Pharmacokinetics and Pharmacodynamic Effect of a Blood-Brain Barrier-Crossing Fusion Protein Therapeutic for Alzheimer's Disease in Rat and Dog.

PURPOSE: We have recently demonstrated the brain-delivery of an Amyloid-ß oligomer (Aßo)-binding peptide-therapeutic fused to the BBB-crossing single domain antibody FC5. The bi-functional fusion protein, FC5-mFc-ABP (KG207-M) lowered both CSF and brain Aß levels after systemic dosing in transgenic mouse and rat models of Alzheimer's disease (AD). For development as a human therapeutic, we have humanized and further engineered the fusion protein named KG207-H. The purpose of the present study was to carry out comparative PK/PD studies of KG207-H in wild type rat and beagle dogs (middle-aged and older) to determine comparability of systemic PK and CSF exposure between rodent species and larger animals with more complex brain structure such as dogs. METHOD: Beagle dogs were used in this study as they accumulate cerebral Aß with age, as seen in human AD patients, and can serve as a model of sporadic AD. KG207-H (5 to 50 mg/kg) was administered intravenously and serum and CSF samples were serially collected for PK studies and to assess target engagement. KG207-H and Aß levels were quantified using multiplexed selected reaction monitoring mass spectrometry. RESULTS: After systemic dosing, KG207-H demonstrated similar serum pharmacokinetics in rats and dogs. KG207-H appeared in the CSF in a time- and dose-dependent manner with similar kinetics, indicating CNS exposure. Further analyses revealed a dose-dependent inverse relationship between CSF KG207-H and Aß levels in both species indicating target engagement. CONCLUSION: This study demonstrates translational attributes of BBB-crossing Aß-targeting biotherapeutic KG207-H in eliciting a pharmacodynamic response, from rodents to larger animal species.

Preclinical in vivo longitudinal assessment of KG207-M as a disease-modifying Alzheimer's disease therapeutic.

In vivo biomarker abnormalities provide measures to monitor therapeutic interventions targeting amyloid-ß pathology as well as its effects on downstream processes associated with Alzheimer's disease pathophysiology. Here, we applied an in vivo longitudinal study design combined with imaging and cerebrospinal fluid biomarkers, mirroring those used in human clinical trials to assess the efficacy of a novel brain-penetrating anti-amyloid fusion protein treatment in the McGill-R-Thy1-APP transgenic rat model. The bi-functional fusion protein consisted of a blood-brain barrier crossing single domain antibody (FC5) fused to an amyloid-ß oligomer-binding peptide (ABP) via Fc fragment of mouse IgG (FC5-mFc2a-ABP). A five-week treatment with FC5-mFc2a-ABP (loading dose of 30 mg/Kg/iv followed by 15 mg/Kg/week/iv for four weeks) substantially reduced brain amyloid-ß levels as measured by positron emission tomography and increased the cerebrospinal fluid amyloid-ß42/40 ratio. In addition, the 5-week treatment rectified the cerebrospinal fluid neurofilament light chain concentrations, resting-state functional connectivity, and hippocampal atrophy measured using magnetic resonance imaging. Finally, FC5-mFc2a-ABP (referred to as KG207-M) treatment did not induce amyloid-related imaging abnormalities such as microhemorrhage. Together, this study demonstrates the translational values of the designed preclinical studies for the assessment of novel therapies based on the clinical biomarkers providing tangible metrics for designing early-stage clinical trials.

7-Fluorosialyl Glycosides Are Hydrolysis Resistant but Readily Assembled by Sialyltransferases Providing Easy Access to More Metabolically Stable Glycoproteins.

