Clinical Prostate Cancer Cases Research Articles

Stochastic Local Search for the Direct Aperture Optimisation Problem

Intensity modulated radiation therapy (IMRT) is a widely applied cancer treatment technique that aims at effectively deliver radiation to cancerous cells while sparing surrounding healthy tissues. To this end, the radiation coming from a linear accelerator is modulated using a physical device called multi-leaf collimator.Traditionally, a sequential approach is applied to generate treatment plans in IMRT. In this approach, the optimal intensities for each beam angle are computed (Fluence Map Optimisation, FMO), and then a sequencing problem is solved to obtain the collimator setup (aperture shapes) required to achieve the intensities computed for the FMO problem. The sequencing step is critical as the treatment plans computed to solve the FMO problem are not clinically acceptable. Unfortunately, treatment plans obtained by the sequencing step are severely impaired w.r.t. those obtained in the FMO step. One approach that aims to deal with the problem described above is the Direct Aperture Optimisation (DAO) approach. The DAO problem aims at simultaneously determining deliverable aperture shapes and a set of radiation intensities. This approach considers both physical and delivery time constraints, allowing to generate clinically acceptable treatment plans.In this paper, we propose a stochastic local search algorithm to solve the DAO problem. Our approach alternates the search between two neighbourhood definitions; the first focused on the fluence map (intensities) and the second on the aperture shapes. We analyse the algorithmic components, parameters, and overall results obtained by our algorithm on a set of clinical prostate cancer cases. We compare the obtained treatment plans to the ones obtained by the traditional two-step approach. Results show that our algorithm is able to find deliverable treatment plans without major impairments in treatment plans quality.

Abstract 1566: Notch-1 regulation of the PTEN - mTOR axis in prostate

Abstract Prostate cancer affects one in three men over the age of 60. Loss of expression or function of PTEN is the most commonly observed molecular defect in human prostate cancer. Thirty to 70% of clinical cases exhibit loss of this critical tumor suppressor. PTEN is an essential negative regulator of PI3K/Akt signaling. Together with the mTOR pathway, the PTEN/PI3K/Akt cascade forms a network for cellular responses to growth factors and nutrients. Studies in mice have demonstrated that small changes in PTEN dose can influence cancer development. Thus, understanding the regulation of PTEN expression and function is key to understanding tumor progression. We have previously reported that signaling through the Notch-1 receptor pathway results in increased transcriptional expression of the tumor suppressor PTEN. We further reported that Notch-1 signaling was lost in the tumor foci of clinical prostate cancer cases as compared to the surrounding benign tissue. Herein, we report that Notch-1 signaling alters the pool of active, unphosphorylated PTEN in the human metastatic prostate tumor cell line DU145. Retroviral transduction was used to generate DU145 cells that express constitutively active Notch-1 (DU/ICN1). In cells with constitutively active Notch-1 (DU/ICN1), the pool of unphosphorylated PTEN was increased roughly 2.5 fold compared to the vector only control. Constitutive Notch-1 signaling also resulted in decreased mTOR signaling as determined by a decrease in phosphorlyated 4E-BP1 and phosphorylated S6 ribosomal protein. Decreased expression of Raptor and Rictor and decreased phosphorylation of mTOR were also observed in the presence of constitutively active Notch-1. To test if Notch-1 signaling influences tumor engraftment and growth in a syngeneic model, the tumorigenic C2 cell line, derived from TRAMP mice, was transduced with constitutively active Notch-1. C2/ICN1 and parental C2 cells were engrafted into C57/BL6 mice. All recipients of the parental C2 cell line developed tumors within 46 days, whereas none that received cells expressing constitutively active Notch-1 (C2/ICN1) had developed tumors. Only after 61 days did one of the four mice that received C2/ICN1 cells develop tumors. We next tested if loss of Notch-1 expression promotes characteristics associated with tumorigenicity by using lentiviral transduction to knock down endogenous Notch-1 expression in DU145 cells (DU/shN1). DU145 cells with loss of Notch-1 (DU/shN1) exhibited decreased expression of PTEN protein and a decreased ability to migrate in transwell experiments as compared with control cells expressing endogenous Notch-1. Collectively, these data indicate a role for Notch-1 receptor signaling in modulating the activity of PI3K/Akt and mTOR axis through regulation of the PTEN tumor suppressor, and suggest a mechanistic basis for Notch-1 tumor suppressive activity in prostate cells. Citation Format: Jennifer M. Nutter, C William Angus, Fred E. Bertrand. Notch-1 regulation of the PTEN - mTOR axis in prostate. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1566. doi:10.1158/1538-7445.AM2014-1566

