Intermittent Hormonal Therapy Research Articles

Prostate-Specific Membrane Antigen PET Positivity in a Lung Mass: Diagnosis of Diffuse Large B-Cell Lymphoma.

An 84-year-old man with nonmetastatic castrate-sensitive prostate cancer was referred for a 68Ga-prostate-specific membrane antigen (PSMA) PET/CT scan with a prostate-specific antigen level of 3.6 ng/mL for restaging. He was 22 years post-radical prostatectomy and had salvage radiation being managed with intermittent hormonal therapy. Imaging revealed a right lower lobe mass with increased PSMA uptake (SUVmax 6.2). Biopsy and subsequent immunostaining determined the mass to be diffuse large B-cell lymphoma. We report a case of diffuse large B-cell lymphoma diagnosed in the setting of PSMA positivity, highlighting awareness for oncologists and radiologists to know this possibility.

Intermittent Hormonal Therapy in Biochemical Recurrence of Prostate Cancer Is Worth Considering Because of Mitigation of Cardiovascular Events and Reduction of Other Effects

Androgen deprivation therapy (ADT) is associated with better outcomes for men with biochemical recurrence following treatment for localized prostate cancer but can predispose patients to a higher risk of cardiovascular events. Intermittent ADT is worth considering in this setting, with close monitoring of prostate-specific antigen to decide when to restart ADT after off-treatment periods.

Prevalence study of intermittent hormonal therapy of Prostate Cancer patients in Spain

Background: Although intermittent androgen deprivation therapy was introduced many years ago to improve patients' quality of life with the same carcinologic efficiency as continuous hormonal therapy, recent data suggest that intermittency could be underutilised. This study aims to estimate the prevalence of prostate cancer patients receiving intermittent androgen deprivation therapy in Spain. Methods: A retrospective, longitudinal study was conducted using electronic drug dispensation data from four Spanish autonomous communities, which encompass 17.23 million inhabitants (36.22% of the total population in Spain). We estimated intermittent androgen therapy use (%IAD) and the prevalence of patients under intermittent androgen therapy in reference to the total number of PC patients using hormonal therapy (P IAD) and stratified by region. Other outcome variables included the pharmaceutical forms dispensed and the total direct annual expenditure on androgen deprivation therapy-associated medications. Results: A total of 863,005 dispensations corresponding to a total of 65,752 men were identified, treated with either luteinizing hormone-releasing hormone (LHRH) analogues (353,162) administered alone or in combination with anti-androgens (509,843). Overall, the mean (±SD) age of the patients was 76.9 (±10.4) years. Results revealed that the mean annual P IAD along the study was 6.6% in the total population studied, and the overall %IAD during the five-year study period was 5.6%. The mean cost of hormonal therapy per year was 25 million euros for LHRH analogues and 6.3 million euros for anti-androgens. Conclusions: Few prostate cancer patients in Spain use the intermittent androgen deprivation therapy suggesting underutilization of a perfectly valid option for a significant proportion of patients, missing the opportunity to improve their quality of life and to reduce costs for the National Health Service with comparable overall survival rates than continuous therapy.

Prevalence study of intermittent hormonal therapy of Prostate Cancer patients in Spain.

Background: Although intermittent androgen deprivation therapy was introduced many years ago to improve patients' quality of life with the same carcinologic efficiency as continuous hormonal therapy, recent data suggest that those patients could be overtreated. This study aims to estimate the prevalence of prostate cancer patients receiving intermittent androgen deprivation therapy in Spain. Methods: A retrospective, longitudinal study was conducted using electronic drug dispensation data from four Spanish autonomous communities, which encompass 17.23 million inhabitants (36.22% of the total population in Spain). We estimated intermittent androgen therapy use (%IAD) and the prevalence of patients under intermittent androgen therapy (P IAD) overall and stratified by region. Other outcome variables included the pharmaceutical forms dispensed and the total direct annual expenditure on androgen deprivation therapy-associated medications. Results: A total of 863,005 dispensations corresponding to a total of 65,752 men were identified, treated with either luteinizing hormone-releasing hormone (LHRH) analogues (353,162) administered alone or in combination with anti-androgens (509,843). Overall, the mean (±SD) age of the patients was 76.9 (±10.4) years. Results revealed that the mean annual P IAD along the study was 6.6% in the total population studied, and the overall %IAD during the five-year study period was 5.6%. The mean cost of hormonal therapy per year was 25 million euros for LHRH analogues and 6.3 million euros for anti-androgens. Conclusions: An important proportion of prostate cancer patients in Spain could benefit from intermittent androgen therapy during the study period while avoiding overtreatment harms associated with continuous hormonal therapy.