The maintenance of therapeutic glycoproteins within the circulatory system is associated, in large part, with the integrity of sialic acids as terminal sugars on the glycans. Glycoprotein desialylation, either by spontaneous cleavage or through host sialidases, leads to protein clearance, mainly through the liver. Thus, the installation of minimally modified sialic acids that are hydrolysis-resistant yet biologically equivalent should lead to increased circulatory half-lives and improved pharmacokinetic profiles. Here we describe the chemoenzymatic synthesis of CMP-sialic acid sugar donors bearing fluorine atoms at the 7-position, starting from the corresponding 4-deoxy-4-fluoro-N-acetylhexosamine precursors. For the derivative with natural stereochemistry we observe efficient glycosyl transfer by sialyltransferases, along with improved stability of the resultant 7-fluorosialosides toward spontaneous hydrolysis (3- to 5-fold) and toward cleavage by GH33 sialidases (40- to 250-fold). Taking advantage of the rapid transfer of 7-fluorosialic acid by sialyltransferases, we engineered the O-glycan of Interferon α-2b and the N-glycans of the therapeutic glycoprotein α1-antitrypsin. Studies of the uptake of the glyco-engineered α1-antitrypsin by HepG2 liver cells demonstrated the bioequivalence of 7-fluorosialic acid to sialic acid in suppressing interaction with liver cell lectins. In vivo pharmacokinetic studies reveal enhanced half-life of the protein decorated with 7-fluorosialic acid relative to unmodified sialic acid in the murine circulatory system. 7-Fluorosialylation therefore offers considerable promise as a means of prolonging circulatory half-lives of glycoproteins and may pave the way toward biobetters for therapeutic use.

Enhanced anti-metastatic bioactivity of an IGF-TRAP re-engineered to improve physicochemical properties.

The insulin-like growth factor (IGF) axis has been implicated in the progression of malignant disease and identified as a clinically important therapeutic target. Several IGF-1 receptor (IGF-1R) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signalling. We previously reported on the production of a soluble fusion protein consisting of the extracellular domain of human IGF-1R fused to the Fc portion of human IgG1 (first generation IGF-TRAP) that bound human IGF-1 and IGF-2 with a 3 log higher affinity than insulin. We showed that the IGF-TRAP had potent anti-cancer activity in several pre-clinical models of aggressive carcinomas. Here we report on the re-engineering of the IGF-TRAP with the aim of improving physicochemical properties and suitability for clinical applications. We show that cysteine-serine substitutions in the Fc hinge region of IGF-TRAP eliminated high-molecular-weight oligomerized species, while a further addition of a flexible linker, not only improved the pharmacokinetic profile, but also enhanced the therapeutic profile of the IGF-TRAP, as evaluated in an experimental colon carcinoma metastasis model. Dose-response profiles of the modified IGF-TRAPs correlated with their bio-availability profiles, as measured by the IGF kinase-receptor-activation (KIRA) assay, providing a novel, surrogate biomarker for drug efficacy. This study provides a compelling example of structure-based re-engineering of Fc-fusion-based biologics for better manufacturability that also significantly improved pharmacological parameters. It identifies the re-engineered IGF-TRAP as a potent anti-cancer therapeutic.

Feasibility of real-time motion management with helical tomotherapy.