A new column-generation-based algorithm for VMAT treatment plan optimization

We study the treatment plan optimization problem for volumetric modulated arc therapy (VMAT). We propose a new column-generation-based algorithm that takes into account bounds on the gantry speed and dose rate, as well as an upper bound on the rate of change of the gantry speed, in addition to MLC constraints. The algorithm iteratively adds one aperture at each control point along the treatment arc. In each iteration, a restricted problem optimizing intensities at previously selected apertures is solved, and its solution is used to formulate a pricing problem, which selects an aperture at another control point that is compatible with previously selected apertures and leads to the largest rate of improvement in the objective function value of the restricted problem. Once a complete set of apertures is obtained, their intensities are optimized and the gantry speeds and dose rates are adjusted to minimize treatment time while satisfying all machine restrictions. Comparisons of treatment plans obtained by our algorithm to idealized IMRT plans of 177 beams on five clinical prostate cancer cases demonstrate high quality with respect to clinical dose–volume criteria. For all cases, our algorithm yields treatment plans that can be delivered in around 2 min. Implementation on a graphic processing unit enables us to finish the optimization of a VMAT plan in 25–55 s.

An efficient approach to incorporating interfraction motion in IMRT treatment planning

Intensity modulated radiation therapy (IMRT) is one of the most widely used delivery modalities for radiation therapy for cancer patients. A patient is typically treated in daily fractions over a period of 5–9 weeks. In this paper, we consider the problem of accounting for changes in patient setup location and internal geometry between the treatment fractions, usually referred to as interfraction motion. The conventional method is to add a margin around the clinical tumor volume (CTV) to obtain a planning target volume (PTV). A fluence map optimization (FMO) model is then solved to determine the optimal intensity profiles to deliver to the patient. However, a margin-based method may not adequately model the changes in dose distributions due to the random nature of organ motion. Accounting for interfraction motion in the FMO model essentially transforms the deterministic optimization problem into a stochastic one. We propose a stochastic FMO model that employs convex penalty functions to control the treatment plan quality and uses a large number of scenarios to characterize interfraction motion uncertainties. Some effects of radiotherapy are impacted mainly by the dose distribution in a given treatment fraction while others tend to manifest themselves over time and depend mostly on the total dose received over the course of treatment. We will therefore formulate an optimization model that explicitly incorporates treatment plan evaluation criteria that apply to the total dose received over all treatment fractions and ones that apply to the dose per fraction. Particularly when many structures fall into the former category, this can lead to significant reductions in the dimension of the optimization model and therefore the time required to solve it. We test an example of our model on five clinical prostate cancer cases, showing the efficacy of our approach. In particular, compared to a traditional margin-based treatment plan, our plans exhibit significantly improved target dose coverage and clinically equivalent critical structure sparing at only a modest increase in computational effort.

