Continuous Androgen Suppression Research Articles

Personalizing Androgen Suppression for Prostate Cancer Using Mathematical Modeling

Using a dataset of 150 patients treated with intermittent androgen suppression (IAS) through a fixed treatment schedule, we retrospectively designed a personalized treatment schedule mathematically for each patient. We estimated 100 sets of parameter values for each patient by randomly resampling each patient’s time points to take into account the uncertainty for observations of prostate specific antigen (PSA). Then, we identified 3 types and classified patients accordingly: in type (i), the relapse, namely the divergence of PSA, can be prevented by IAS; in type (ii), the relapse can be delayed by IAS later than by continuous androgen suppression (CAS); in type (iii) IAS was not beneficial and therefore CAS would have been more appropriate in the long run. Moreover, we obtained a treatment schedule of hormone therapy by minimizing the PSA of 3 years later in the worst case scenario among the 100 parameter sets by searching exhaustively all over the possible treatment schedules. If the most frequent type among 100 sets was type (i), the maximal PSA tended to be kept less than 100 ng/ml longer in IAS than in CAS, while there was no statistical difference for the other cases. Thus, mathematically personalized IAS should be studied prospectively.

Mathematical modeling of continuous and intermittent androgen suppression for the treatment of advanced prostate cancer.

Prostate cancer is one of the most prevalent types of cancer among men. It is stimulated by the androgens, or male sexual hormones, which circulate in the blood and diffuse into the tissue where they stimulate the prostate tumor to grow. One of the most important treatments for advanced prostate cancer has become androgen deprivation therapy (ADT). In this paper we present three different models of ADT for prostate cancer: continuous androgen suppression (CAS), intermittent androgen suppression (IAS), and periodic androgen suppression. Currently, many patients in the U.S. receive CAS therapy of ADT, but many undergo a relapse after several years and experience adverse side effects while receiving treatment. Some clinical studies have introduced various IAS regimens in order to delay the time to relapse, and/or to reduce the economic costs and adverse side effects. We will compute and analyze parameter sensitivity analysis for CAS and IAS which may give insight to plan effective data collection in a future clinical trial. Moreover, a periodic model for IAS is used to develop an analytical formulation for relapse times which then provides information about the sensitivity of relapse to the parameters in our models.

Optimal design of personalized prostate cancer therapy using Infinitesimal Perturbation Analysis

The standard treatment for advanced prostate cancer is hormone therapy in the form of continuous androgen suppression (CAS), which unfortunately frequently leads to resistance and relapse. An alternative scheme is intermittent androgen suppression (IAS), in which patients are submitted to cycles of treatment (in the form of androgen deprivation) and off-treatment periods in an alternating manner. In spite of extensive recent clinical experience with IAS, the design of ideal protocols for any given patient remains a challenge. The level of prostate specific antigen (PSA) is frequently monitored to determine when patients will be taken off therapy and when therapy will resume. In this work, we propose a threshold-based policy for optimal IAS therapy design that is parameterized by lower and upper PSA threshold values and is associated with a cost metric that combines clinically relevant measures of therapy success. We use a Stochastic Hybrid Automaton (SHA) model of prostate cancer evolution under IAS and perform Infinitesimal Perturbation Analysis (IPA) to adaptively adjust PSA threshold values so as to improve therapy outcomes. We also apply this methodology to clinical data from real patients, and obtain promising results and valuable insights for personalized IAS therapy design.

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.

A partial differential equation model and its reduction to an ordinary differential equation model for prostate tumor growth under intermittent hormone therapy

Hormonal therapy with androgen suppression is a common treatment for advanced prostate tumors. The emergence of androgen-independent cells, however, leads to a tumor relapse under a condition of long-term androgen deprivation. Clinical trials suggest that intermittent androgen suppression (IAS) with alternating on- and off-treatment periods can delay the relapse when compared with continuous androgen suppression (CAS). In this paper, we propose a mathematical model for prostate tumor growth under IAS therapy. The model elucidates initial hormone sensitivity, an eventual relapse of a tumor under CAS therapy, and a delay of a relapse under IAS therapy, which are due to the coexistence of androgen-dependent cells, androgen-independent cells resulting from reversible changes by adaptation, and androgen-independent cells resulting from irreversible changes by genetic mutations. The model is formulated as a free boundary problem of partial differential equations that describe the evolution of populations of the abovementioned three types of cells during on-treatment periods and off-treatment periods. Moreover, the model can be transformed into a piecewise linear ordinary differential equation model by introducing three new volume variables, and the study of the resulting model may help to devise optimal IAS schedules.

