Trending Topic

Breast Cancer
29 mins

Trending Topic

Developed by Touch
Mark CompleteCompleted
BookmarkBookmarked

Endocrine therapy (ET) has changed the natural history of hormone receptor-positive (HR+) breast cancer (BC) and is the cornerstone of the treatment of HR+ BC. There are several ETs approved for the treatment of BC, including selective oestrogen receptor modulators (SERMs; tamoxifen), aromatase inhibitors (AIs; anastrazole, letrozole and exemestane) and selective oestrogen receptor degraders (SERDs; fulvestrant […]

Recent Developments in Androgen Deprivation Therapy for Locally Advanced Prostate Cancer

David A Bader, Jasmina Z Cerne, Sean E McGuire
Share
Facebook
X (formerly Twitter)
LinkedIn
Via Email
Mark CompleteCompleted
BookmarkBookmarked
Copy LinkLink Copied
Download as PDF
Published Online: Nov 21st 2014 Oncology & Hematology Review, 2014;10(2):133–8 DOI: https://doi.org/10.17925/OHR.2014.10.2.133
Select a Section…
1

Abstract

Overview

Locally advanced prostate cancer (LAPC) is often managed with a combination of external beam radiation therapy (EBRT) and androgen
deprivation therapy (ADT). Clinical protocols combining ADT and EBRT for the treatment of LAPC were developed based on clinical trials that
used conventional-dose EBRT (~70 Gy) and luteinizing hormone-releasing hormone (LHRH) analog monotherapy. However, dose-escalated
EBRT (>74 Gy) is in widespread clinical use and potent second-generation agents targeting the androgen axis have recently received US Food
and Drug Administration (FDA) approval. These and other recent developments challenge the current standard of care for LAPC. Determining
the optimal duration and potency of ADT in combination with dose-escalated EBRT in LAPC is an active area of clinical research seeking
to balance the side-effect profile of ADT with its well-established therapeutic benefits. Prospective randomized clinical trials incorporating
dose-escalated EBRT and second-generation androgen axis inhibitors are necessary to clarify the role of ADT in this new arena. Further, since
biochemical response to neoadjuvant ADT predicts for efficacy of EBRT, new trials should seek to achieve maximal androgen suppression prior
to EBRT to increase clinical benefit. Last, recent clinical and preclinical research efforts hold significant promise and seek to provide better
predictive markers and expand the therapeutic target spectrum in prostate cancer.

Keywords

Locally advanced prostate cancer (LAPC), androgen deprivation therapy (ADT), androgen receptor (AR), dose-escalation, external beam radiotherapy (EBRT), conformal radiotherapy (CRT), continuous and intermittent ADT (CAD, IAD), prostate specific antigen (P

2

Article

Prostate cancer is the most commonly diagnosed noncutaneous cancer and second leading cause of cancer mortality in American men. The lifetime risk for prostate cancer is estimated at one in six; 30,000 men die of the disease annually in the US.1 Prostate cancer is driven by the hormonally responsive transcription factor androgen receptor (AR) and the majority of prostate cancers are detected via serum level increase of the AR target gene prostate-specific antigen (PSA). Localized and low-risk prostate cancer is actively monitored or treated via radical prostatectomy (RP), brachytherapy, or external beam radiation therapy (EBRT).2,3 A small but significant percentage of prostate cancer is locally advanced or metastatic at the time of initial diagnosis. The management of locally advanced prostate cancer (LAPC) is challenging and most often includes the combination of ‘long-term’ (24–36 months) androgen deprivation therapy (ADT) and EBRT. ADT is typically initiated in the neoadjuvant setting, given concurrently with radiotherapy, and continued in the adjuvant setting. Recent studies investigating the duration of androgen deprivation and widespread clinical use of dose-escalated EBRT challenge the role of conventional ADT in LAPC. Further, the consistent finding that biochemical response to neoadjuvant ADT predicts efficacy of subsequent EBRT is supported by recent molecular findings and begs the question as to whether potent second-generation agents targeting the AR axis should be incorporated in the neoadjuvant setting for the treatment of LAPC. However, ADT carries a significant, additive side effect profile and recent efforts to minimize ADT exposure have utilized intermittent ADT and demonstrate that it may be as effective as continuous ADT while reducing ADT-associated side effects in some patients. This review will focus on recent clinical and molecular insights, which will guide management of LAPC in a rational, evidence-based manner. We conclude with a brief section highlighting recent preclinical developments in basic prostate cancer research and novel therapeutic approaches to the treatment of the disease, which may be integrated into future clinical protocols.