Modeling the synergistic properties of drugs in hormonal treatment for prostate cancer

Prostate cancer is one of the most prevalent cancers in men, with increasing incidence worldwide. This public health concern has inspired considerable effort to study various aspects of prostate cancer treatment using dynamical models, especially in clinical settings. The standard of care for metastatic prostate cancer is hormonal therapy, which reduces the production of androgen that fuels the growth of prostate tumor cells prior to treatment resistance. Existing population models often use patients’ prostate-specific antigen levels as a biomarker for model validation and for finding optimal treatment schedules; however, the synergistic effects of drugs used in hormonal therapy have not been well-examined. This paper describes the first mathematical model that explicitly incorporates the synergistic effects of two drugs used to inhibit androgen production in hormonal therapy. The drugs are cyproterone acetate, representing the drug family of anti-androgens that affect luteinizing hormones, and leuprolide acetate, representing the drug family of gonadotropin-releasing hormone analogs. By fitting the model to clinical data, we show that the proposed model can capture the dynamics of serum androgen levels during intermittent hormonal therapy better than previously published models. Our results highlight the importance of considering the synergistic effects of drugs in cancer treatment, thus suggesting that the dynamics of the drugs should be taken into account in optimal treatment studies, particularly for adaptive therapy. Otherwise, an unrealistic treatment schedule may be prescribed and render the treatment less effective. Furthermore, the drug dynamics allow our model to explain the delay in the relapse of androgen the moment a patient is taken off treatment, which supports that this delay is due to the residual effects of the drugs.

Correlation between innate cytokine levels and progression in men with biochemically recurrent prostate cancer treated with intermittent hormonal therapy.

e16554 Background: Suppressive cytokines have the potential to drive prostate cancer progression with consequent decreased survival. Assessing longitudinal cytokine changes may shed light on mechanisms of disease progression, resistance to therapy, and suggest new therapeutic targets. Methods: Thirty-seven men with biochemically recurrent (BCR) prostate cancer who received 6 months of androgen deprivation therapy (ADT) and were monitored until the time of PSA progression (TTPP) were identified from a previously conducted phase III trial (NCT00020085). Serum samples were archived at baseline, three months after administration of ADT, and at TTPP. Cytokine concentrations were quantified using a 36-parameter electrochemiluminescence assay (MesoScale Discovery). Wilcoxon signed rank sum test was used to compare paired observations between time points. Kaplan-Meier analysis was used to calculate progression function (TTPP) dichotomized by above or below the median value of cytokines with Bonferroni adjustment. Pearson’s rank correlation coefficient was used to compare continuous variables. Results: Median TTPP was 399 days (range, 114 - 1641). Median PSA at baseline and progression were 8.5 ng/ml, (range, 1.0 - 76.6) and 5.3 ng/mL (range, 1.2 - 19.4), respectively. Twenty-three patients (62%) achieved undetectable PSA with ADT. TNF-α (P = 0.002), IL-23 (P = 0.002), and IP-10 (P = 0.001) significantly increased from baseline to post ADT. Patients with a detectable PSA after ADT had moderately elevated levels of IL-6 (P = 0.049) and IL-8 (P = 0.013) at PSA progression as compared to those with an undetectable PSA. There was a trend toward shorter TTPP in patients with TNF-α levels above the median (P = 0.042). TNF-α was strongly correlated with IL-23 (r = 0.72, P < 0.001) and IL-8 (r = 0.59, P < 0.001) from baseline to after ADT and to PSA progression. NLR correlated strongly with IL-27 (r = 0.57, P < 0.001) and MIP-3α (r = 0.56, P < 0.001). Conclusions: Cytokines associated with the innate immune response were associated with an unfavorable clinical outcome in early prostate cancer. These data suggest cytokine blockade combined with ADT may warrant future investigation.