Chemotherapy in hormone-refractory prostate cancer: Docetaxel with and without VT122.

e16062 Background: Randomized study in metastatic castration resistant prostate cancer treated with docetaxel and the benefit of adding VT122. Methods: Castration resistant prostate cancer with bone metastasis, symptomatic were treated with docetaxel 75 mg/m2 every 3 week and prednisolone with continued androgen suppression, LHRH analogue and zoledronic acid, every 28 days with or without VT122. VT122 is a drug combination of etodolac, a COX-2 inhibitor and propranolol, a beta blocker with anti angiogenic properties; this combination has previously been shown to be anti cachectic, anti neoplastic.The dose of etodolac was titrated by C-reactive protein levels to a maximum of 800 mg/day. The dose of propranolol was titrated to keep heart rate at around 60 b/min to 70 b/min. GCSF was allowed, all patients were given Calcium and VitaminD. The primary end point was time to progression, a composite end point of objective progression by RECIST criteria, PSA progression or pain progression, whichever occurred first was applied.The McGill questionnaire was applied to patients. Number of patients 69; 34 in docetaxel arm; 35 in VT122 arm. Age between 50-65 years. Taken from 3 centers with PS ECOG <2 controlled comorbidity with stable analgesic regime. All patients were planned for 6 cycles of docetaxel. Follow-up was for a period of two years. Results: Median age of 62 years with ECOG status 1 was seen in 88%. The median PSA value was seen as 138 ng/ml (10 - 600). 66% in both arms had measurable disease. Conclusions: Addition of VT122 improves response rates, duration of response and symptom scales along with 1-year survival which are statistically significant; toxicities are also significantly decreased and indicating increased efficacy and safety profile of docetaxel. The efficacy and control of toxicity and easy to administer makes this an attractive combination. [Table: see text]

Type I Collagen Synthesis Marker Procollagen I N-Terminal Peptide (PINP) in Prostate Cancer Patients Undergoing Intermittent Androgen Suppression

Intermittent androgen suppression (IAS) therapy for prostate cancer patients attempts to maintain the hormone dependence of the tumor cells by cycles alternating between androgen suppression (AS) and treatment cessation till a certain prostate-specific antigen (PSA) threshold is reached. Side effects are expected to be reduced, compared to standard continuous androgen suppression (CAS) therapy. The present study examined the effect of IAS on bone metabolism by determinations of serum procollagen I N-terminal peptide (PINP), a biochemical marker of collagen synthesis. A total of 105 treatment cycles of 58 patients with prostate cancer stages ≥pT2 was studied assessing testosterone, PSA and PINP levels at monthly intervals. During phases of AS lasting for up to nine months PSA levels were reversibly reduced, indicating apoptotic regression of the prostatic tumors. Within the first cycle PINP increased at the end of the AS period and peaked in the treatment cessation phase. During the following two cycles a similar pattern was observed for PINP, except a break in collagen synthesis as indicated by low PINP levels in the first months off treatment. Therefore, measurements of the serum PINP concentration indicated increased bone matrix synthesis in response to >6 months of AS, which uninterruptedly continued into the first treatment cessation phase, with a break into each of the following two pauses. In summary, synthesis of bone matrix collagen increases while degradation decreases during off-treatment phases in patients undergoing IAS. Although a direct relationship between bone matrix turnover and risk of fractures is difficult to establish, IAS for treatment of biochemical progression of prostate tumors is expected to reduce osteoporosis in elderly men often at high risk for bone fractures representing a highly suitable patient population for this kind of therapy.

Intermittent vs continuous androgen suppression after radical therapy: survival just as good, quality of life may be better

British Journal of Hospital MedicineVol. 72, No. 4 Clinical NewsIntermittent vs continuous androgen suppression after radical therapy: survival just as good, quality of life may be betterStephen PinnStephen PinnSearch for more papers by this authorStephen PinnPublished Online:16 Aug 2013https://doi.org/10.12968/hmed.2011.72.4.191aAboutSectionsView articleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareShare onFacebookTwitterLinked InEmail View article FiguresReferencesRelatedDetails 1 April 2011Volume 72Issue 4ISSN (print): 1750-8460ISSN (online): 1759-7390 Metrics History Published online 16 August 2013 Published in print 1 April 2011 Information© MA Healthcare LimitedPDF download

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

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.

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.

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.

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.

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.

