Intermittent Androgen Suppression Research Articles

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.

Intermittent androgen suppression for prostate cancer

Although androgen deprivation therapy (ADT) has been a cornerstone of the management of prostate cancer for more than 50 years, controversy remains regarding its optimum application. Intermittent androgen suppression (IAS) has been researched since the mid-1980s as a way of reducing the adverse effects and cost of continuous androgen suppression. With preclinical evidence suggesting a potential benefit in terms of time to androgen independence, IAS has been the focus of a number of clinical phase II and III trials. Overall, these trials suggest that IAS is neither inferior nor superior to continuous androgen suppression, with respect to time to castration resistance and cancer-specific survival, but has significant advantages in terms of adverse effects, quality of life and cost. A number of unresolved questions remain, however, including how to select patients for therapy, the optimum duration of therapy, when to restart therapy after the off cycle, and how to define progression to castration-resistant disease. Landmark randomized clinical trials comparing IAS to continuous androgen suppression are in progress and will hopefully answer many of these questions. In future, the use of second-line drugs in the off-treatment phase holds potential for delaying disease progression in men on IAS. At present, men with advanced disease who are deemed candidates for ADT should be informed of IAS as a treatment option, considered experimental from an informed consent point of view, but promising based on current evidence.

Intermittent versus continuous androgen suppression therapy: do we have consensus yet?

Androgen deprivation therapy (ADT) has been a cornerstone in the management of advanced prostate cancer for more than 50 years, but several aspects of the therapy remain controversial. Research since the mid-1980s has looked at the use of intermittent androgen suppression (IAS) as a way to reduce the side effects and costs of continuous androgen suppression. During that same time, testing for prostate-specific antigen resulted in forward stage migration both at diagnosis and at the time of treatment initiation. Earlier treatment has led to prolonged periods of ADT and increasing recognition of the resultant metabolic complications. With preclinical evidence suggesting a potential benefit for ias in terms of time to androgen independence, with phase II and III studies producing optimistic results, and with the potential for reductions in cost and complications, ias has become a popular modality of therapy around the globe. Large prospective randomized studies, currently ongoing, will ultimately determine the legitimate place of IAS in the treatment of prostate cancer.

Measurement of bone turnover in prostate cancer patients receiving intermittent androgen suppression therapy

Measurement of bone turnover in prostate cancer patients receiving intermittent androgen suppression therapy

Measurement of bone turnover in prostate cancer patients receiving intermittent androgen suppression therapy

PurposeReports on clinical measurements of bone mineral density (BMD) in prostate cancer patients undergoing intermittent androgen suppression therapy (IAS) that allows for hormonal recovery between treatment cycles indicate decreased osteoporosis compared to continuous androgen suppression therapy (CAS). In the present study the effect of IAS on bone metabolism by determinations of CrossLaps, a biochemical marker of collagen degradation, were examined.MethodIn total 100 IAS treatment cycles of 75 patients with prostate cancer stages ≥ pT2 were studied. Clinical data and monthly laboratory tests (testosterone, prostate-specific antigen; PSA) of these patients were monitored together with measurements of C-terminal telopeptide collagen fragments using CrossLaps® ELISA assays.ResultsDuring phases of androgen suppression (AS) lasting for 9 months serum testosterone (<1 ng/mL) and PSA (<2 ng/mL) levels were reversibly reduced, indicating partial growth arrest and apoptotic regression of the prostatic tumors. Serum CrossLaps concentrations peaked at the last 2 months of the AS phases (0.91 ± 0.25 μg/L; mean ± SEM) and were reduced below initial values (0.21 ± 0.43 versus baseline of 0.43 ± 0.06 μg/L) during therapy cessation periods until tumor progression-related increases.ConclusionMeasurements of the serum concentration of CrossLaps in prostate cancer patients receiving IAS indicated that treatment cessation phases rapidly reversed increased bone degradation associated with AS phases, in strong agreement with the clinical observations reporting reduced loss of BMD in IAS when compared to CAS. In terms of clinical outcomes, IAS seems to be as effective as CAS while showing reduced side effects, as demonstrated here by the reduction of androgen-induced bone matrix degradation.