Definition of Locally Advanced Prostate Cancer
LAPC has breached the prostatic capsule or invaded the seminal vesicles but has not spread to regional lymph nodes or metastatic sites (T3-4, N0-X, M0). These tumors are often bulky and most risk classification schemes (National Comprehensive Cancer Network,3 Radiation Therapy Oncology Group,4 and D’Amico5) place patients diagnosed with LAPC at high risk for disease recurrence, necessitating the need for aggressive therapeutic approaches up front to maximize the likelihood of a durable response or cure. Since extracapsular extension of the tumor often (not always—see Bonney6 and Stephenson7 for review of RP trials) makes these patients poor surgical candidates, the standard of care at most centers for men diagnosed with LAPC is high-dose conformal EBRT (>74 Gy8) combined with ADT. For these patients, ADT is generally initiated 2–6 months prior to EBRT, given concurrently with EBRT, and continued in the adjuvant setting for a total of 2–3 years.

Origins of the Standard of Care for Locally Advanced Prostate Cancer
The standard of care for LAPC has been continuously refined with contributions from multiple randomized clinical trials over the last ~30 years. A comprehensive review of all major trials is outside the scope of this review. However, recent trials that have influenced the standard of care in locally advanced and high-risk prostate cancer while setting the stage for current and future trials include the European Organisation for Research and Treatment of Cancer (EORTC) 22863 trial,9 the Radiation Therapy Oncology Group (RTOG) 92-02 trial,10 the Trans-Tasman Radiation Oncology Group (TROG) 96.01 trial,11 the EORTC 22961 trial,12 and the TROG 03.04 trial13 (see Table 1). These will be briefly reviewed here.

  • EORTC 228639 enrolled 415 men with high grade or LAPC to determine the impact of ADT concurrent with and adjuvant to EBRT (70 Gy). The addition of 36 months of adjuvant ADT improved 10-year disease-free survival by 25 % (hazard ratio [HR] 0.42; p<0.0001), overall survival by 18.3 % (HR 0.6; p=0.0004), and prostate cancer-specific mortality by 20.1 % (HR 0.38; p<0.0001) compared with EBRT alone with no measurable differences in cardiovascular mortality.
  • RTOG 92-0210 compared EBRT (65–70 Gy) with 4 or 28 months of ADT in a two-arm trial with 1,554 men. Compared with 4-month ADT, the 28-month ADT arm had decreased local progression (22.2 % versus 12.3 %; p<0.0001), distant metastasis (22.8 % versus 14.8 %; p<0.0001), and biochemical failure (68.1 % versus 51.9 %; p<0.0001). While the 28-month ADT arm had increased disease-free survival (13.2 % versus 22.5 %; p<0.0001), both groups displayed equivalent overall survival (51.6 % versus 53.9 %; p=0.36). However, in a post-hoc analysis limited to high-grade tumors (Gleason score [GS] 8–10), a significant difference in overall survival was detected (31.9 % versus 45.1 %; p=0.0061), suggesting high-grade tumors should be treated with long-term (>24 month) ADT.
  • TROG 96.0111 enrolled 818 men with T2b-T4 tumors to investigate the use of 0, 3, or 6 months of neoadjuvant ADT (NeoADT) prior to EBRT (66 Gy). The addition of NeoADT to EBRT significantly improved all study endpoints with greatest gains in the 6-month NeoADT arm. Compared with EBRT alone, 6 months of NeoADT reduced PSA progression (adjusted HR [aHR] 0.57; p<0.0001) local progression (aHR 0.45; p=0.0001), distant progression (aHR 0.49; p=0.001), all-cause mortality (aHR 0.63; p=0.0008), and prostate cancer specific mortality (aHR 0.49; p=0.0008) while improving event-free survival (aHR 0.51; p≤0.0001).
  • EORTC 2296112 is a follow up to EORTC 22863 and compared EBRT (70 Gy) supplemented with short- (6 months) or long-term (36 months) ADT with the hypothesis that short-term ADT would increase quality of life by decreasing ADT side effects while achieving therapeutic performance similar to long-term ADT. However, short-term ADT proved inferior to long-term ADT in terms of overall survival at 5 years and the study found no significant difference in overall quality of life.
  • TROG 03.0413 randomized 1,071 men to 6- or 18-month ADT (5 months of which were neoadjuvant) with or without the bisphosphonate zoledronic acid. Five-year interim analysis revealed no difference between the four treatment arms in terms of prostate cancer specific mortality but posthoc analyses suggested reductions in PSA progression and decreased need for secondary therapeutic interventions (e.g. further androgen suppression) in the 18-month ADT plus zoledronic acid arm when the analysis was restricted to high-grade tumors (GS 8–10). No differences were detected in quality of life scores between groups.