PURPOSE: This study investigates the potential application of image-based motion tracking and real-time motion correction to a helical tomotherapy system. METHODS: A kV x-ray imaging system was added to a helical tomotherapy system, mounted 90 degrees offset from the MV treatment beam, and an optical camera system was mounted above the foot of the couch. This experimental system tracks target motion by acquiring an x-ray image every few seconds during gantry rotation. For respiratory (periodic) motion, software correlates internal target positions visible in the x-ray images with marker positions detected continuously by the camera, and generates an internal-external correlation model to continuously determine the target position in three-dimensions (3D). Motion correction is performed by continuously updating jaw positions and MLC leaf patterns to reshape (effectively re-pointing) the treatment beam to follow the 3D target motion. For motion due to processes other than respiration (e.g., digestion), no correlation model is used - instead, target tracking is achieved with the periodically acquired x-ray images, without correlating with a continuous camera signal. RESULTS: The system's ability to correct for respiratory motion was demonstrated using a helical treatment plan delivered to a small (10 mm diameter) target. The phantom was moved following a breathing trace with an amplitude of 15 mm. Film measurements of delivered dose without motion, with motion, and with motion correction were acquired. Without motion correction, dose differences within the target of up to 30% were observed. With motion correction enabled, dose differences in the moving target were less than 2%. Nonrespiratory system performance was demonstrated using a helical treatment plan for a 55 mm diameter target following a prostate motion trace with up to 14 mm of motion. Without motion correction, dose differences up to 16% and shifts of greater than 5 mm were observed. Motion correction reduced these to less than a 6% dose difference and shifts of less than 2 mm. CONCLUSIONS: Real-time motion tracking and correction is technically feasible on a helical tomotherapy system. In one experiment, dose differences due to respiratory motion were greatly reduced. Dose differences due to nonrespiratory motion were also reduced, although not as much as in the respiratory case due to less frequent tracking updates. In both cases, beam-on time was not increased by motion correction, since the system tracks and corrects for motion simultaneously with treatment delivery.

Enhanced Delivery of Galanin Conjugates to the Brain through Bioengineering of the Anti-Transferrin Receptor Antibody OX26.

The blood-brain barrier (BBB) is a formidable obstacle for brain delivery of therapeutic antibodies. However, antibodies against the transferrin receptor (TfR), enriched in brain endothelial cells, have been developed as delivery carriers of therapeutic cargoes into the brain via a receptor-mediated transcytosis pathway. In vitro and in vivo studies demonstrated that either a low-affinity or monovalent binding of these antibodies to the TfR improves their release on the abluminal side of the BBB and target engagement in brain parenchyma. However, these studies have been performed with mouse-selective TfR antibodies that recognize different TfR epitopes and have varied binding characteristics. In this study, we evaluated serum pharmacokinetics and brain and CSF exposure of the rat TfR-binding antibody OX26 affinity variants, having KDs of 5 nM, 76 nM, 108 nM, and 174 nM, all binding the same epitope in bivalent format. Pharmacodynamic responses were tested in the Hargreaves chronic pain model after conjugation of OX26 affinity variants with the analgesic and antiepileptic peptide, galanin. OX26 variants with affinities of 76 nM and 108 nM showed enhanced brain and cerebrospinal fluid (CSF) exposure and higher potency in the Hargreaves model, compared to a 5 nM affinity variant; lowering affinity to 174 nM resulted in prolonged serum pharmacokinetics, but reduced brain and CSF exposure. The study demonstrates that binding affinity optimization of TfR-binding antibodies could improve their brain and CSF exposure even in the absence of monovalent TfR engagement.

Investigating the clinical advantages of a robotic linac equipped with a multileaf collimator in the treatment of brain and prostate cancer patients.

The purpose of this study was to evaluate the performance of a commercially avail-able CyberKnife system with a multileaf collimator (CK-MLC) for stereotactic body radiotherapy (SBRT) and standard fractionated intensity-modulated radiotherapy (IMRT) applications. Ten prostate and ten intracranial cases were planned for the CK-MLC. Half of these cases were compared with clinically approved SBRT plans generated for the CyberKnife with circular collimators, and the other half were compared with clinically approved standard fractionated IMRT plans generated for conventional linacs. The plans were compared on target coverage, conformity, homogeneity, dose to organs at risk (OAR), low dose to the surrounding tissue, total monitor units (MU), and treatment time. CK-MLC plans generated for the SBRT cases achieved more homogeneous dose to the target than the CK plans with the circular collimators, for equivalent coverage, conformity, and dose to OARs. Total monitor units were reduced by 40% to 70% and treatment time was reduced by half. The CK-MLC plans generated for the standard fractionated cases achieved prescription isodose lines between 86% and 93%, which was 2%-3% below the plans generated for conventional linacs. Compared to standard IMRT plans, the total MU were up to three times greater for the prostate (whole pelvis) plans and up to 1.4 times greater for the intracranial plans. Average treatment time was 25min for the whole pelvis plans and 19 min for the intracranial cases. The CK-MLC system provides significant improvements in treatment time and target homogeneity compared to the CK system with circular collimators, while main-taining high conformity and dose sparing to critical organs. Standard fractionated plans for large target volumes (> 100 cm3) were generated that achieved high prescription isodose levels. The CK-MLC system provides more efficient SRS and SBRT treatments and, in select clinical cases, might be a potential alternative for standard fractionated treatments.