Current Medical and Surgical Options for Androgen Deprivation in Prostate Cancer Patients

The growth of prostate cancer cells is driven by androgens. Thus, androgen deprivation, is one of the main treatment modalities in the management of prostate cancer. Historically, bilateral orchiectomy, which achieves 95% reduction of testosterone levels within 3 hours, was the only effective androgen deprivation therapy (ADT). In the 1980s, luteinizing hormone-releasing hormone agonists (LHRH-A) were introduced to reduce testosterone to castration levels. After the 1980s, nonsteroidal antiandrogens were developed in addition to steroidal antiandrogens. Since then, so-called maximum androgen blockade (MAB)/combined androgen blockade (CAB), which is a combination of surgical or medical castration and oral antiandrogens, has been suggested. More recently, novel treatment modalities have been developed, such as intermittent androgen suppression (IAS), nonsteroidal antiandrogen monotherapy, and alternative antiandrogen therapy after relapse from the initial MAB/CAB. ADT, whether surgical or medical, provides important quality of life (QOL) benefits in patients with advanced and metastatic prostate cancer. While the principle of the therapy has remained unchanged, the role, type and timing of these therapies is continuously evolving. This review will focus on the current medical and surgical options for ADT in advanced and metastatic prostate cancer, summarizing the results of several recent clinical trials and discuss their implications for clinical practice and for future research in this disease.

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.

A MODEL AT THE MACROSCOPIC SCALE OF PROSTATE TUMOR GROWTH UNDER INTERMITTENT ANDROGEN SUPPRESSION

The relapse of tumor is a crucial problem in hormonal therapy of prostate cancer. The so-called androgen-independent cells are considered to be responsible for such a recurrence. These cells are not sensitive to androgen suppression but rather apt to proliferate even in an androgen-poor environment. Bruchovsky et al. in their experimental and clinical studies suggested that intermittent androgen suppression may delay or prevent the relapse when compared with continuous androgen suppression. This paper proposes a model at the macroscopic scale of prostate tumor growth under intermittent androgen suppression. Qualitative analysis shows that the tumor relapse cannot be avoided under continuous androgen suppression for typical parameter values. Numerical simulation supports the above-mentioned experimental and clinical suggestion, and implies an optimal medication scheme of intermittent androgen suppression therapy.

Le traitement hormonal du cancer de la prostate chez le patient âgé

Prostate cancer (PaC) is a significant health problem. Elderly have the highest incidence of the disease as age is its strongest risk factor. Despite its complications, the use of androgen suppression in aging patients with prostate cancer has become extremely frequent with probable excess. However, some of these complications carry specific mortality and all of them have a negative impact on quality of life. It is critical to perform a geriatric assessment, concerning physical, mental and social items, before to consider androgen suppression in this population. Indications of androgen suppression for the treatment of prostate cancer follow the guidelines of CCAFU. Delayed treatment deserves a special attention when possible. Treatment modalities are no specific to the elderly, but complications have to be anticipated with preventive measures. Intermittent androgen suppression should be considered with caution. Close follow up will focus on the diagnosis of adverse effects of androgen suppression.

Long‐term effects of intermittent androgen suppression on testosterone recovery and bone mineral density: results of a 33‐month observational study

To investigate changes in bone mineral density (BMD) and osteoporosis, over 3 years of intermittent androgen-suppression therapy (IAST). This was a Phase II individual cohort study of 72 patients with prostate cancer without metastatic bone disease, enrolled between 1999 and 2002. Patients had 9 months flutamide (250 mg, three times daily) and leuprolide (22.5 mg, 3-monthly depot) after which, patients ceased therapy providing that their PSA levels were <4 ng/mL. AST re-commenced when the PSA level exceeded the pretreatment level or was >20 ng/mL. BMD for hip and spine was the primary endpoint; assessed at baseline; completion of initial treatment period; and at 1 and 2 years after initial treatment (POST period). Osteoporosis increased from 7% at baseline to 10% at 3 years. The BMD declined after 9 months treatment, at -1.9% and -3.3% at hip and spine, respectively (P < 0.001). Subsequent BMD decline in the POST period was attenuated; at 1 years and 2 years later, hip -0.6% (not significant), and -0.8% (P < 0.014), and spine +1.0% and +0.2% (not significant). The BMD change in those remaining 'off' therapy for 2 years (n = 20) was strongly associated with the level of testosterone recovery; a peak testosterone level of <5 nmol/L associated with a greater then normal physiological loss. Testosterone recovery was less likely in older men. The attenuation of spine and hip BMD decline after 3-year IAST compared with those reported for continuous AST appears to be due to testosterone driven BMD recovery in the POST period. Failure of testosterone recovery was associated with worse final BMD. By reducing the potential risk for adverse bone complications, intermittent therapy may become an important consideration when the therapeutic ratio is narrow.