Controllability of hybrid PDE‐ODE systems with structural instability and applications to mathematical models on intermittent hormonal therapy for prostate cancer

Several mathematical models on intermittent androgen suppression (IAS) therapy for prostate cancer are classified into hybrid PDE‐ODE system with structural instability. The purpose of this paper is to give a unified strategy to prove the controllability of the mathematical models on the IAS therapy. For this aim, we prove that (1) a generalized hybrid PDE‐ODE system is controllable for any initial data and (2) the result given by (1) is applicable to the mathematical models on the IAS therapy. Finally, we conclude that the mathematical models on the IAS therapy for prostate cancer are controllable for any initial data.

Solitary testicular prostate cancer metastasis detected by 18 F Choline PET/CT

Objectives Testicular metastases of prostate cancer are rare, usually clinically silent and present in the late stage of disease. We present the case of a patient with a solitary right testicular metastasis of a prostate cancer Gleason score 5 detected by 18 F Choline PET/CT, 16 yrs after total prostatectomy and 6 yrs after surgery of a left testicular metastasis. Material and methods A 80-year-old patient was directed to our department with a biochemically relapse of a prostate carcinoma. He had a laparoscopic prostatectomy in 2000, at age 65. Two 2 mm microcarcinomas of prostate cancer at the right base and apex and a left middle carcinoma of 8 mm were found. The Gleason score was 5. There was an extracapsular extension and the tumor was classified pT3a. Eight month after surgery the PSA was 0.08 ng/ml. In 2004 a rising PSA was observed, 0.48 ng/ml, and a salvage prostate bed radiotherapy was performed, with PSA nadir 0.24 ng/ml. The patient was then treated with intermittent hormonal therapy until July 2010, when he presented with a large left testicle. The PSA was 2.35 ng/ml. The ultrasonography found multiples left testicular nodules. Surgery was performed and histopathology confirmed a 6 × 4-cm testicular metastasis of the prostate carcinoma with extension to the rete testis and to the epididymis and with lymphatic emboli. Post-surgery the PSA dropped at 0.59 ng/ml and 10 months later it was 0.28, with a nadir of 0.21 in November 2011. The patient did not have additional treatment. A new biochemically relapse was diagnosed in March 2016, PSA 5.25 ng/ml, PSA DT 3.89 months, velocity 4.03 ng/ml/year, and the patient was addressed to our department. F Choline TEP/CT was performed after injection of 165 MBq 18 F Choline, 2.9 MBq/kg, with a dynamic phase of 10 minutes at the pelvis level, followed by an acquisition from the upper thigh to the base of skull. Results The 18 F Choline TEP/CT detected a high uptake on the right testicle, SUV max = 8, without other suspect lesions. Surgery was performed and the histology confirmed a new 4 cm testicular metastasis of the known prostate carcinoma. Post-surgery the PSA level was undetectable. Conclusion TEP F Choline is highly reliable in the detection of prostate carcinoma recurrence as in the case we present of a rarely solitary testicular metastasis of prostate cancer Gleason score 5. The testicles have to be well included on PET/CT field of view in order not to overlook such atypical metastases.

Stability analysis on a hybrid PDE–ODE system describing intermittent hormonal therapy of prostate cancer

We consider the stability of control prescribed by hybrid PDE–ODE systems modeling intermittent hormonal therapy of prostate cancer. Hybrid systems can be regarded as a generalization of optimal control. However, since the purpose of hybrid systems is not only minimization or maximization of a corresponding functional, it is not clear what is optimal in hybrid systems. In this paper, we shall give a concept of stability of the control prescribed by the hybrid PDE–ODE systems. Moreover, we show a sufficient condition on initial data for the existence of the stable control. Finally, we apply the main result to several mathematical models describing intermittent hormonal therapy of prostate cancer.