Evaluation of an innovative population pharmacokinetic-based design for behavioral pharmacodynamic endpoints.

Pre-clinical behavioral pharmacology studies supporting indications like analgesia typically consist of at least three different studies; dose-finding, duration of effect, and tolerance-development studies. Pharmacokinetic (PK) plasma samples are generally taken from a parallel group of animals to avoid disruption of the behavioral pharmacodynamic (PD) endpoint. Our objective was to investigate if pre-clinical behavioral pharmacology studies in rats could be performed effectively by combining three studies into a single experimental design and using sparse PK sampling in the same animals as for PD. A refined dosing strategy was applied for a muscarinic agonist, AZD6088, using the rat spinal nerve ligation heat hyperalgesia model. PD measurements were performed on day 1, 3, 5 and 8. Two PK samples per day were taken day 2 and 4. In a separate control group, PD measurements were performed on rats without PK sampling. Data was analyzed using a population approach in NONMEM. The animals produced a consistent and reproducible response irrespective of day of testing suggesting that blood sampling on alternate days did not interfere with the PD responses. A direct concentration-effect relationship with good precision was established and no tolerance development was observed. The new design combining three studies into one and eliminating a satellite PK group realized substantial savings compared to the old design; animal use was reduced by 58% and time required to generate results was reduced by 55%. The design described here delivers substantial savings in animal lives, time, and money whilst still delivering a good quality and precise description of the PKPD relationship.

N-Methyl-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamides as a novel class of cannabinoid receptors agonists with low CNS penetration.

Cannabinoid CB(1) receptor agonists exhibit potent analgesic effects in rodents and humans, but their clinical utility as analgesic drugs is often limited by centrally mediated side effects. We report herein the preparation of N-methyl-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamides as a novel class of hCB(1)/hCB(2) dual agonists with attractive physicochemical properties. More specifically, (R)-N,9-dimethyl-N-(4-(methylamino)-4-oxobutyl)-3-(tetrahydro-2H-pyran-4-yl)-2,3,4,9-tetrahydro-1H-carbazole-6-carboxamide, displayed an extremely low level of CNS penetration (Rat Cbr/Cplasma=0.005 or 0.5%) and was devoid of CNS side effects during pharmaco-dynamic testing.

γ-Carbolines: a novel class of cannabinoid agonists with high aqueous solubility and restricted CNS penetration.

An oral, peripherally restricted CB1/CB2 agonist could provide an interesting approach to treat chronic pain by harnessing the analgesic properties of cannabinoids but without the well-known central side effects. γ-Carbolines are a novel class of potent mixed CB1/CB2 agonists characterized by attractive physicochemical properties including high aqueous solubility. Optimization of the series has led to the discovery of 29, which has oral activity in a rat inflammatory pain model and limited brain exposure at analgesic doses, consistent with a lower risk of CNS-mediated tolerability issues.

Blocking spinal CCR2 with AZ889 reversed hyperalgesia in a model of neuropathic pain.

