Intermittent Androgen Suppression: Estimating Parameters for Individual Patients Based on Initial PSA Data in Response to Androgen Deprivation Therapy.

When a physician decides on a treatment and its schedule for a specific patient, information gained from prior patients and experience in the past is taken into account. A more objective way to make such treatment decisions based on actual data would be useful to the clinician. Although there are many mathematical models proposed for various diseases, so far there is no mathematical method that accomplishes optimization of the treatment schedule using the information gained from past patients or "rapid learning" technology. In an attempt to use this approach, we integrate the information gained from patients previously treated with intermittent androgen suppression (IAS) with that from a current patient by first fitting the time courses of clinical data observed from the previously treated patients, then constructing the prior information of the parameter values of the mathematical model, and finally, maximizing the posterior probability for the parameters of the current patient using the prior information. Although we used data from prostate cancer patients, the proposed method is general, and thus can be applied to other diseases once an appropriate mathematical model is established for that disease.

Quantitative mathematical modeling of PSA dynamics of prostate cancer patients treated with intermittent androgen suppression.

If a mathematical model is to be used in the diagnosis, treatment, or prognosis of a disease, it must describe the inherent quantitative dynamics of the state. An ideal candidate disease is prostate cancer owing to the fact that it is characterized by an excellent biomarker, prostate-specific antigen (PSA), and also by a predictable response to treatment in the form of androgen suppression therapy. Despite a high initial response rate, the cancer will often relapse to a state of androgen independence which no longer responds to manipulations of the hormonal environment. In this paper, we present relevant background information and a quantitative mathematical model that potentially can be used in the optimal management of patients to cope with biochemical relapse as indicated by a rising PSA.

Mathematically modelling and controlling prostate cancer under intermittent hormone therapy.

In this review, we summarize our recently developed mathematical models that predict the effects of intermittent androgen suppression therapy on prostate cancer (PCa). Although hormone therapy for PCa shows remarkable results at the beginning of treatment, cancer cells frequently acquire the ability to grow without androgens during long-term therapy, resulting in an eventual relapse. To circumvent hormone resistance, intermittent androgen suppression was investigated as an alternative treatment option. However, at the present time, it is not possible to select an optimal schedule of on- and off-treatment cycles for any given patient. In addition, clinical trials have revealed that intermittent androgen suppression is effective for some patients but not for others. To resolve these two problems, we have developed mathematical models for PCa under intermittent androgen suppression. The mathematical models not only explain the mechanisms of intermittent androgen suppression but also provide an optimal treatment schedule for the on- and off-treatment periods.

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.

Mathematical modelling of prostate cancer growth and its application to hormone therapy.

Hormone therapy in the form of androgen deprivation is a major treatment for advanced prostate cancer. However, if such therapy is overly prolonged, tumour cells may become resistant to this treatment and result in recurrent fatal disease. Long-term hormone deprivation also is associated with side effects poorly tolerated by patients. In contrast, intermittent hormone therapy with alternating on- and off-treatment periods is a possible clinical strategy to delay progression to hormone-refractory disease with the advantage of reduced side effects during the off-treatment periods. In this paper, we first overview previous studies on mathematical modelling of prostate tumour growth under intermittent hormone therapy. The model is categorized into a hybrid dynamical system because switching between on-treatment and off-treatment intervals is treated in addition to continuous dynamics of tumour growth. Next, we present an extended model of stochastic differential equations and examine how well the model is able to capture the characteristics of authentic serum prostate-specific antigen (PSA) data. We also highlight recent advances in time-series analysis and prediction of changes in serum PSA concentrations. Finally, we discuss practical issues to be considered towards establishment of mathematical model-based tailor-made medicine, which defines how to realize personalized hormone therapy for individual patients based on monitored serum PSA levels.

Piecewise affine systems modelling for optimizing hormone therapy of prostate cancer.

Prostate cancer is one of the most common malignant neoplasms in men with an overall incidence of approximately 15 per cent during the normal life span. Androgen-deprivation therapy (hormone therapy) is an effective treatment of this disease when progressed to an advanced stage. Despite impressive responses, such treatment when applied on a continuous basis is not curative and eventually culminates in androgen-independent disease. On the other hand, intermittent androgen suppression (IAS) was first conceived as a potential way of delaying progression to androgen-independence, in addition offering the possibility of reducing adverse effects and improving the quality of life. Although the validity of this approach has been confirmed in several clinical studies, the optimal scheduling of the cycles of on- and off-treatment remains to be explored. In the present article, we show that IAS lends itself to mathematical modelling with hybrid dynamical systems and that the model we have developed can be used to select the best strategy for keeping prostate cancer in an androgen-dependent state as long as possible. Our results also suggest that the current way of using IAS exceeds what is necessary for optimal control; in fact, we have found that to achieve optimal control, the amount of therapy (dose and duration of drugs) can be reduced by a factor of one half.