Combined brachytherapy with intermittent hormonal therapy in treating clinical moderate and high risk non-metastatic prostate cancer

Objective To investigate the clinical value of 125I particle implantation brachytherapy combined with intermittent hormonal therapy for treating clinical moderate and high risk non-metastatic prostate cancer. Methods A prospective study was proceeded and 100 cases with moderate and high risk(cT≥T2b, Gleason score≥7, pre-biopsy PSA≥10 ng/ml)non-metastatic prostate cancer were included. The selected patients were divided into two group. In the study group, patients were treated with 125I particle implantation combined with intermittent hormonal therapy. In the control group, patients were treated with only intermittent hormonal therapy. Hormonal therapy was maximal androgen blockage for two groups, including bicalutamide 50 mg oral every day and Leuprorelin 3.75 mg subcutaneous injection every 28 days. There were 50 cases in each group and clinical trial agreements were signed. During follow-up, PSA were tested every month. Chest X-ray and whole-body bone scanning were checked every 6 months. Hormonal therapy was stopped when patient's PSA level fell to 0.2 ng/ml, and keep stabilized for 3 months. When PSA level elevated for 3 times continuously and over 1ng/ml, hormonal therapy was initiated again. The IPSS scores were documented before treatment and every 3 months after treatment. Adverse reactions of urinary tract and rectum were assessed every 3 months after 125I particle implantation in study group. The ratio of the first time to stop hormonal therapy, the time duration of first hormonal therapy and stable phase, re-hormonal therapy free survival rate, bone metastasis free survival rate, castration resistance prostate cancer(CRPC) free survival rate, cancer-specific free survival rate and overall survival rate were compared. Results The 100 cases in this study were followed up for 24-40 months, with an average time of 31.6 months. In study group, the PSA level in all cases descended to the level of stopping hormonal therapy. The time duration of hormone therapy ranged from 4 to 12 months, with an average time of 6.3 months. 21 (42%) cases had a PSA elevation again to restart hormonal therapy. In control group, the PSA level in 47 cases descended to the level of stopping hormonal therapy. The time duration of hormone therapy ranged from 5 to 15 months, with an average time of 7.2 months. 34 (68%) cases had a PSA elevation again to restart hormonal therapy. There was no significant difference in percentage of cases of stopping hormone therapy and in time duration of hormonal therapy for the first cycle. Instead, there were significant differences in stable phase after first cycle hormonal therapy between two groups ( 27.2 months vs. 17.7 months; P<0.001). When analyzed by Kaplan-Meier survival curve, there was no significant difference in cancer-specific survival rate and overall survival rate. There were significant differences in Re-hormonal therapy free survival (P=0.002), bone metastasis free survival (P=0.04) and CRPC free survival(P=0.005). Conclusions Compared with intermittent hormonal therapy alone, 125I particle implantation brachytherapy combined with intermittent hormonal therapy could prolong the hormonal sensitive time in moderate and high risk non-metastatic prostate cancer patients and control the progress of the prostate cancer. Key words: Prostaticneoplasms; Brachytherpay; Hormonal therapy

Hormone naïve prostate cancer: predicting and maximizing response intervals.

Hormone naïve advanced prostate cancer is subdivided into two disease states: biochemical recurrence and traditional M1 (metastatic) prostate cancer and characterized by no prior hormonal therapy or androgen deprivation therapy (ADT). In biochemical recurrence/prostate-specific antigen (PSA) recurrence, men should be risk-stratified based on their PSA doubling time, the Gleason score and the timing of the recurrence. In general, only men who are at high risk should be considered for early/immediate ADT although this is best done using shared decision with the patient. The type of ADT to be used in biochemical recurrence ranging from oral-only peripheral blockade (peripheral androgen deprivation) to complete hormonal therapy (combined androgen blockade [CAB]) remains in debate owing to lack of randomized controlled trials (RCT). However, there is good RCT support for use of intermittent hormonal therapy (IHT). There is also limited research on biomarker response (PSA and testosterone decline) to predict prognosis. On the other hand, in the setting of M1 hormone naïve prostate cancer, there are many more RCT's to inform our decisions. CAB and gonadotrophin-releasing hormone antagonists perhaps provide a slight efficacy advantage while IHT may be slightly inferior with minimal M1 disease. The PSA nadir at 7 months after starting ADT is a powerful prognostic tool for M1 patients. There is growing recognition that serum testosterone (T) control while on ADT is linked to the development of castrate-resistant prostate cancer. Especially for a M1 patient, maintaining a serum T below 20–30 ng dl−1 prolongs the response to ADT. Novel oral agents (abiraterone and enzalutamide) may soon find use in hormone naïve disease and may alter the treatment landscape. Despite over 75 years of experience with ADT, many questions remain, and the field continues to evolve.

