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June  2017, 14(3): 777-804. doi: 10.3934/mbe.2017043

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

 1 United Services Automobile Association, 9800 Fredericksburg Rd, San Antonio, TX 78288, USA 2 Sam Houston State University, Department of Mathematics and Statistics, Huntsville, TX 77341, USA

* Corresponding author: edward.swim@shsu.edu

Received  August 04, 2016 Published  December 2016

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.

Citation: Alacia M. Voth, John G. Alford, Edward W. Swim. Mathematical modeling of continuous and intermittent androgen suppression for the treatment of advanced prostate cancer. Mathematical Biosciences & Engineering, 2017, 14 (3) : 777-804. doi: 10.3934/mbe.2017043
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Solutions for all three compartments in the CAS model are presented. Baseline values for all parameters are used, as shown in Table 1.
CAS sensitivity of androgen concentration, sγa, with respect to the concentration rate γ. The negative sensitivity indicates that as γ is increased, androgen concentration will decrease
CAS sensitivity of androgen dependent cells (x1) to the proliferation rate α1, shown in (a), and the apoptosis rate β1, shown in (b)
CAS sensitivity of androgen independent tumor cells, sγx2, with respect to the androgen concentration rate γ.
CAS sensitivity of androgen independent tumor cells, sx2m1, with respect to the maximum mutation rate m1
Sample plots of the treatment function u(t), as determined by (19), based on a parameter value of λ = 1100. Here we illustrate the behavior for κ = 0 in (a) and κ = 1 − β2/α2 in (b).
These graphs illustrate the long term behavior of the androgen levels a(t), plotted as a dotted line, and serum PSA concentration y(t), plotted as a solid line, using the model from equations (22)-(25). The plots in (a) correspond to κ = 0 and in (b) correspond to κ = 1 − β2/α2.
Sensitivity analysis for androgen concentration, sγa, androgen dependent tumor cells, sγx1, and androgen independent tumor cells, sγx2, with respect to the parameter γ for intermittent treatment. The left column presents results for κ = 0, while the right column presents the sensitivities when κ = 1 − β2/α2. Here red depicts on-treatment while black depicts off-treatment.
Sensitivity analysis for androgen concentration, sam1, androgen dependent tumor cells, sx1m1, and androgen independent tumor cells, sx2m1, with respect to the mutation parameter m1 for intermittent treatment. The left column presents results for κ = 0, while the right column presents the sensitivities when κ = 1 − β2/α2. Here red depicts on-treatment while black depicts off-treatment.
Sensitivity analysis for androgen concentration, sar0, androgen dependent tumor cells, sx1r0, and androgen independent tumor cells, sx2r0, with respect to the parameter r0 for intermittent treatment. The left column presents results for κ = 0, while the right column presents the sensitivities when κ = 1 − β2/α2. Here red depicts on-treatment while black depicts off-treatment.
These boxplots illustrate the relative sensitivity of the IAS model to each parameter for the case κ = 0. In subfigure (b) data for the three parameters for which the median relative sensitivity exceeded the others by at least an order of magnitude are summarized. For clarity of the display, boxplots for the remaining parameters are presented in (a).