Optimization of couch translational corrections to compensate for rotational and deformable target deviations in image guided radiotherapy

The utilization of image-guided radiotherapy (IGRT) technologies helps correct temporal and spatial deviations of the target volume relative to planned radiation beams. With the aid of these IGRT technologies, it becomes possible to better identify the target volume before and even during radiation treatment. However, since components of the detected deviations may be translational, rotational, and deformable, the question remains whether simple treatment-couch translational movement can be optimized to compensate for these complicated deviations. Deviation of the target volume and changes in patient body shape from that acquired for treatment planning may further add to the variations from planned dose distribution. In this study, an optimization strategy is developed to investigate these issues. The optimization process involved the use of the hill climbing algorithm, the detected target volume and patient body shape, and the dose distribution based on acquired images at treatment. During the process, the planned dose distribution was iteratively adjusted to reflect the changes of depth and distance as the translational treatment couch movement was being optimized. The optimal treatment couch movement was considered achieved when the highest fraction of the detected target volume was covered by prescription dose. This optimization strategy was evaluated on clinical prostate cancer cases. For each of the cases, cone beam computed tomography (CBCT) images were acquired right after fiducial marker-based kilovolt orthogonal imaging verification and setup adjustment. Based on the CBCT images, the clinical target volume at the treatment was delineated and the translational treatment-couch movements were optimized with the developed strategy. The resultant dose coverage was compared to that without the optimization. The results showed that with the present strategy, rotational and deformable target deviations can be further compensated with translational couch correction.

Deletion at chromosome arms 6q16–22 and 10q22.3–23.1 associated with initiation of prostate cancer

Loss of heterozygosity (LOH) at 6q16-22 and 10q22.3-23.1 is common chromosomal alteration in advanced prostate cancer and suggests that one or more tumor suppressor genes may lie within these chromosome arms. However, the genetic changes in early stage prostate cancer and premalignant lesions remain to be investigated. We used 11 informative microsatellite markers at 6q16-22 and 10q22.3-23.1 in Japanese patients to compare the frequency of LOH in 53 lesions of high-grade prostatic intraepithelial neoplasia (HGPIN), 38 cases (38 lesions) of incidental prostate cancer (IPC) and 107 cases (168 lesions) of clinical prostate cancer (CPC). The frequency of LOH at 6q16-22 with at least one marker was 38 and 49% in IPC and CPC cases, respectively. Similarly, allelic loss at 10q22.3-23.1 was present in 35 and 39% of IPC and CPC, respectively. High-frequency LOH was detected in both the clinically insignificant and significant prostate cancers at 6q16-22 and 10q22.3-23.1 (P>0.05). However, no allelic loss was detected in any markers at the same regions in HGPIN (0%), which is usually considered a premalignant lesion to prostate cancer. Deletions of both the chromosome regions, 6q16-22 and 10q22.3-23.1, are more likely important events in the initiation and/or promotion of prostate cancer.

A strategy to objectively evaluate the necessity of correcting detected target deviations in image guided radiotherapy

Image guided radiotherapy technologies are being increasingly utilized in the treatment of various cancers. These technologies have enhanced the ability to detect temporal and spatial deviations of the target volume relative to planned radiation beams. Correcting these detected deviations may, in principle, improve the accuracy of dose delivery to the target. However, in many situations, a clinical decision has to be made as to whether it is necessary to correct some of the deviations since the relevant dosimetric impact may or may not be significant, and the corresponding corrective action may be either impractical or time consuming. Ideally this decision should be based on objective and reproducible criteria rather than subjective judgment. In this study, a strategy is proposed for the objective evaluation of the necessity of deviation correction during the treatment verification process. At the treatment stage, without any alteration from the planned beams, the treatment beams should provide the desired dose coverage to the geometric volume identical to the planning target volume (PTV). Given this fact, the planned dose distribution and PTV geometry were used to compute the dose coverage and PTV enclosure of the clinical target volume (CTV) that was detected from imaging during the treatment setup verification. The spatial differences between the detected CTV and the planning CTV are essentially the target deviations. The extent of the PTV enclosure of the detected CTV as well as its dose coverage were used as criteria to evaluate the necessity of correcting any of the target deviations. This strategy, in principle, should be applicable to any type of target deviations, including both target deformable and positional changes and should be independent of how the deviations are detected. The proposed strategy was used on two clinical prostate cancer cases. In both cases, gold markers were implanted inside the prostate for the purpose of treatment setup verification and were used to determine potential target deviations. To derive the detected CTV geometry from the planning CTV based on the locations of the gold markers, the CTV was approximated with an elastic semirigid body model. The derived CTV geometry and shape were confirmed with CBCT imaging. The evaluation results and the related mathematical equations and computational algorithm are presented. It is concluded that the proposed strategy is potentially useful in establishing objective criteria for the necessity of correction of the target deviations.