A new protocol for intermittent androgen suppression therapy of prostate cancer with unstable saddle-point dynamics

Intermittent androgen suppression (IAS) therapy is a class of hormonal treatment for prostate cancer, in which a drug-induced androgen deprivation can reduce the population of prostate cancer cells. In IAS therapy, drugs are administrated only in on-treatment periods that are separated intermittently by off-treatment periods. The presence of off-treatment periods may be beneficial for maintaining the sensitivity of the tumor cells to androgen deprivation. Thus, IAS can be superior to continuous androgen suppression (CAS) for delaying or possibly preventing relapse of a tumor. IAS therapy usually monitors the level of serum prostate-specific antigen (PSA), which is related to the population of tumor cells. Each on-treatment period begins when the PSA level is greater than an upper threshold; treatment results in a decrease in the PSA level. The on-treatment period is suspended when the PSA level falls below a lower threshold; the PSA level then rises again until the beginning of the next on-treatment period. To determine the transitions between on- and off-treatment periods, we propose a new IAS protocol that uses a model-based estimate of the state point in the phase space of the tumor dynamics. We show that the proposed protocol is effective if, in each of the on- and off-treatment periods, the tumor dynamics exhibits a saddle-point instability accompanied by a stable manifold. Mathematical analysis reveals that tumor dynamics can be controlled in a more effective and robust manner with the proposed protocol than with conventional IAS. We also discuss the clinical feasibility of the proposed protocol as an alternative to conventional IAS therapy.

Clinical significance of suboptimal hormonal levels in men with prostate cancer treated with LHRH agonists

We examined the serum levels of testosterone (T) (total and bioavailable) dehydroepiandrosterone (DHEA), follicle-stimulating hormone (FSH), luteinizing hormone (LH), and prostate-specific antigen (PSA) in men receiving treatment with luteinizing hormone releasing-hormone (LHRH) agonists for metastatic prostate cancer. In doing this, we want to determine the efficacy of these agents in lowering T levels and whether a possible relationship exists between PSA values, as a surrogate measure of tumour activity, and hormone levels. This was a single centre prospective study of patients on LHRH agonists. Of all the 100 eligible patients, 31 did not qualify (10 were receiving their first injection, 13 were on intermittent hormonal therapy, 7 refused to enter the trial and 1 patient's blood sample was lost). Therefore in total, 69 patients were included in the final analysis. Each patient had their blood sample drawn immediately before the administration of a LHRH agonist. The new proposed criteria of <20 ng/dL (0.69 nmol/L) of total testosterone was used to define optimal levels of the hormone in this population. Of the 69 patients, 41 were on goserelin injections, 21 on leuprolide, and 7 on buserelin. There was no statistical difference in hormone levels between any of the medications. Overall, 21% of patients failed to reach optimal levels of total testosterone. PSA levels were higher in this group. There was a statistically significant correlation between PSA and testosterone levels, as well as between PSA and FSH. Serum levels of PSA, however, did not correlate with those of bioavailable testosterone. Failure to reach optimal levels of testosterone occurs in patients on LHRH agonist therapy. Higher PSA values are more commonly found in patients with suboptimal levels of testosterone receiving LHRH analogs, but the clinical importance of this finding has not been established. There is no significant difference with respect to hormonal levels reached among patients on a variety of LHRH agonists. Total testosterone determinations should be considered in patients on LHRH agonist therapy, particularly when the PSA values begin to rise since it may lead to further beneficial hormonal manipulation.

Locally Advanced and Metastatic Prostate Cancer Treated with Intermittent Androgen Monotherapy or Maximal Androgen Blockade: Results from a Randomised Phase 3 Study by the South European Uroncological Group