Prostate cancer: finasteride extends PSA doubling time during intermittent hormone therapy.

OBJECTIVES: Finasteride has been shown to prolong the time off-treatment in men with prostate cancer during intermittent androgen suppression therapy, but it is not clear whether this results from an increase in prostate-specific antigen (PSA) doubling time or a delay in PSA responsiveness to regained testicular function. In the following study, we distinguish between these two possibilities and consider how the effectiveness of finasteride might be altered if androgens are synthesized within the malignant cell rather than the testis. SUBJECTS AND METHODS: Six patients were followed on intermittent androgen suppression for intervals ranging from 7 to 10 years. The effects of finasteride on the length of the off-treatment period in at least one cycle in each patient were measured with monthly determinations of serum PSA and testosterone and calculation of PSA doubling time using linear regression analysis. RESULTS: Administration of finasteride was associated with a reduction in the rate of increase of serum PSA in the off-treatment period of any given cycle within a sequence of 5. In a total of 15 cycles, finasteride extended PSA doubling time from a mean of 7.7 weeks (n = 11, range 2.3-29.8 weeks) to a mean of 45.1 weeks (n = 6, range 13.8-99.7 weeks). One patient was characterized by an apparent pseudo-resistance to finasteride in the 2nd cycle of treatment and another patient by complete resistance to finasteride in the 4th cycle. CONCLUSIONS: Finasteride can be introduced into any cycle of intermittent androgen suppression with the expectation of an extension of PSA doubling time.

Development of a mathematical model that predicts the outcome of hormone therapy for prostate cancer.

We propose a mathematical model that quantitatively reproduces the dynamics of the serum prostate-specific antigen (PSA) level under intermittent androgen suppression (IAS) for prostate cancer. Taking into account the biological knowledge that there are reversible and irreversible changes in a malignant cell, we constructed a piecewise-linear dynamical model where the testosterone dynamics are modelled with rapid shifts between two levels, namely the normal and castrate concentrations of the male hormone. The validity of the model was supported by patient data obtained from a clinical trial of IAS. It accurately reproduced the kinetics of the therapeutic reduction of PSA and predicted the future nadir level correctly. The coexistence of reversible and irreversible changes within the malignant cell provided the best explanation of early progression to androgen independence. Finally, since the model identified patients for whom IAS was effective, it potentially offers a novel approach to individualized therapy requiring the input of time sequence values of PSA only.

Hybrid optimal scheduling for intermittent androgen suppression of prostate cancer.

We propose a method for achieving an optimal protocol of intermittent androgen suppression for the treatment of prostate cancer. Since the model that reproduces the dynamical behavior of the surrogate tumor marker, prostate specific antigen, is piecewise linear, we can obtain an analytical solution for the model. Based on this, we derive conditions for either stopping or delaying recurrent disease. The solution also provides a design principle for the most favorable schedule of treatment that minimizes the rate of expansion of the malignant cell population.

Quality of life, morbidity, and mortality results of a prospective phase II study of intermittent androgen suppression for men with evidence of prostate-specific antigen relapse after radiation therapy for locally advanced prostate cancer.

BACKGROUND: Observations of quality of life (QOL), morbidity, and mortality were obtained from the results of a prospective phase II study of intermittent androgen suppression for recurrent prostate cancer after radiation therapy. PATIENTS AND METHODS: Patients with histologically confirmed adenocarcinoma of the prostate and a rising serum prostate-specific antigen level after external-beam radiation of the prostate were treated intermittently with a 36-week course of cyproterone and leuprolide. At predetermined intervals, QOL was assessed using the Southwest Oncology Group 9346 QOL and the American Urological Association symptom score questionnaires. Progression-free and overall survival rates were estimated using the Kaplan-Meier method. Parameters related to progression were explored with univariate and multivariate analyses. RESULTS: The incidence of adverse events was higher when patients were on treatment. Fatigue, dyspnea, and hematuria were the most common symptoms and signs recorded (50.5%, 24.8%, and 17.4%, respectively). Less frequent were myocardial infarction (7.3%), cerebrovascular accident (6.4%), and deep vein thrombosis (5.5%). Quality of life improved when off treatment, as indicated by a shift toward baseline levels in the scales depicting physical and work functions, hot flashes, impotence, sexual performance, urgency, and nocturia. Biochemical recurrence-free survival at 5 years was 70%, with a median > 6 years. The overall 5-year survival was 80%, similar to that of an age-matched population of normal men. CONCLUSION: Intermittent androgen suppression is a potentially useful treatment for locally recurrent prostate cancer after radiation therapy with QOL benefits in the off-treatment interval and no apparent deleterious effects on short- to medium-term survival.