On the basis of these and other trials,14–16 the current standard of care at most centers for men diagnosed with LAPC is EBRT coupled with neoadjuvant (2–6 months), concurrent, and adjuvant (2–3 years) ADT. Interestingly, multiple clinical studies,17–21 including our own,22,23 have demonstrated that biochemical response to neoadjuvant ADT, as measured by monitoring PSA just prior to radiation, independently predicts the survival benefit conferred by combination ADT + EBRT therapy. Several factors likely contribute to this observation. For example, when combined with EBRT, neoadjuvant ADT minimizes radiation to adjacent healthy tissues because it reduces prostate size.24 Further, neoadjuvant ADT decreases local recurrence because it inhibits repopulation of the irradiated target area,25 and improves long-term clinical outcomes because it is synergistic with EBRT.9,26 Several trials have likewise demonstrated a significant survival advantage is conferred by the use of ADT adjuvant to EBRT.10,12 However, the optimal duration of ADT in the adjuvant setting remains to be defined and likely varies based on tumor grade and patient characteristics. Regardless, treating physicians must balance the clinical benefits of ADT with its side effects. While long-term adjuvant ADT appears necessary to maximize clinical benefit, there is a growing appreciation that its use is associated with increased morbidity.27–31

Recent Developments and Future Directions for Clinical Management of Locally Advanced Prostate Cancer
Irrespective of the agents used to accomplish castration, ADT carries a significant side-effect profile, including sexual dysfunction, hypogonadism, anemia, sarcopenia, cognitive dysfunction, increased risk for cardiovascular events, and metabolic dysfunction.30,32,33 In an attempt to minimize these side effects, Nabid and colleagues compared EBRT combined with either 18 or 36 months of ADT. Six hundred and thirty men with high-grade (GS >7) T1c-T2a-b or T3-T4 tumors (N0-X, M0) were randomized to 18 or 36 months of ADT initiated 4 months prior to EBRT (70 Gy to the prostate; 44 Gy to pelvic lymph nodes).34 The 10-year overall survival was 63.2 % in the 18-month ADT arm and 63.6 % in the 36-month ADT arm (p=0.429). On the surface, these results seem to indicate ADT may be safely reduced from 36 to 18 months in patients diagnosed with LAPC. However, the study is yet to fully mature and several limitations must be considered when interpreting its results.35 First, (75.4 %) of patients in this study had localized (T1c-T2a-b) high-grade tumors (GS >7) and 24.6 % of patients had T3-T4.

This is in contrast to the reference study, EORTC 22863, where 89.6 % of tumors were T3-T4. Second, increased patient enrollment is required to generate the statistical power necessary to confidently conclude the two arms are equivalent in terms of overall survival. Therefore, while these results are suggestive that 18 months may be sufficient duration of ADT, the standard of care for locally advanced tumors (T3-T4) should remain 2–3 years of adjuvant ADT based on RTOG 92-02 and EORTC 22961 (discussed above).

While the optimal duration of adjuvant ADT in patients with LAPC may not be conclusively defined, three principles may be drawn from these trials: 1) ADT in combination with EBRT improves outcomes (all trials), 2) ADT prior to and concurrent with EBRT improves outcomes (RTOG 86-10, TROG 96.01), and 3) ADT concurrent and adjuvant to EBRT improves outcomes (EORTC 22863, EORTC 22961). However, the extrapolation of these principles into current practice is not clear-cut owing to widespread use of dose-escalated (>74 Gy) radiotherapy,8 recent approval of second-generation androgen axis inhibitors,36,37 and the observation that neoadjuvant biochemical response predicts therapeutic outcomes.21–23 To address these matters, the next generation of clinical trials must include ADT optimized to achieve maximal androgen suppression prior to the initiation of dose-escalated EBRT. For example, RTOG 1115 (NCT01546987) began enrolling patients in 2012 to compare ADT (GnRH agonist + flutamide or bicalutamide) with ADT + TAK-700 (a second-generation AR axis inhibitor targeting CYP17A1) in the context of dose-escalated EBRT. The goal of this study was to determine whether maximal androgen suppression in combination with dose-escalated EBRT would improve LAPC outcomes compared with conventional ADT alone. Unfortunately, TAK-700 development was voluntarily terminated in May 2014 following equivocal results in two phase III clinical trials (ELM-PC4 and ELM-PC5) in men with metastatic castrate-resistant prostate cancer. At present, the future of this trial is uncertain. Nonetheless, the design of RTOG 1115 represents the next generation of clinical trials for men with LAPC and recent molecular insights are beginning to explain why achieving maximal androgen suppression results in synergistic therapeutic effects when combined with EBRT.

Finally, several trials have recently investigated the use of intermittent androgen deprivation (IAD) strategies in men with LAPC with the goal of decreasing long-term ADT-related morbidity. While IAD is traditionally used in men with metastatic castrate resistant prostate cancer, Crook and colleagues recently reported that IAD is noninferior to continuous androgen deprivation (CAD) in terms of overall survival in a group of 1,386 patients treated with EBRT who had a serum PSA level >3 ng/ml more than 1 year after EBRT. These patients were randomized to CAD (696 patients, median survival 9.1 years) or IAD (690 patients, median survival 8.8 years).38 Notably, there were no reported differences in adverse events between groups though the IAD arm reported improvement in several quality of life factors (fatigue, hot flashes, libido, etc.) In addition to minimizing the side effects associated with CAD, it is hypothesized that IAD may also delay the emergence of castration resistance by decreasing selective pressure against hormonally responsive tumor clonal populations. Unfortunately, time to hormone resistance could not be determined due to inherent bias in the study design, although it was likely similar between groups.38 A recent meta-analysis of nine studies totaling 5,508 patients likewise failed to detect superiority of CAD over IAD in terms of clinical benefit, but did advocate use of IAD based on cost savings and decreased exposure to androgen deprivation in IAD cohorts, which resulted in decreased side effects.39 Because ADT is not often prescribed for >36 months in patients with LAPC, the direct applicability of these trials to patients diagnosed with LAPC is uncertain. However, IAD represents a potential mechanism to minimize ADT-related toxicities and future trials in this area may ultimately prove useful in the treatment of LAPC.