Androgen deprivation therapy: progress in understanding mechanisms of resistance and optimizing androgen depletion.

Androgen deprivation therapy remains a critical component of treatment for men with advanced prostate cancer, and data support its use in metastatic disease and in conjunction with surgery or radiation in specific settings. Alternatives to standard androgen deprivation therapy, such as intermittent androgen suppression and estrogen therapy, hold the potential to improve toxicity profiles while maintaining clinical benefit. Current androgen deprivation strategies seem to incompletely suppress androgen levels and androgen-receptor-mediated effects at the tissue level. Advances in the understanding of mechanisms that contribute to castration-resistant prostate cancer are leading to rationally designed therapies targeting androgen metabolism and the androgen receptor. The results of large trials investigating the optimization of primary androgen deprivation therapy, including evaluation of intermittent androgen suppression and phase III studies of novel androgen synthesis inhibitors, such as abiraterone acetate, are eagerly awaited.

MATHEMATICAL MODELING OF PROSTATE TUMOR GROWTH UNDER INTERMITTENT ANDROGEN SUPPRESSION WITH PARTIAL DIFFERENTIAL EQUATIONS

Since most prostate tumors are initially hormone-sensitive, hormonal therapy with androgen suppression is a major treatment for them. In this hormonal therapy, however, a tumor relapse is a crucial problem. Androgen-independent tumor cells are considered to be responsible for such a relapse. These cells are not sensitive to androgen suppression but rather apt to proliferate even in an androgen-poor environment. Bruchovsky et al. proposed intermittent androgen suppression (IAS), which may prolong the relapse time when compared with continuous androgen suppression (CAS). IAS therapy is based on switching of medication through monitoring of the serum prostate-specific antigen (PSA). Namely, the medication is suspended when the PSA concentration falls below the lower threshold during on-treatment periods and it is reinstituted when the concentration exceeds the upper threshold during off-treatment periods. In this paper, we propose a model of partial differential equations (PDE) for IAS therapy, on the basis of our previous model of ordinary differential equations, under the assumption that the prostate tumor is a mixed assembly of androgen-dependent (AD) and androgen-independent (AI) cells. Numerical analysis compares the effect of the IAS therapy with that of the CAS therapy for different growth rates of the AI cells, which suggests an optimal protocol of the IAS therapy.

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

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

POD-3.01: Intermittent Androgen Suppression Delayed the Time to PSA Failure in Locally-Advanced and Metastatic Prostate Cancer Compared with Continuous Androgen Suppression in Japan

POD-3.01: Intermittent Androgen Suppression Delayed the Time to PSA Failure in Locally-Advanced and Metastatic Prostate Cancer Compared with Continuous Androgen Suppression in Japan

A Mathematical Model of Intermittent Androgen Suppression for Prostate Cancer

For several decades, androgen suppression has been the principal modality for treatment of advanced prostate cancer. Although the androgen deprivation is initially effective, most patients experience a relapse within several years due to the proliferation of so-called androgen-independent tumor cells. Bruchovsky et al. suggested in animal models that intermittent androgen suppression (IAS) can prolong the time to relapse when compared with continuous androgen suppression (CAS). Therefore, IAS has been expected to enhance clinical efficacy in conjunction with reduction in adverse effects and improvement in quality of life of patients during off-treatment periods. This paper presents a mathematical model that describes the growth of a prostate tumor under IAS therapy based on monitoring of the serum prostate-specific antigen (PSA). By treating the cancer tumor as a mixed assembly of androgen-dependent and androgen-independent cells, we investigate the difference between CAS and IAS with respect to factors affecting an androgen-independent relapse. Numerical and bifurcation analyses show how the tumor growth and the relapse time are influenced by the net growth rate of the androgen-independent cells, a protocol of the IAS therapy, and the mutation rate from androgen-dependent cells to androgen-independent ones.

Current topics and perspectives relating to hormone therapy for prostate cancer

Prostate cancer is androgen-dependent, and hormone therapy, mainly achieved by androgen deprivation, has been one of the main treatment modalities in the clinical management of prostate cancer patients for more than six decades. In the 1980s, luteinizing hormone-releasing hormone agonists, which reduce testosterone to castration levels, were introduced Also, after the 1980s, nonsteroidal antiandrogens were developed in addition to steroidal antiandrogens. Since then, so-called maximum androgen blockade (MAB)/combined androgen blockade (CAB), which is a combination of surgical or medical castration and oral antiandrogens, has been developed. More recently, novel treatment modalities have been developed, such as intermittent androgen suppression, nonsteroidal antiandrogen monotherapy, and alternative antiandrogen therapy after relapse from initial MAB/CAB, The present article focuses on these treatment modalities to review current topics and perspectives with respect to hormone therapy for prostate cancer.