These boxplots illustrate the relative sensitivity of the IAS model to each parameter for the case κ = 1 − β2/α2. Here we have preserved the same arrangement of parameters as displayed in Figure 11
These curves show the relapse time from (36) with y = 20 and the on-treatment time from (37) where κ = 0 in (a) and κ = 1 − β2/α2 in (b). The solid curves use the ITTA model for IAS with u as in (11) and the dashed curves use our model for IAS with u as in (19).
The periodic androgen suppression model where y(t) = x1(t) + x2(t) is plotted (solid) with x1(t) and x2(t) computed as in (41) with κ = 0 on the left and κ = 1 − β2/α2 on the right. The androgen level a(t) is also plotted (dash-dot) and oscillates with period T = 200 in both cases. The initial conditions are a(0) = 30, x1(0) = 15, and x2(0) = 0.01.
The solid and dash-dot curves show the relapse time TR and on-treatment time Ton respectively for the PAS model with TR as in (36) where y = 20 and Ton from (37). Here we use κ = 0 in (a) and κ = 1 − β2/α2 in (b). The dashed curves show the approximation of relapse time from (61) in (a) and (64) in (b).
This plot depicts the relapse time as it depends on κ for the continuous model. The dashed curve is the relapse time TR (where y = 20) as a function of κ estimated from (61) with |ζ1| as in (66). The solid curve is the relapse time as it depends on κ computed using the model equations (2) and (3) with continuous androgen suppression and solving x1(t) + x2(t) = 20 for t.
This figure shows the sensitivity indices of relapse time TR from (67) for the periodic model. The box plots summarize the values of $\Upsilon$θTR computed from 100 random draws of the period T distributed normally with mean 425 days and standard deviation 25 days. In the top row κ = 0 and the relapse time TR was computed from (61). In the bottom row κ = 1 − β2/α2 and the relapse time TR was computed from (64). The parameter values p are displayed along the horizontal axis. Outliers are not displayed.
This figure shows the sensitivity indices of relapse time TR from (67) for the continuous model. The box plots summarize the values of $\Upsilon$θTR computed from 100 random draws of κ distributed normally with mean 0.5 and standard deviation 0.165. The relapse time TR was computed from (61) with |ζ1| replaced by (66). The parameter values p are displayed along the horizontal axis. Outliers are not displayed.
Parameter values used for continuous, intermittent and periodic androgen suppression models are listed with their baseline value, units of measurement, and a range of values used for data simulation
 Parameter Variable Baseline Value Range Normal androgen level $a_0$ 30 nmol/l 26.25-33.75 nmol/l Androgen concentration rate $\gamma$ 0.08 days$^{-1}$ 0.0425-0.1175 days$^{-1}$ Androgen dependent proliferation rate $\alpha_1$ 0.0204 days$^{-1}$ 0.0129-0.0279 days$^{-1}$ Androgen dependent apoptosis rate $\beta_1$ 0.0076 days$^{-1}$ 0.00685-0.00835 days$^{-1}$ Androgen independent proliferation rate $\alpha_2$ 0.0242 days$^{-1}$ 0.0216-0.0268 days$^{-1}$ Androgen independent apoptosis rate $\beta_2$ 0.0168 days$^{-1}$ 0.0130-0.0206 days$^{-1}$ Maximum mutation rate $m_1$ 0.00005 days$^{-1}$ 1.25-8.75$\times10^{-5}$ days$^{-1}$ AD proliferation half-saturation level $k_2$ 2 nmol/l 1.25-2.75 nmol/l AD androgen free apoptosis constant $k_3$ 8 7.25-8.75 AD apoptosis rate half-saturation level $k_4$ 0.5 nmol/l 0.275-0.725 nmol/l Minimum PSA concentration $r_0$ 10 ng/ml 6.5-13.5 ng/ml Maximum PSA concentration $r_1$ 15 ng/ml 11.5-18.5 ng/ml Treatment transition rate $\lambda$ 1100 days$^{-1}$ 500-1700 days$^{-1}$