Molecular Basis for Synergy of Androgen Deprivation Therapy with External Beam Radiation Therapy
Although protocols combining radiation with androgen deprivation have been in clinical use for nearly 2 decades, the molecular mechanisms by which ADT improves radiosensitivity have remained elusive. Recent work by Polkinghorn and colleagues and Goodwin and colleagues has uncovered that activation of the AR axis increases expression of a network of DNA repair genes, including DNA-dependent protein kinase catalytic subunit (DNAPKcs—a critical component of the nonhomologous end joining machinery), enhancing radioresistance by promoting resolution of radiotherapy-induced double-stranded DNA (dsDNA) breaks.40,41 Polkinghorn et al. demonstrated that pretreatment with R1881, a synthetic androgen, increases expression of a variety of DNA repair genes and significantly reduces the number of γ-H2AX foci (an indicator of nonresolved dsDNA breaks) induced by ionizing radiation. Conversely, Goodwin et al. demonstrated that androgen deprivation significantly increases the number of γ-H2AX foci induced by radiation.

In terms of clinical management, despite achieving castrate levels of serum testosterone (<0.5 ng/ml), conventional ADT results in a decrease of intraprostatic androgens by only ~75 %.42,43 Residual adrenal androgens44 and de novo intratumoral androgen synthesis45 may enable a compensatory accumulation of intraprostatic androgens, initially allowing for tumor survival, but, ultimately, resulting in adaptation to castration and the emergence of castration resistant prostate cancer (CRPC) through reactivation of the AR axis as reflected by increasing PSA under castrate conditions.46,47 Therefore, failure to efficiently inhibit the AR axis through the use of neoadjuvant and concurrent ADT may result in decreased therapeutic response to EBRT because tumor cells with an active AR axis will be primed to repair radiation-induced dsDNA breaks. Consistent with this hypothesis, animal studies have demonstrated that RT is most effective when delivered after maximal tumor shrinkage in response to ADT, an effect that is almost completely lost if the tumor is allowed to re-grow in an androgen-independent manner following initial androgen ablation.48–50 Many clinical trials are in line with these animal studies, reporting a biochemical response to neoadjuvant ADT independently predicts the survival benefit conferred by ADT with subsequent EBRT.17–23 In addition, multivariate analysis in our trials22,23 revealed high-risk prostate cancer patients who achieved a pre-EBRT PSA of <0.5 ng/ ml (versus >0.5 ng/ml) after neoadjuvant ADT displayed longer time to distant metastatic spread and had improved failure-free, prostate cancer-specific, and overall survival at a median follow-up of 7 years.22,23 In sum, the clinical outcome of prostate cancer patients treated with ADT and EBRT may be closely linked to the efficacy of intratumoral androgen ablation and AR axis signaling suppression. In our experience, patients may be risk stratified as early as 3 months after initiation of ADT and those who fail to achieve a robust decrease in PSA are less likely to obtain the maximal therapeutic benefit that may be provided by the addition of EBRT. Encouragingly, both animal and clinical data support the molecular model that AR signaling supports resolution of DNA damage, highlighting an important new therapeutic angle in prostate cancer and also providing a rational explanation as to why prostate tumors treated with ADT often develop significant genomic instability.40 In sum, active AR signaling primes cells for DNA repair and conventional ADT does not effectively abrogate AR signaling prior to EBRT initiation. Therefore, the use of potent second-generation agents in the neoadjuvant setting is expected to increase ADT-EBRT synergy, resulting in improved long-term outcomes.

Prognostic Biomarkers, Noninvasive Imaging to Diagnose and Monitor Prostate Cancer, and New Treatment Approaches
The majority of patients diagnosed with prostate cancer will die with, rather than of, the disease. The Gleason histopathologic grading system is commonly used to determine whether a tumor is likely to be aggressive (GS >8) and to guide subsequent therapy.51 However, a reliable molecular test or biomarker panel to distinguish patients who may benefit from the addition of ADT to EBRT is lacking despite significant efforts. Analysis of tissue specimens collected in the phase III clinical trials RTOG 9202 and RTOG 8610 indicated p16, Ki-67, MDM2, Cox-2, and PKA may be useful for predicting whether a patient will benefit from long-term ADT.52 More broadly, the search for a reliable molecular test to differentiate indolent from lethal prostate cancer is an area of active study. Recently, Irshad et al. combined gene set enrichment analysis and a decision tree learning model to nominate a panel of three genes (FGFR1, PMP22, and CDKN1A) that accurately predicted the outcome of low GS tumors (GS <8) as validated by immunohistochemical staining of patient samples.53