Allelotyping analysis at chromosome arm 8p of high‐grade prostatic intraepithelial neoplasia and incidental, latent, and clinical prostate cancers

In this study, we used 7 informative microsatellite markers at 8p22, 23.1, and 23.2 in Japanese patients to compare frequency of loss of heterozygosity (LOH) in 53 lesions of high-grade prostatic intraepithelial neoplasia (HGPIN), 38 cases (38 lesions) of incidental prostate cancer (IPC), 31 cases (41 lesions) of latent prostate cancer (LPC), and 102 cases (168 lesions) of clinical prostate cancer (CPC). The frequency of LOH at 8p22-23.2 with at least 1 marker was 0%, 33%, 57%, and 51% in the HGPIN, IPC, LPC, and CPC cases, respectively. No statistically significant difference was found at 8p22-23.2 between the types of prostate cancer. However, the frequency of 8p22 deletion was significantly higher in CPC and LPC cases than in IPC cases (P = 0.0003) or lesions (P = 0.0017). The frequency of LOH at 8p22 and 8p23.1 loci in high-grade tumors was significantly higher than in low-grade tumors in both the LPCs/IPCs and CPCs (P < 0.05). Allelic loss at 8p22 was significantly more frequent in CPC than in IPC (P = 0.002) and in pT4 CPC than in earlier-stage CPC (P = 0.038). These findings suggest that deletion of 8p is an important event in both the initiation and metastasis of prostate cancer. The extremely high frequency of LOH at 8p22-23.1 in high-grade tumors suggests the existence of a novel putative tumor-suppressor gene associated with the progression of prostate cancer. These results should be useful in identifying the target gene of deletion at 8p.

Genetic abnormalities specifically associated with varying metastatic potential of prostate cancer cell lines as detected by comparative genomic hybridization

Established recently are two in vivo prostate tumor progression models in which subclones of the PC3M and LNCaP cell lines were selected for varying growth characteristics and metastatic potential after successive orthotopic implantation in the prostate of nude mice. In this study, we used comparative genomic hybridization (CGH) to compare the chromosomal abnormalities between the parental cell lines and their respective variants and to determine if specific chromosomal abnormalities can be identified that are associated with different growth properties. PC3M and its derivative cell lines PC3M-Pro4 and PC3M-LN4 shared gains of 8q22–qter, 10q21–q22, and Xq27–qter and loss of 13q33–qter. PC3M-Pro4, a derivative line that produced significantly larger tumors in the prostate, had a unique gain of 3q13. In contrast, PC3M-LN4, the derivative line that produced significantly larger metastatic tumors in the lymph nodes and had higher incidences of distant metastases, had a specific gain of 1q21–q22 and losses of 10q23–qter and 18q12–q21. In the second in vivo model, LNCaP and its derivative cell lines shared gain of 3q27–qter and loss on 13q21–qter. The derivative line that produced significantly larger tumors in the prostate, LNCaP-Pro5, had a unique gain on 13q12–q13. In comparison, LNCaP-LN3, a derivative line that had a significantly higher incidence of lymph node metastases and produced significantly larger metastatic tumors in the lymph nodes, had specific losses of 16q23–qter and 21q. Interestingly, some regions of loss (e.g., 10q23→qter, 16q23→qter, and 18q12→q21) detected in the variant cell lines correlated well with abnormalities seen in clinical prostate cancer cases. Thus, our data suggest not only that these cell lines are relevant in vivo models for prostate cancer progression, but also that CGH is a valuable tool for uncovering chromosomal regions that are important for aggressive growth and metastsis of prostate cancer cells.