BackgroundFew randomised studies have compared antiandrogen intermittent hormonal therapy (IHT) with continuous maximal androgen blockade (MAB) therapy for advanced prostate cancer (PCa). ObjectiveTo determine whether overall survival (OS) on IHT (cyproterone acetate; CPA) is noninferior to OS on continuous MAB. Design, setting, and participantsThis phase 3 randomised trial compared IHT and continuous MAB in patients with locally advanced or metastatic PCa. InterventionDuring induction, patients received CPA 200mg/d for 2 wk and then monthly depot injections of a luteinising hormone-releasing hormone (LHRH; triptoreline 11.25mg) analogue plus CPA 200mg/d. Patients whose prostate-specific antigen (PSA) was <4 ng/ml after 3 mo of induction treatment were randomised to the IHT arm (stopped treatment and restarted on CPA 300mg/d monotherapy if PSA rose to ≥20 ng/ml or they were symptomatic) or the continuous arm (CPA 200mg/d plus monthly LHRH analogue). Outcome measurements and statistical analysisPrimary outcome measurement was OS. Secondary outcomes included cause-specific survival, time to subjective or objective progression, and quality of life. Time off therapy in the intermittent arm was recorded. Results and limitationsWe recruited 1045 patients, of which 918 responded to induction therapy and were randomised (462 to IHT and 456 to continuous MAB). OS was similar between groups (p=0.25), and noninferiority of IHT was demonstrated (hazard ratio [HR]: 0.90; 95% confidence interval [CI], 0.76–1.07). There was a trend for an interaction between PSA and treatment (p=0.05), favouring IHT over continuous therapy in patients with PSA ≤1 ng/ml (HR: 0.79; 95% CI, 0.61–1.02). Men treated with IHT reported better sexual function. Among the 462 patients on IHT, 50% and 28% of patients were off therapy for ≥2.5 yr or >5 yr, respectively, after randomisation. The main limitation is that the length of time for the trial to mature means that other therapies are now available. A second limitation is that T3 patients may now profit from watchful waiting instead of androgen-deprivation therapy. ConclusionsNoninferiority of IHT in terms of survival and its association with better sexual activity than continuous therapy suggest that IHT should be considered for use in routine clinical practice.

Abstract P2-14-08: The Pilot Trial of Intermittent Exemestane Therapy for Metastatic Breast Cancer

Abstract Background: While aromatase inhibitors are effective for ER/PR positive breast cancer, resistance frequently develops. EXE is a steroidal AI and has a weak hormone-like activity. Long-term EXE treatment up-regulated amphiregulin-mediated EGFR activation and EXE resistance could result from ER-EGFR cross-talk. In cell culture and animal studies, acquired resistance to EXE was significantly delayed with intermittent use, associated with decreased production of amphiregulin. For first line therapy in MBC, EXE had a median progression free survival (PFS) of 10 mos. As second and third line therapies, PFS decreased to 4.7 mos and 2 mos, respectively. After ≥ 2 of prior endocrine therapy, PFS to EXE ranged between 3.4 mos to 3.7 mos. The rationale for this study was that after long-term estrogen deprivation clinically equivalent to long-term exposure to AI, estrogen may induce apoptosis. With intermittent EXE use, we hope to delay the acquired AI resistance. Methods: Aims were to: 1) assess the PFS and 2) compete response (CR), partial response (PR) and clinical benefit rate [CBR=CR +PR + Stable disease (SD)≥ 6 mos], assessment of toxicity, compliance with medication adherence, and quality of life with assessment of bone health. The study included: 1) ER/PR positive MBC in first, second line/third line hormonal therapy, and one prior chemotherapy for MBC with no prior EXE allowed. EXE was given 25 mg daily × 14 days then 7 days off treatment, each 21-day cycle, imaging was done after every three cycles. Correlatives with estradiol level were drawn at day 1 and day 15 in each cycle. Results: From June 2008 to 2012 we enrolled 33 MBC patients ER/PR positive MBC with a median age of 60 yrs (42–79). At this cut off data date, 2 were inevaluable due to incidental colon cancer and change in treatment choice. 17 patients received treatment as first line (52%), 10 as second or third line hormonal therapy (30%), and 6 who received chemotherapy for MBC (18%). Median PFS and (95% CI) was 6.2 mos (1.9–12.2), 4.2 mos (2.1–10.1), and 3.2 mos (2.1-NR), respectively. For first line patients, there were 3 PRs and 4 with SD&amp;gt;6 mos for a CBR of 7/14 (50%). For second/third line, there were 3 with SD&amp;gt;6 mos for a CBR of 3/9(33%), no response seen in the prior chemotherapy group. The major metastatic sites included bone, liver, lung. 4 patients were Her2+ (13%). Adverse effects including hot flashes (62%), insomnia (31%), nausea (24%), bone pain (17%), fatigue (41%), joint pain (31%) were observed. Median number of cycles delivered is 6 (2–24) for first line, 5.5 (1–15) for second/third line, and 5 (2–9) for prior chemotherapy. Correlatives and QOL assessments are ongoing. Conclusions: Compared to the standard continuous EXE, PFS and CBR is inferior in the intermittent EXE as first line therapy, as second and third line therapy, the median PFS was 4.2 comparable to reported 3.7 mos with the CBR was 33% to 31.5% observed in the EFFECT trial. Interestingly, hot-flash rate was much higher at 62% compared to 11.2% in the EFFECT trial. Arthralgia is comparable at 31%. Patients who already received chemotherapy do not appear to respond favorably to intermittent hormonal therapy. Full response data with correlatives regarding the estradiol levels will be presented. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-14-08.