Metabolic profiling reliably distinguishes benign prostate tissue from prostate cancer and may be useful for diagnosis and monitoring of prostate cancer, particularly given that certain metabolites can be detected using noninvasive magnetic resonance spectroscopic imaging54 rather than a needle biopsy. For example, using real-time in vivo imaging, Nelson and colleagues determined biopsy-confirmed regions of prostate cancer take up hyperpolarized pyruvate much more rapidly than adjacent benign tissue.55 Other compelling metabolic markers include spermine,56 citrate,57 sarcosine,58 and choline.59 In addition to diagnosis and monitoring, metabolic differences may be leveraged to enable specific therapeutic targeting of prostate cancer. Recent preclinical studies have demonstrated efficacy in targeting a broad range of metabolic targets or processes including AMPK,60,61 amino acid trafficking,62,63 and lipid metabolism.64,65 Other approaches include the use of immuneactivating monoclonal antibodies (e.g. ipilimumab)66 and the alpha emitter radium-223.67 Last, the use of mouse avatar modeling systems, in which a patient-derived prostate tumor xenograft is implanted into a cohort of immunocompromised mice, which are then treated using various regiments in an effort to guide patient therapy in real time, is beginning to emerge in so-called co-clinical trials.68,69

Future Clinical Directions for Combinatorial Androgen Deprivation Therapy with External Beam Radiation Therapy
ADT improves outcomes in patients diagnosed with LAPC treated with conventional dose EBRT. However, since most centers currently use doseescalation therapy, appropriately powered prospective clinical trials are needed to clarify the role and efficacy of ADT when used in combination with dose-escalated EBRT for the treatment of high-risk or LAPC. Several high-priority questions remain to be addressed. First, whether the addition of ADT to dose-escalated EBRT improves clinical outcomes in highrisk or LAPC and whether short-term (~12–18 months) adjuvant ADT is equivalent to long-term adjuvant ADT in this cohort. Second, whether the replacement of conventional ADT (luteinizing hormone-releasing hormone [LHRH] analog monotherapy) with next-generation maximal androgen blockade (combining LHRH analogs with second-generation androgen axis inhibitors) as a first-line therapy before, during, and after dose-escalated EBRT improves disease-free and overall survival in LAPC. Last, whether neoadjuvant (3–6 month) biochemical response to ADT prior to EBRT may be used to tailor subsequent ADT. For example, patients with a robust decrease in PSA may not require (or benefit from) long-term adjuvant ADT following EBRT, patients with a moderate decline in PSA may benefit from additional neoadjuvant and longer adjuvant ADT, and patients with a marginal decline in PSA may require the addition of second-generation AR axis inhibitors prior to and following EBRT to obtain maximal clinical benefit. Randomized clinical trials will provide valuable insight to guide therapy and allow physicians and patients to accurately weigh the significant side effect profile of ADT against its proven therapeutic benefits.

2

References

  1. Siegel R, Naishadham D, Jemal A, Cancer statistics, 2013,
    Cancer J Clin, 2013;63:11–30.

  2. Heidenreich A, Bellmunt J, Bolla M, et al., EAU guidelines on
    prostate cancer. Part 1: screening, diagnosis, and treatment of
    clinically localised disease, Eur Urol, 2011;59:61–71.

  3. Mohler JL, Kantoff PW, Armstrong AJ, et al., Prostate cancer,
    version 1.2014, J Natl Compr Canc Netw, 2013;11:1471–9.

  4. Noël G, Mazeron JJ, Predicting long-term survival, and the need
    for hormonal therapy: a meta-analysis of RTOG prostate cancer
    trials. Cancer Radiother, 2001;5:205.

  5. D’Amico AV, Whittington R, Malkowicz SB, et al., Biochemical
    outcome after radical prostatectomy, external beam radiation
    therapy, or interstitial radiation therapy for clinically localized
    prostate cancer, JAMA, 1998;280:969–74.

  6. Bonney WW, Schned AR, Timberlake DS, Neoadjuvant androgen
    ablation for localized prostatic cancer: pathology methods,
    surgical end points and meta-analysis of randomized trials,
    J Urol, 1998;160:1754–60.

  7. Stephenson AJ, Kattan MW, Eastham JA, et al., Prostate cancerspecific
    mortality after radical prostatectomy for patients
    treated in the prostate-specific antigen era, J Clin Oncol,
    2009;27:4300–5.

  8. Swisher-McClure S, Mitra N, Woo K, et al., Increasing use of
    dose-escalated external beam radiation therapy for men with
    nonmetastatic prostate cancer, Int J Radiat Oncol Biol Phys,
    2014;89:103–12.