Continuous versus Six Months a Year Maximal Androgen Blockade in the Management of Prostate Cancer: A Randomised Study

ObjectiveTo evaluate systematically interrupted androgen suppression (SIAS) 6 mo a year compared with continuous androgen suppression (CAS) in prostate cancer treatment. Patients and MethodsAll patients underwent maximal androgen blockade for 6 mo. Then, depending on the randomisation arm, they continued (CAS) or stopped their treatment for 6 mo before they resumed it a year later and so on (SIAS). Primary end points were patient's health-related quality of life (HQOL) and time to progression. Secondary end points were cancer-specific and overall survival. Progression was defined by a clinical event or PSA value exceeding double the value obtained at the end of the first 6 mo of therapy. ResultsSixty-two patients were randomised to CAS and 67 to SIAS. There were no significant differences between groups at baseline. Androgen suppression was associated with HQOL deterioration except for an improvement in urinary symptoms. The 6-mo off-therapy period was not long enough to regain normal testosterone values. There was no difference in HQOL scores between CAS and SIAS except that men in the latter group reported a greater need for painkillers but a better ability to have an erection. Progression occurred in 62 patients (48.1%) with no significant difference between CAS and SIAS with a mean follow-up of 44.8 mo. Death occurred in 41 patients and specific death in 19 patients (10% and 19% of the CAS and SIAS groups, respectively). ConclusionsAlthough patients in the SIAS group were maintained off-therapy 50% of the time, insufficient testosterone recovery in this group likely explains why differences between the two groups were moderate or absent with regards to HQOL and survival, respectively.

Intermittent versus continuous androgen suppression for prostatic cancer

After lung cancer, prostate cancer is the most common cause of death among males. The aim of treatment is to prevent disease-related morbidity and mortality while minimizing intervention-related adverse events. Androgen suppression therapy (AST) to reduce circulating serum testosterone and disease progression is considered a mainstay of treatment for men with advanced prostate cancer. It has been increasingly utilized for early stage disease despite a lack of evidence of effectiveness. Evaluate the effectiveness and safety of intermittent androgen suppression (IAS) compared to continuous androgen suppression for treating prostatic cancer. The following databases were searched to identify randomised or quasi-randomised, controlled trials comparing intermittent and continuous androgen suppression in the treatment of any stage of prostate cancer: the Cochrane Central Register of Controlled Trials; EMBASE and LILACS. Studies were included if they were randomised or quasi-randomized, and compare the effects of IAS versus CAS. Two reviewers selected relevant trials, assessed methodological quality and extracted data. Five randomized studies involving 1382 patients were included in this review. All the included studies involved advanced (T3 or T4) prostate cancer, had relatively small populations, and were of short duration. Few events were reported and did not assess disease-specific survival or metastatic disease. Only one study (N = 77) evaluated biochemical outcomes. A subgroup analysis found no significant differences in biochemical progression (defined by the authors as PSA >/= 10 ng/mL) between IAS and CAS for Gleason scores 4 - 6, 7, and 8 - 10. For patients with a Gleason score > 6, reduction in biochemical progression favoured the IAS group (RR 0.10, 95% CI 0.01 to 0.67, P = 0.02). Studies primarily reported on adverse events. One trial (N = 43) found no difference in adverse effects (gastrointestinal, gynecomastia and asthenia) between IAS ( two events) and CAS (five events), with the exception of impotence, which was significantly lower in the IAS group (RR 0.72, 95% CI 0.56 to 0.92, P = 0.008). Data from RCTs comparing IAS to CAS are limited by small sample size and short duration. There are no data for the relative effectiveness of IAS versus CAS for overall survival, prostate cancer-specific survival, or disease progression. Limited information suggests IAS may have slightly reduced adverse events. Overall, IAS was also as effective as CAS for potency, but was superior during the interval of cycles (96%).

POS-03.108: Impacts of intermittent androgen suppression on bone mineral density, fat metabolism and anemia in patients with locally advanced prostate cancer

Long-term androgen suppression (AS) with external beam radiation therapy (EBRT) may be one of the most effective treatments for patients with locally advanced prostate cancer. Alternatively, long-term AS may make bone mineral density (BMD), fat metabolism, anemia and other physiological factors get worse. We are now working on randomized controlled trial (RCT) comparing adjuvant IAS vs. continuous AS (CAS) following 14-month of AS and EBRT for patients with locally advanced prostate cancer (Prostate 63: 56, 2005).

Hormone‐refractory prostate cancer: what have we learned?

The current EAU guidelines recommend continued androgen suppression in patients not treated by orchidectony and with HRPC, although few studies have addressed the benefits of this approach. The EAU recommendation was based primarily on evidence reported by Manni et al. [4], who conducted a small randomized trial to determine whether androgen priming potentiates the cytotoxic effects of chemotherapy. In all, 85 men with disease progression despite orchidectomy were randomly selected to receive androgen priming or chemotherapy alone. The median survival of men who received androgen priming (10 months) was significantly worse than that of men who did not (15 months; P = 0.005), a result indicating that continuous androgen blockade might be beneficial in men with HRPC.