mitigates tolerance 52. Abdel-Wahab M, Schwartz G, Howard G, et al. Calcifediol in recurrent pros- to a prostate/prostate cancer-restricted antigen. Cancer Cel . 2005;7:239-249.
tate cancer-A phase II trial. Proc Am Soc Clin Oncol. 2003;22:1708.
34. Madan RA, Gulley JL, Schlom J, et al. Analysis of overall survival in patients 53. Keizman D, Zahurak M, Sinibaldi V, et al. Lenalidomide in nonmetastatic with nonmetastatic castration-resistant prostate cancer treated with vaccine, nilu- biochemically relapsed prostate cancer: results of a phase I/II double-blinded, tamide, and combination therapy. Clin Cancer Res. 2008;14:4526-4531.
randomized study. Clin Cancer Res. 2010;16:5269-5276.
35. Stewart RJ, Panigrahy D, Flynn E, Folkman J. Vascular endothelial growth factor 54. Liu G, Chen YH, Kolesar J, et al. Eastern Cooperative Oncology Group phase expression and tumor angiogenesis are regulated by androgens in hormone respon- II trial of lapatinib in men with biochemically relapsed, androgen dependent pros- sive human prostate carcinoma: evidence for androgen dependent destabilization of tate cancer. Urol Oncol. 2011. [epub ahead of print] vascular endothelial growth factor transcripts. J Urol. 2001;165:688-693.
55. McNeel DG, Dunphy EJ, Davies JG, et al. Safety and immunological efficacy 36. Nicholson B, Gulding K, Conaway M, Wedge SR, Theodorescu D. Com- of a DNA vaccine encoding prostatic acid phosphatase in patients with stage D0 bination antiangiogenic and androgen deprivation therapy for prostate cancer: a prostate cancer. J Clin Oncol. 2009;27:4047-4054.
promising therapeutic approach. Clin Cancer Res. 2004;10:8728-8734.
56. Cheung E, Pinski J, Dorff T, et al. Oral fenretinide in biochemically recur- 37. Carver BS, Chapinski C, Wongvipat J, et al. Reciprocal feedback regulation of rent prostate cancer: a California cancer consortium phase II trial. Clin Genitourin PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer 57. Beer TM, Bernstein GT, Corman JM, et al. Randomized trial of autologous 38. Pantuck AJ, Leppert JT, Zomorodian N, et al. Phase II study of pomegranate cellular immunotherapy with sipuleucel-T in androgen-dependent prostate cancer. juice for men with rising prostate-specific antigen following surgery or radiation Clin Cancer Res. 2011;17:4558-4567.
for prostate cancer. Clin Cancer Res. 2006;12:4018-4026.
58. Lin J, Zahurak M, Beer TM, et al. A non-comparative randomized phase II study 39. Hudson TS, Hartle DK, Hursting SD, et al. Inhibition of prostate cancer of 2 doses of ATN-224, a copper/zinc superoxide dismutase inhibitor, in patients with growth by muscadine grape skin extract and resveratrol through distinct mecha- biochemical y recurrent hormone-naive prostate cancer. Urol Oncol. 2011. [epub nisms. Cancer Res. 2007;67:8396-8405.

Source: http://www.hematologyandoncology.net/files/2013/05/ho0113_antonarakis1.pdf


Revista de GeoGRafía espacios Vol. 3, No6: 63-97, 2013 La memoria emplazada: proceso de memorialización y lugaridad en post-dictaduraTHE PLACED MEMORY: THE PROCESS OF MEMORIALIZATION AND PLACE IN POST- DICTATORSHIP. Gabriela Raposo QuintanaFacultad de Arquitectura y Urbanismo, Universidad de ChileE-mail: gabi.gabiraposo@gmail.com ResumenEste texto expone y discute temáticas y conceptos útiles a la comprensión del proceso de me-morialización en Chile, tanto aquel impulsado desde el Estado como aquellos que nacen desde su oposición. Paralelamente se realiza una bajada práctica a partir de la exposición de un caso de estudio –Villa Francia– haciéndolo dialogar con los principales tópicos que hoy en día se trabajan desde los estudios de las memorias post-dictadura. Uno de los aspectos centrales que se aborda es la relación entre espacialidad y memoria, como resultado de las expresiones materiales y sim-bólicas que ha conllevado el proceso de memorialización. Ejemplificado en Villa Francia, se expone como se da esta relación en una comunidad que disiente de los contenidos y expresiones de la memoria oficial. Para la incorporación del caso se ha recurrido a información obtenida a partir de entrevistas en profundidad, observación de campo y recopilación de imágenes fotográficas1.Palabras Clave: Memorialización, dictadura militar, geografía cultural, lugaridad, Villa Francia


RIASSUNTO DELLE CARATTERISTICHE DEL PRODOTTO 1. DENOMINAZIONE DEL MEDICINALE "nome del medicinale" 150 mg compresse / capsule rigide "nome del medicinale" 300 mg compresse 2. COMPOSIZIONE QUALITATIVA E QUANTITATIVA Una compressa / capsula contiene: principio attivo: litio carbonato 150 / 300 mg Per l'elenco completo degli eccipienti, vedere 6.1. 3. FORMA FARMACEUTICA Compresse / Capsule rigide