  9. Bolla M, Van Tienhoven G, Warde P, et al., External irradiation
    with or without long-term androgen suppression for prostate
    cancer with high metastatic risk: 10-year results of an EORTC
    randomised study, Lancet Oncol, 2010;11:1066–73.

  10. Horwitz EM, Bae K, Hanks GE, et al., Ten-year follow-up of
    radiation therapy oncology group protocol 92-02: a phase III
    trial of the duration of elective androgen deprivation in locally
    advanced prostate cancer, J Clin Oncol, 2008;26:2497–504.

  11. Denham JW, Steigler A, Lamb DS, et al., Short-term neoadjuvant
    androgen deprivation and radiotherapy for locally advanced
    prostate cancer: 10-year data from the TROG 96.01 randomised
    trial, Lancet Oncol, 2011;12:451–9.

  12. Bolla M, de Reijke TM, Van Tienhoven G, et al., Duration of
    androgen suppression in the treatment of prostate cancer,
    N Engl J Med, 2009;360:2516–27.

  13. Denham JW, Joseph D, Lamb DS, et al., Short-term androgen
    suppression and radiotherapy versus intermediate-term
    androgen suppression and radiotherapy, with or without
    zoledronic acid, in men with locally advanced prostate cancer
    (TROG 03.04 RADAR): an open-label, randomised, phase 3
    factorial, Lancet Oncol, 2014;15:1076–89.

  14. Pilepich MV, Winter K, John MJ, et al., Phase III radiation therapy
    oncology group (RTOG) trial 86-10 of androgen deprivation
    adjuvant to definitive radiotherapy in locally advanced
    carcinoma of the prostate, Int J Radiat Oncol Biol Phys,
    2001;50:1243–52.

  15. Pilepich MV, Winter K, Lawton CA, et al., Androgen suppression
    adjuvant to definitive radiotherapy in prostate carcinoma—
    long-term results of phase III RTOG 85-31, Int J Radiat Oncol Biol
    Phys, 2005;61:1285–90.

  16. Jones CU, Hunt D, McGowan DG, et al., Radiotherapy and
    short-term androgen deprivation for localized prostate cancer,
    N Engl J Med, 2011;365:107–18.

  17. Alexander A, Crook J, Jones S, et al., Is biochemical response
    more important than duration of neoadjuvant hormone therapy
    before radiotherapy for clinically localized prostate cancer? An
    analysis of the 3- versus 8-month randomized trial, Int J Radiat
    Oncol Biol Phys, 2010;76:23–30.

  18. Zelefsky MJ, Lyass O, Fuks Z, et al., Predictors of improved
    outcome for patients with localized prostate cancer
    treated with neoadjuvant androgen ablation therapy and
    three-dimensional conformal radiotherapy, J Clin Oncol,
    1998;16:3380–5.

  19. Ludgate CM, Bishop DC, Pai H, et al., Neoadjuvant hormone
    therapy and external-beam radiation for localized high-risk
    prostate cancer: the importance of PSA nadir before radiation,
    Int J Radiat Oncol Biol Phys, 2005;62:1309–15.

  20. Mitchell DM, McAleese J, Park RM, et al., Failure to achieve
    a PSA level Zelefsky MJ, Gomez DR, Polkinghorn WR, et al., Biochemical
    response to androgen deprivation therapy before external
    beam radiation therapy predicts long-term prostate cancer
    survival outcomes, Int J Radiat Oncol Biol Phys, 2013;86:529–33.

  21. McGuire SE, Lee AK, Cerne JZ, et al., PSA response to
    neoadjuvant androgen deprivation therapy is a strong
    independent predictor of survival in high-risk prostate cancer in
    the dose-escalated radiation therapy era, Int J Radiat Oncol Biol
    Phys, 2013;85:e39–46.

  22. Cerne JZ, McGuire SE, Grant SR, et al., Factors associated with
    improved biochemical response to neoadjuvant androgen
    deprivation therapy before definitive radiation therapy in
    prostate cancer patients, Prostate Cancer Prostatic Dis,
    2013;16:346–51.

  23. Zelefsky MJ, Harrison A, Neoadjuvant androgen ablation prior
    to radiotherapy for prostate cancer: reducing the potential
    morbidity of therapy, Urology, 1997;49:38–45.

  24. Bolla M, Laramas M, Combined hormone therapy and radiation
    therapy for locally advanced prostate cancer, Crit Rev Oncol
    Hematol, 2012;84(Suppl. 1):e30–4.

  25. Widmark A, Klepp O, Solberg A, et al., Endocrine treatment, with
    or without radiotherapy, in locally advanced prostate cancer
    (SPCG-7/SFUO-3): an open randomised phase III trial, Lancet,
    2009;373:301–8.

  26. D’Amico AV, Denham JW, Crook J, et al., Influence of androgen
    suppression therapy for prostate cancer on the frequency
    and timing of fatal myocardial infarctions, J Clin Oncol,
    2007;25:2420–5.