Locally advanced prostate cancer--biochemical results from a prospective phase II study of intermittent androgen suppression for men with evidence of prostate-specific antigen recurrence after radiotherapy.

BACKGROUND: Biochemical results from a prospective Phase II trial of intermittent androgen suppression for recurrent prostate cancer after radiotherapy were analyzed for correlations to the onset of hormone-refractory disease. METHODS: Patients with histologically confirmed adenocarcinoma of the prostate and a rising serum prostate-specific antigen (PSA) level after external beam irradiation of the prostate were treated intermittently with a 36-week course of cyproterone acetate and leuprolide acetate. Then, patients were stratified according to their serum PSA range at the start of each cycle and were followed with further biochemical testing until disease progression was evident. RESULTS: The mean PSA reduction was 95.2% irrespective of stratification group. A baseline serum PSA level <10 microg/L and a serum PSA nadir or=7.5 nmol/L was observed in 75%, 50%, 40%, and 30% of men in Cycles 1 to 4, respectively, and was sufficient to normalize the level of hemoglobin in each cycle, which dropped by an average of 10.8 g/L during treatment (P < .0001). CONCLUSIONS: The length of the off-treatment interval during cyclic androgen withdrawal therapy was related inversely to baseline and nadir levels of serum PSA. Nadir PSA was a powerful predictor of early progression to androgen independence.

Final results of the Canadian prospective phase II trial of intermittent androgen suppression for men in biochemical recurrence after radiotherapy for locally advanced prostate cancer: clinical parameters.

BACKGROUND: This prospective Phase II study was undertaken to evaluate intermittent androgen suppression as a form of therapy in men with localized prostate cancer who failed after they received external beam irradiation. METHODS: Patients who demonstrated a rising serum prostate-specific antigen (PSA) level after they received radiotherapy and who were without evidence of distant metastasis were accepted into the study. Treatment in each cycle consisted of cyproterone acetate given as lead-in therapy for 4 weeks, followed by a combination of leuprolide acetate and cyproterone acetate, which ended after a total of 36 weeks. RESULTS: Of 109 patients registered, 103 patients were eligible for interruption of treatment, yielding a PSA response rate of 95%. The study continued for 6 years with a mean follow-up of 3.7 years (median follow-up, 4.2 years). The time off treatment averaged 53% of the total cycle time but, in absolute terms, decreased with each succeeding cycle, ranging from 63.7 weeks in Cycle 1 to 25.6 weeks in Cycle 5. Prostate volume was reduced by 40% in Cycle 1 and by 34% in Cycle 2, and there were no decreases in Cycle 3 or Cycle 4. At the end of the trial, 38.5% of patients still were receiving treatment, 23.9% of patients had failed, and 15.6% of patients had died. Only 2% of deaths were cancer-specific. CONCLUSIONS: Biochemical recurrence after irradiation for localized prostate cancer was amenable to cyclic androgen withdrawal therapy and showed a high response rate. Despite progressively shorter treatment cycles, the off-treatment interval remained appreciable, ranging from 65% in Cycle 1 to 46% in Cycle 5.

Dihydrotestosterone and the prostate: the scientific rationale for 5alpha-reductase inhibitors in the treatment of benign prostatic hyperplasia.

PURPOSE: We reviewed the physiological and pathogenic role of dihydrotestosterone (DHT), evidence for the beneficial effects of decreasing DHT through 5alpha-reductase inhibition and the effects of altering the androgen balance with these agents. MATERIALS AND METHODS: A review of the relevant literature was done using published studies identified from the MEDLINE database. RESULTS: The androgens DHT and testosterone have complementary roles in male physiology. Each is mediated through the intracellular androgen receptor. It has been hypothesized that DHT may provide an amplification mechanism for testosterone, which could be a beneficial adaptation in men with low circulating testosterone. The recognition of the central role of DHT in benign prostatic hyperplasia (BPH) has changed the way the disease is viewed and has led to the introduction of 5alpha-reductase inhibitors, which can prevent and retard the progression of BPH by suppressing DHT synthesis. The 5alpha-reductase inhibitors decrease prostate volume. In doing so they improve symptoms and urinary flow, and decrease the risks of acute urinary retention and the need for BPH related surgery. The predominant drug related adverse events with 5alpha-reductase inhibitors are reproductive events, that is typically decreased libido, impotence and ejaculatory dysfunction. These events occur in a minority of men and tend to decrease with a longer treatment duration. CONCLUSIONS: DHT appears to have an obligatory role in the development of BPH. The role of 5alpha-reductase inhibitors in the treatment of BPH has been firmly established with an adverse events profile that is suitable for long-term use.

Osteoblast-derived factors induce androgen-independent proliferation and expression of prostate-specific antigen in human prostate cancer cells.