Intermittent hormonal therapy in the treatment of metastatic prostate cancer: a randomized trial

Study Type - Therapy (RCT) Level of Evidence 1b. What's known on the subject? and What does the study add? Intermittent androgen deprivation therapy (ADT) involves cycling ADT, allowing hormonal recovery during off-treatment periods. This could lead to a better quality of life during off-treatment periods and could delay progression to castration resistance. Safety and feasibility of intermittent ADT have been shown but tolerability and health-related quality of life improvement have been suggested but questioned by others. Results from randomized trials, including relapsing or mixed populations, have suggested intermittent ADT to be as effective as continuous ADT. In this study of only metastatic patients, no statistical difference in either overall survival or progression-free survival was shown between intermittent and continuous ADT and suggests that intermittent might be as safe as continuous castration. It could be an option in highly responding and well-informed metastatic patients even if no clear benefit in health-related quality of life was shown. This intermittent modality could be of interest in metastatic patients with significant treatment-induced side-effects. • To compare intermittent androgen deprivation therapy (ADT) and continuous ADT after 6 months of induction of ADT in patients with metastatic prostate cancer (PCa). • This is an open-label randomized multi-centre study conducted in 58 centres in Europe. • Patients with metastatic PCa and prostate-specific antigen (PSA) level >20 ng/mL at selection were randomized after 6 months of induction of ADT (leuprorelin and flutamide) if PSA level had decreased below 4 ng/mL. • Patients received either continuous or intermittent ADT. All patients were treated until signs of disease progression under treatment or until study end with a monthly central PSA determination and follow-up visits were performed every 3 months. • The primary endpoint was overall survival. Secondary endpoints included progression-free survival, health-related quality of life (QLQ C30 questionnaire) and safety criteria. • Of 383 selected patients, 173 had a PSA level below 4 ng/mL after 6 months of induction of ADT and were randomized. Median overall survival (52 vs 42 months, P= 0.75) and median progression-free survival (15.1 vs 20.7 months, P= 0.74) were not significantly different between continuous and intermittent ADT. • Although some differences in quality of life were observed, most of the functional and symptom scales showed no significant difference between the two groups. • Significantly fewer treatment-emergent adverse events occurred in the intermittent group (P= 0.042), with the incidence of headache and hot flushes also lower. • This first randomized trial comparing continuous with intermittent ADT in metastatic PCa suggests that intermittent ADT might be as safe as continuous ADT. • It could be an option in highly responding and well-informed patients even if no clear benefit in health-related quality of life was shown.