  27. Keating NL, O’Malley AJ, Smith MR, Diabetes and cardiovascular
    disease during androgen deprivation therapy for prostate
    cancer, J Clin Oncol, 2006;24:4448–56.

  28. Smith JC, Bennett S, Evans LM, et al., The effects of induced
    hypogonadism on arterial stiffness, body composition, and
    metabolic parameters in males with prostate cancer, J Clin
    Endocrinol Metab, 2001;86:4261–7.

  29. Ahmadi H, Daneshmand S, Androgen deprivation therapy:
    evidence-based management of side effects, BJU Int,
    2013;111:543–8.

  30. Holzbeierlein JM, Castle E, Thrasher JB, Complications of
    androgen deprivation therapy: prevention and treatment,
    Oncology (Williston Park), 2004;18:303–9; discussion 310, 315,
    319–21.

  31. Freedland SJ, Eastham J, Shore N, Androgen deprivation
    therapy and estrogen deficiency induced adverse effects in the
    treatment of prostate cancer, Prostate Cancer Prostatic Dis,
    2009;12:333–8.

  32. Sharifi N, Gulley JL, Dahut WL, Androgen deprivation therapy for
    prostate cancer, JAMA, 2005;294:238–44.

  33. Nabid A, Carrier N, Martin A-G, et al., High risk prostate cancer
    treated with pelvic radiotherapy and 36 vs 18 month androgen
    blockade: results of a phase III randomized trial, Proc. ASCO
    Genitourin. Cancers Symp. 2013, Orlando, Florida, USA.

  34. Bolla M, Words of wisdom: Re: High-risk prostate cancer treated
    with pelvic radiotherapy and 36 versus 18 months of androgen
    blockade: results of a phase III randomized study [abstract 3],
    Eur Urol, 2013;64:513.

  35. Scher HI, Fizazi K, Saad F, et al., Increased survival with
    enzalutamide in prostate cancer after chemotherapy, N Engl J
    Med, 2012;367:1187–97.

  36. de Bono JS, Logothetis CJ, Molina A, et al., Abiraterone and
    increased survival in metastatic prostate cancer, N Engl J Med,
    2011;364:1995–2005.

  37. 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.

  38. Niraula S, Le LW, Tannock IF, Treatment of prostate cancer with intermittent versus

    continuous androgen deprivation:
    a systematic review of randomized trials, J Clin Oncol,
    2013;31:2029–36.

  39. Polkinghorn WR, Parker JS, Lee MX, et al., Androgen receptor
    signaling regulates DNA repair in prostate cancers, Cancer
    Discov, 2013;1245–53.

  40. Goodwin JF, Schiewer MJ, Dean JL, et al., A hormone-DNA repair
    circuit governs the response to genotoxic insult, Cancer Discov,
    2013;3:1254–71.

  41. Page ST, Lin DW, Mostaghel EA, et al., Persistent intraprostatic
    androgen concentrations after medical castration in healthy
    men, J Clin Endocrinol Metab, 2006;91:3850–6.

  42. Mostaghel EA, Page ST, Lin DW, et al., Intraprostatic
    androgens and androgen-regulated gene expression persist
    after testosterone suppression: therapeutic implications
    for castration-resistant prostate cancer, Cancer Res,
    2007;67:5033–41.

  43. Labrie F, Intracrinology, Mol Cell Endocrinol, 1991;78:C113–8.
  44. Dillard PR, Lin M-F, Khan SA, Androgen-independent prostate
    cancer cells acquire the complete steroidogenic potential of
    synthesizing testosterone from cholesterol, Mol Cell Endocrinol,
    2008;295:115–20.

  45. Mitsiades N, A road map to comprehensive androgen receptor
    axis targeting for castration-resistant prostate cancer, Cancer
    Res, 2013;73:4599–605.

  46. Chen Y, Clegg NJ, Scher HI, Anti-androgens and androgendepleting
    therapies in prostate cancer: new agents for an
    established target, Lancet Oncol, 2009;10:981–91.

  47. Zietman AL, Prince EA, Nakfoor BM, Park JJ, Androgen
    deprivation and radiation therapy: sequencing studies using
    the Shionogi in vivo tumor system, Int J Radiat Oncol Biol Phys,
    1997;38:1067–70.

  48. Joon DL, Hasegawa M, Sikes C, et al., Supraadditive apoptotic
    response of R3327-G rat prostate tumors to androgen ablation
    and radiation, Int J Radiat Oncol Biol Phys, 1997;38:1071–7.

  49. Kaminski JM, Hanlon AL, Joon DL, et al., Effect of sequencing
    of androgen deprivation and radiotherapy on prostate cancer
    growth, Int J Radiat Oncol Biol Phys, 2003;57:24–8.

  50. Epstein JI, Allsbrook WC, Amin MB, Egevad LL, The
    2005 International Society of Urological Pathology (ISUP)
    Consensus Conference on Gleason Grading of Prostatic
    Carcinoma, Am J Surg Pathol, 2005;29:1228–42.