PURPOSE: Prostate cancer metastasizes to the skeleton to form osteoblastic lesions. Androgen ablation is the current treatment for metastatic prostate cancer. This therapy is palliative, and the disease will return in an androgen-independent form that is preceded by a rising titer of prostate-specific antigen (PSA). Here, we investigated the possibility that human osteoblasts might secrete factors that contribute to the emergence of androgen-independent prostate cancer. EXPERIMENTAL DESIGN: Primary cultures of human osteoblasts were used as a source of conditioned medium (OCM). Proliferation, expression of androgen-regulated genes, and transactivation of the androgen receptor (AR) were monitored in LNCaP human prostate cancer cells in response to OCM using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Northern blot analysis, and reporter gene constructs. Levels of interleukin-6 (IL-6) present in OCM were measured, and its contribution to proliferation and expression of PSA were investigated by neutralization studies with anti IL-6 antibodies. RESULTS: OCM increased the proliferation and expression of PSA at both the protein and RNA levels in LNCaP cells. Synergistic increases in the activities of PSA (6.1 kb)- and pARR(3)-tk-luciferase reporters were measured in cells cotreated with both OCM and androgen. OCM targeted the NH(2)-terminal domain of the AR. The effect of OCM on transcriptional activity of the AR was inhibited by an antiandrogen. Neutralizing antibodies to IL-6 blocked proliferation and expression of PSA by OCM. CONCLUSION: Osteoblasts secrete factors, such as IL-6, that cause androgen-independent induction of PSA gene expression and proliferation of prostate cancer cells by a mechanism that partially relies on the AR. Identifying such molecular mechanisms may lead to improved clinical management of metastatic prostate cancer.

Ligand-independent activation of the androgen receptor by interleukin-6 and the role of steroid receptor coactivator-1 in prostate cancer cells.

The androgen receptor (AR) can be activated in the absence of androgens by interleukin-6 (IL-6) in human prostate cancer cells. The events involved in ligand-independent activation of the AR are unknown, but have been suggested to involve phosphorylation of the AR itself or a receptor-associated protein. Steroid receptor coactivator-1 (SRC-1) has been shown to interact with the human AR and to modulate ligand-dependent AR transactivation and is regulated by phosphorylation by MAPK. To date, no one has examined the role of SRC-1 in ligand-independent activation of the AR by IL-6 or other signaling pathways known to activate the full-length receptor. This study addressed this and has revealed the following. 1) SRC-1 similarly enhanced ligand-independent activation of the AR by IL-6 to the same magnitude as that obtained via ligand-dependent activation. 2) Androgen and IL-6 stimulated the MAPK pathway. 3) MAPK was required for both ligand-dependent and ligand-independent activation of the AR. 4) Phosphorylation of SRC-1 by MAPK was required for optimal ligand-independent activation of the AR by IL-6. 5) Protein-protein interaction between endogenous AR and SRC-1 was dependent upon treatment of LNCaP cells with IL-6 or R1881. 6) Protein-protein interaction between the AR N-terminal domain and SRC-1 was independent of MAPK. 7) Ligand-independent activation of the AR did not occur by a mechanism of overexpression of either solely wild-type SRC-1 or mutant SRC-1 that mimics its phosphorylated form.

Activation of the androgen receptor N-terminal domain by interleukin-6 via MAPK and STAT3 signal transduction pathways.

The androgen receptor (AR) is a ligand-activated transcription factor that mediates the biological responses of androgens. However, non-androgenic pathways have also been shown to activate the AR. The mechanism of cross-talk between the interleukin-6 (IL-6) and AR signal transduction pathways was investigated in LNCaP human prostate cancer cells. IL-6 induced several androgen-response element-driven reporters that are dependent upon the AR, increased the phosphorylation of mitogen-activated protein kinase (MAPK), and activated the AR N-terminal domain (NTD). Inhibitors to MAPK and JAK decreased the IL-6-induced phosphorylation of MAPK and activation of the AR NTD. Immunoprecipitation and transactivation studies showed a direct interaction between amino acids 234-558 of the AR NTD and STAT3 following IL-6 treatment of LNCaP cells. These results demonstrate that activation of the human AR NTD by IL-6 was mediated through MAPK and STAT3 signal transduction pathways in LNCaP prostate cancer cells.

Mechanisms of androgen-independent tumor growth.

In the setting of advanced prostatic carcinoma, castration results in a high initial response rate. Unfortunately, the benefit of such therapy is usually temporary owing to the fact that surviving tumor cells generally progress to an untreatable androgen-independent condition. Progression to androgen independence is a complex process. Several hypotheses for the mechanism of androgen independence exist, including clonal selection, tumor adaptation, and the activation of previously androgen-repressed genes that substitute for androgens in maintaining the viability of tumor-causing stem cells. In this article we will discuss the theoretical concepts underlying androgen independence as well as the concepts of androgen dependence, stepwise malignant transformation, and upregulation of constitutive growth factors.