132 Pooled analysis of two protocols of intermittent hormonal therapy, in advance prostatic cancer

INTRODUCTION AND OBJECTIVES: Few randomised studies have compared intermittent hormonal therapy with continuous therapy for the treatment of advanced prostate cancer. We present pooled results from two randomized trials which used similar protocols and had identical data collection and follow up management systems. The objective is to compare overall and cause specific survival between patients receiving intermittent therapy. METHODS: In MAB 626 patients (aged 50-88, mean 73), were randomized 314 to continuous therapy and 312 to intermittent. In CAB 917 patients (aged 44-81, mean 72) have been randomized 462 to Intermittent therapy and 455 to Continuous.The statistical analysis is through a pooled individual level meta analysis with interaction tests to assess the constancy of treatment comparisons across studies. In both protocols, patients received cyproterone acetate (CPA) 200 mg for two weeks and then monthly depot injections of a LHRH analogue plus 200 mg of CPA daily during induction. In both protocols, patients randomised to the continuous arm received the same treatment. MAB patients, in intermittent arm, when they are on treatment received the same scheme, while in CAB protocol, when on treatment received cyproterone acetate (CPA), 300 mg/daily. RESULTS: A total of 477 patients are known to have died in the MAB study and 525 in the CAB study. There was no evidence that the effect of intermittent therapy was different in the two studies and pooling the data is appropriate. There is no difference in overall survival: adjusting for study as the death rate in CAB is lower than in MAB, PSA, Metastatics Status, Gleason Score and Age, p 90, with hazard ratio (HR) 0.99 (95% CI 0.88 to 1.13). Patients who are M0, gleason less than 7 age 75 and randomization PSA 1ng/ml have a good prognosis and 213 (14%) patients are in this group. Among this group the hazard rate for continuous therapy compared to intermittent is 1.46 (95% CI 0.98, 2.18), p 0.065. Patients who are predicted to be off therapy for a long time are M0, randomization PSA 1ng/ml, gleason less than 7 but age 65-79. 269 (17%) of patients are in this group and Intermittent therapy is not significantly worse than Continuous therapy, p 0.38 HR 1.16 (95% CI 0.83, 1.63), for Continuous compared to Intermittent adjusting for study only. Sexual activity is better in the intermittent group. CONCLUSIONS: Intermittent therapy should be considered for use in routine practice since it is associated with no reduction in survival, and better sexual activity. It may be particularly beneficial for patients who are good responders to therapy.

Nonlinear systems identification by combining regression with bootstrap resampling

A new parameter estimation method for nonlinear systems from time series data is proposed. For the purpose of unbiased estimation, we employ the idea of bootstrap method on regression problems. Our method can be applied into even short and noisy data and is expected to give us a robust estimation. Some benchmarks of estimating chaotic models show its practical applicability. We also try to apply this method to analysis for intermittent hormonal therapy for prostate cancer by using a mathematical model and real clinical data.

Intermittent hormonal therapy for prostate cancer

Intermittent hormonal therapy (IHT) for prostate cancer aims to minimize treatment-related side-effects, to improve overall quality of life, to reduce the cost of care, and possibly to delay progression to castration-resistant prostate cancer. With preclinical evidence suggesting a potential benefit for IHT in terms of time to androgen independence, with phase II and phase III studies producing optimistic results, and with the potential for reductions in cost and complications, IHT has become a popular modality of therapy around the globe. In the near future intermittent therapy will have place in the treatment strategy in the management of prostate cancer, particularly on men with locally advanced disease.

35 Intermittent hormonal therapy in the treatment of prostate cancer

BRD4, a member of the bromodomain and extra-terminal domain (BET) protein family, plays a role in the organization of super-enhancers and transcriptional activation of oncogenes in cancer and is recognized as a promising target for cancer therapy. microRNAs (miRNAs), endogenous small noncoding RNAs, cause mRNA degradation or inhibit protein translation of their target genes by binding to complementary sequences. miRNA mimics simultaneously targeting several tumor-promoting genes and BRD4 may be useful as therapeutic agents of tumor-suppressive miRNAs (TS-miRs) for cancer therapy. To investigate TS-miRs for the development of miRNA-based cancer therapeutics, we performed function-based screening in 10 cancer cell lines with a library containing 2,565 human miRNA mimics. Consequently, miR-1293, miR-876-3p, and miR-6571-5p were identified as TS-miRs targeting BRD4 in this screening. Notably, miR-1293 also suppressed DNA repair pathways by directly suppressing the DNA repair genes APEX1 (apurinic-apyrimidinic endonuclease 1), RPA1 (replication protein A1), and POLD4 (DNA polymerase delta 4, accessory subunit). Concurrent suppression of BRD4 and these DNA repair genes synergistically inhibited tumor cell growth in vitro. Furthermore, administration of miR-1293 suppressed in vivo tumor growth in a xenograft mouse model. These results suggest that miR-1293 is a candidate for the development of miRNA-based cancer therapeutics.