  51. Roach M, Waldman F, Pollack A, Predictive models in external
    beam radiotherapy for clinically localized prostate cancer,
    Cancer, 2009;115:3112–20.

  52. Irshad S, Bansal M, Castillo-Martin M, et al., A molecular
    signature predictive of indolent prostate cancer, Sci Transl Med,
    2013;5:202ra122.

  53. Kurhanewicz J, Swanson MG, Nelson SJ, Vigneron DB, Combined
    magnetic resonance imaging and spectroscopic imaging
    approach to molecular imaging of prostate cancer, J Magn
    Reson Imaging, 2002;16:451–63.

  54. Nelson SJ, Kurhanewicz J, Vigneron DB, et al., Metabolic imaging
    of patients with prostate cancer using hyperpolarized [1-13C]
    pyruvate, Sci Transl Med, 2013;5:198ra108.

  55. Giskeødegård GF, Bertilsson H, Selnæs KM, et al., Spermine and
    citrate as metabolic biomarkers for assessing prostate cancer
    aggressiveness, PLoS One, 2013;8:e62375.

  56. Costello LC, Feng P, Milon B, et al., Role of zinc in the pathogenesis
    and treatment of prostate cancer: critical issues to resolve,
    Prostate Cancer Prostatic Dis, 2004;7:111–7.

  57. Sreekumar A, Poisson LM, Rajendiran TM, et al., Metabolomic
    profiles delineate potential role for sarcosine in prostate cancer
    progression, Nature, 2009;457:910–4.

  58. van Asten JJ, Cuijpers V, Hulsbergen-van de Kaa C, et al.,
    High resolution magic angle spinning NMR spectroscopy for
    metabolic assessment of cancer presence and Gleason score in
    human prostate needle biopsies, MAGMA, 2008;21:435–42.

  59. Zadra G, Photopoulos C, Tyekucheva S, et al., A novel direct
    activator of AMPK inhibits prostate cancer growth by blocking
    lipogenesis, EMBO Mo Med, 2014;6:519-38.

  60. Tennakoon JB, Shi Y, Han JJ, et al., Androgens regulate prostate
    cancer cell growth via an AMPK-PGC-1α-mediated metabolic
    switch, Oncogene, 2013;1–11.

  61. Wang Q, Tiffen J, Bailey CG, et al., Targeting amino acid transport
    in metastatic castration-resistant prostate cancer: effects on
    cell cycle, cell growth, and tumor development, J Natl Cancer
    Inst, 2013;105:1463–73.

  62. Putluri N, Shojaie A, Vasu VT, et al., Metabolomic profiling reveals
    a role for androgen in activating amino acid metabolism and
    methylation in prostate cancer cells, PLoS One, 2011;6:e21417.

  63. Chen H-W, Chang Y-F, Chuang H-Y., et al., Targeted therapy with
    fatty acid synthase inhibitors in a human prostate carcinoma
    LNCaP/tk-luc-bearing animal model, Prostate Cancer Prostatic
    Dis, 2012;15:260–4.

  64. Schlaepfer IR, Rider L, Rodrigues LU, et al., Lipid catabolism via
    CPT1 as a therapeutic target for prostate cancer, Mol Cancer
    Ther, 2014;13:2361–71.

  65. Kwon ED, Drake CG, Scher HI, et al., Ipilimumab versus placebo
    after radiotherapy in patients with metastatic castrationresistant
    prostate cancer that had progressed after docetaxel
    chemotherapy (CA184-043): a multicentre, randomised, doubleblind,
    phase 3 trial, Lancet Oncol, 2014;15:700–12.

  66. Parker C, Nilsson S, Heinrich D, Alpha emitter radium-223
    and survival in metastatic prostate cancer, N Engl J Med,
    2013;369:213–23.

  67. Malaney P, Nicosia SV, Davé V, One mouse, one patient
    paradigm: New avatars of personalized cancer therapy,
    Cancer Lett, 344, 2014;1–12.

  68. Lunardi A, Ala U, Epping MT, et al., A co-clinical approach identifies
    mechanisms and potential therapies for androgen deprivation
    resistance in prostate cancer, Nat Genet, 2013;45:747–55.
3

Article Information

Disclosure

David A Bader, BS, Jasmina Z Cerne, PhD, and Sean E McGuire, MD, PhD, have no conflicts of interest to declare. No funding was received in the publication of
this article.

Correspondence

Sean E McGuire, MD, PhD, Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, US. E: semcguir@mdanderson.org

Received

2014-09-10T00:00:00

4

Further Resources

Share
Facebook
X (formerly Twitter)
LinkedIn
Via Email
Mark CompleteCompleted
BookmarkBookmarked
Copy LinkLink Copied
Download as PDF

This Functionality is for
Members Only

Explore the latest in medical education and stay current in your field. Create a free account to track your learning.

Close Popup