Kinetics of Serum Androgen Normalization and Factors Associated With Testosterone Reserve After Limited Androgen Deprivation Therapy for Nonmetastatic Prostate Cancer

Groups have investigated time to testosterone recovery in patients who have undergone androgen deprivation therapy, usually by measuring androgen every 3 months, with varying results. To our knowledge this represents the largest study using monthly testosterone and dihydroxytestosterone measurement to evaluate the kinetics of androgen recovery following limited androgen deprivation therapy. Monthly serum androgen levels were analyzed following 2, 6-month cycles of gonadotropin-releasing hormone agonist therapy as part of a randomized, placebo controlled study of the role of thalidomide in delaying time to prostate specific androgen progression. By the Kaplan-Meier method the median time to testosterone normalization in cycles 1 vs 2 was 15.4 vs 18.3 weeks with similar dihydroxytestosterone recovery times. Neither on-study prostate specific antigen, Gleason score nor thalidomide treatment had a significant impact on time to testosterone normalization. However, in cycle 1 men with low baseline dihydroxytestosterone and those who were more than 67 years old had significantly longer time to T normalization on Cox model analysis. Additionally, in cycle 2 patients with prior local radiation therapy had longer time to testosterone normalization, although this was no longer significant on Cox model analysis. Cox model analysis in cycle 2 showed that low baseline dihydroxytestosterone and testosterone, low testosterone nadir and white race were associated with longer time to testosterone normalization. Findings of delayed testosterone recovery may be useful for designing and analyzing clinical trials of limited androgen deprivation therapy and for estimating the duration of treatment associated side effects in patients undergoing limited androgen deprivation therapy.

Chemotherapy for Advanced Prostate Cancer: 25 Years Later

Chemotherapy for Advanced Prostate Cancer: 25 Years Later

Bifurcation analysis on a hybrid systems model of intermittent hormonal therapy for prostate cancer

Hybrid systems are widely used to model dynamical phenomena that are characterized by interplay between continuous dynamics and discrete events. An example of biomedical application is modeling of disease progression of prostate cancer under intermittent hormonal therapy, where continuous tumor dynamics is switched by interruption and reinstitution of medication. In the present paper, we study a hybrid systems model representing intermittent androgen suppression (IAS) therapy for advanced prostate cancer. Intermittent medication with switching between on-treatment and off-treatment periods is intended to possibly prevent a prostatic tumor from developing into a hormone-refractory state and is anticipated as a possible strategy for delaying or hopefully averting a cancer relapse which most patients undergo as a result of long-term hormonal suppression. Clinical efficacy of IAS therapy for prostate cancer is still under investigation but at least worth considering in terms of reduction of side effects and economic costs during off-treatment periods. In the model of IAS therapy, it depends on some clinically controllable parameters whether a relapse of prostate cancer occurs or not. Therefore, we examine nonlinear dynamics and bifurcation structure of the model by exploiting a numerical method to clarify bifurcation sets in the hybrid system. Our results suggest that adjustment of the normal androgen level in combination with appropriate medication scheduling could enhance the possibility of relapse prevention. Moreover, a two-dimensional piecewise-linear system reduced from the original model highlights the origin of nonlinear phenomena specific to the hybrid system.

A nonlinear model with competition between prostate tumor cells and its application to intermittent androgen suppression therapy of prostate cancer

The recurrence of a tumor is a crucial problem in hormonal therapy of prostate cancer. Recent studies suggest that intermittent androgen suppression administration may prolong or hopefully prevent the progression to the recurrence. It was shown that a simple mathematical model is useful to understand how and why intermittent administration can be effective and to seek a better medication scheme. In this paper, we propose a new model for the intermittent androgen suppression therapy. What is central in the new model is that the competitive effect between androgen-dependent and independent cancer cells is assumed to be essential for the decrease of androgen-independent cells under a normal androgen level. In the newly proposed model, the separatrix in the phase space for a normal androgen level plays an important role. There is crucial difference between the previous model and the new one in the phase diagram of success and failure of the permanent tumor control by intermittent androgen suppression administration. That means that the suggestions from the models for clinical problems can be different. We also consider the combined model of the previous and newly proposed models, which can smoothly bridge two models.