 Parameter Variable Baseline Value Range Normal androgen level $a_0$ 30 nmol/l 26.25-33.75 nmol/l Androgen concentration rate $\gamma$ 0.08 days$^{-1}$ 0.0425-0.1175 days$^{-1}$ Androgen dependent proliferation rate $\alpha_1$ 0.0204 days$^{-1}$ 0.0129-0.0279 days$^{-1}$ Androgen dependent apoptosis rate $\beta_1$ 0.0076 days$^{-1}$ 0.00685-0.00835 days$^{-1}$ Androgen independent proliferation rate $\alpha_2$ 0.0242 days$^{-1}$ 0.0216-0.0268 days$^{-1}$ Androgen independent apoptosis rate $\beta_2$ 0.0168 days$^{-1}$ 0.0130-0.0206 days$^{-1}$ Maximum mutation rate $m_1$ 0.00005 days$^{-1}$ 1.25-8.75$\times10^{-5}$ days$^{-1}$ AD proliferation half-saturation level $k_2$ 2 nmol/l 1.25-2.75 nmol/l AD androgen free apoptosis constant $k_3$ 8 7.25-8.75 AD apoptosis rate half-saturation level $k_4$ 0.5 nmol/l 0.275-0.725 nmol/l Minimum PSA concentration $r_0$ 10 ng/ml 6.5-13.5 ng/ml Maximum PSA concentration $r_1$ 15 ng/ml 11.5-18.5 ng/ml Treatment transition rate $\lambda$ 1100 days$^{-1}$ 500-1700 days$^{-1}$
Median relative sensitivities of the cost function J to the parameters in the IAS model. These statistics are based on 100 simulated data sets generated using random samples of the parameters from independent normal distributions with means given by the baseline values in Table 1 and standard deviations that limit the sample coefficients of variation to no more than 30%.
 $\theta$ $\Upsilon^J_{\theta}$, $\kappa=0$ $\Upsilon^J_{\theta}$, $\kappa=1-\beta_2/\alpha_2$ $r_0$ $-1362$ $-50.19$ $\alpha_2$ $-292.9$ $-9.261$ $\beta_2$ $+189.3$ $+6.416$ $m_1$ $-9.609$ $-0.2761$ $\alpha_1$ $-8.772$ $+0.8986$ $\beta_1$ $+6.459$ $+1.246$ $\gamma$ $+3.463$ $-0.3032$ $k_3$ $+2.658$ $+0.07086$ $k_4$ $+1.807$ $+0.1499$ $k_2$ $+1.433$ $+0.2360$ $a_0$ $+0.3096$ $-0.6929$ $\lambda$ $-0.03408$ $-0.003861$ $r_1$ $-0.002916$ $-0.0003114$
 $\theta$ $\Upsilon^J_{\theta}$, $\kappa=0$ $\Upsilon^J_{\theta}$, $\kappa=1-\beta_2/\alpha_2$ $r_0$ $-1362$ $-50.19$ $\alpha_2$ $-292.9$ $-9.261$ $\beta_2$ $+189.3$ $+6.416$ $m_1$ $-9.609$ $-0.2761$ $\alpha_1$ $-8.772$ $+0.8986$ $\beta_1$ $+6.459$ $+1.246$ $\gamma$ $+3.463$ $-0.3032$ $k_3$ $+2.658$ $+0.07086$ $k_4$ $+1.807$ $+0.1499$ $k_2$ $+1.433$ $+0.2360$ $a_0$ $+0.3096$ $-0.6929$ $\lambda$ $-0.03408$ $-0.003861$ $r_1$ $-0.002916$ $-0.0003114$
Average sensitivity indices of relapse time TR for the data depicted in Figures 17 and 18 where Periodic (ⅰ) is κ = 0 and Periodic (ⅱ) is κ = 1 − β2/α2
 Parameter Periodic (ⅰ) Periodic (ⅱ) Continuous $a_0$ $-0.017$ $-0.0091$ $-0.0058$ $\gamma$ $+0.069$ $+0.035$ $+0.032$ $\alpha_1$ $-0.075$ $-0.041$ $-0.054$ $\beta_1$ $+0.13$ $+0.070$ $+0.11$ $\alpha_2$ $-3.12$ $-1.69$ $-3.15$ $\beta_2$ $+2.18$ $+1.18$ $+2.20$ $m_1$ $-0.13$ $-0.074$ $-0.13$ $k_2$ $+0.0069$ $+0.0037$ $+0.0034$ $k_3$ $+0.10$ $+0.054$ $+0.091$ $k_4$ $+0.0099$ $+0.0053$ $+0.0024$ $T$ $+0.033$ $+0.47$ $-$
 Parameter Periodic (ⅰ) Periodic (ⅱ) Continuous $a_0$ $-0.017$ $-0.0091$ $-0.0058$ $\gamma$ $+0.069$ $+0.035$ $+0.032$ $\alpha_1$ $-0.075$ $-0.041$ $-0.054$ $\beta_1$ $+0.13$ $+0.070$ $+0.11$ $\alpha_2$ $-3.12$ $-1.69$ $-3.15$ $\beta_2$ $+2.18$ $+1.18$ $+2.20$ $m_1$ $-0.13$ $-0.074$ $-0.13$ $k_2$ $+0.0069$ $+0.0037$ $+0.0034$ $k_3$ $+0.10$ $+0.054$ $+0.091$ $k_4$ $+0.0099$ $+0.0053$ $+0.0024$ $T$ $+0.033$ $+0.47$ $-$
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