BACKGROUND: The CCR2/CCL2 system has been identified as a regulator in the pathogenesis of neuropathy-induced pain. However, CCR2 target validation in analgesia and the mechanism underlying antinociception produced by CCR2 antagonists remains poorly understood. In this study, in vitro and in vivo pharmacological approaches using a novel CCR2 antagonist, AZ889, strengthened the hypothesis of a CCR2 contribution to neuropathic pain and provided confidence over the possibilities to treat neuropathic pain with CCR2 antagonists. RESULTS: We provided evidence that dorsal root ganglia (DRG) cells harvested from CCI animals responded to stimulation by CCL2 with a concentration-dependent calcium rise involving PLC-dependent internal stores. This response was associated with an increase in evoked neuronal action potentials suggesting these cells were sensitive to CCR2 signalling. Importantly, treatment with AZ889 abolished CCL2-evoked excitation confirming that this activity is CCR2-mediated. Neuronal and non-neuronal cells in the spinal cord were also excited by CCL2 applications indicating an important role of spinal CCR2 in neuropathic pain. We next showed that in vivo spinal intrathecal injection of AZ889 produced dose-dependent analgesia in CCI rats. Additionally, application of AZ889 to the exposed spinal cord inhibited evoked neuronal activity and confirmed that CCR2-mediated analgesia involved predominantly the spinal cord. Furthermore, AZ889 abolished NMDA-dependent wind-up of spinal withdrawal reflex pathway in neuropathic animals giving insight into the spinal mechanism underlying the analgesic properties of AZ889. CONCLUSIONS: Overall, this study strengthens the important role of CCR2 in neuropathic pain and highlights feasibility that interfering on this mechanism at the spinal level with a selective antagonist can provide new analgesia opportunities.

A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain.

Cannabinoids are analgesic in man, but their use is limited by their psychoactive properties. One way to avoid cannabinoid receptor subtype 1 (CB1R)-mediated central side-effects is to develop CB1R agonists with limited CNS penetration. Activation of peripheral CB1Rs has been proposed to be analgesic, but the relative contribution of peripheral CB1Rs to the analgesic effects of systemic cannabinoids remains unclear. Here we addressed this by exploring the analgesic properties and site of action of AZ11713908, a peripherally restricted CB1R agonist, in rodent pain models. Systemic administration of AZ11713908 produced robust efficacy in rat pain models, comparable to that produced by WIN 55, 212-2, a CNS-penetrant, mixed CB1R and CB2R agonist, but AZ11713908 generated fewer CNS side-effects than WIN 55, 212-in a rat Irwin test. Since AZ11713908 is also a CB2R inverse agonist in rat and a partial CB2R agonist in mouse, we tested the specificity of the effects in CB1R and CB2R knock-out (KO) mice. Analgesic effects produced by AZ11713908 in wild-type mice with Freund's complete adjuvant-induced inflammation of the tail were completely absent in CB1R KO mice, but fully preserved in CB2R KO mice. An in vivo electrophysiological assay showed that the major site of action of AZ11713908 was peripheral. Similarly, intraplantar AZ11713908 was also sufficient to induce robust analgesia. These results demonstrate that systemic administration of AZ11713908, produced robust analgesia in rodent pain models via peripheral CB1R. Peripherally restricted CB1R agonists provide an interesting novel approach to analgesic therapy for chronic pain.

Relationship between isotope half-life and prostatic edema for optimal prostate dose coverage in permanent seed implants.

The robustness of treatment planning to prostatic edema for three different isotopes (125I, 103Pd, and 131Cs) is explored using dynamical dose calculations on 25 different clinical prostate cases. The treatment plans were made using the inverse planning by simulated annealing (IPSA) algorithm. The prescription was 144, 127, and 125 Gy for 125I, 131Cs, and 103Pd, respectively. For each isotope, three dose distribution schemes were used to impose different protection levels to the urethra: V120 = 0%, V150 = 0%, and V150 = 30%. Eleven initial edema values were considered ranging from 1.0 (no edema) to 2.0 (100%). The edema was assumed to resolve exponentially with time. The prostate volume, seed positions, and seed activity were dynamically tracked to produce the final dose distribution. Edema decay half-lives of 10, 30, and 50 days were used. A total of 675 dynamical calculations were performed for each initial edema value. For the 125I isotope, limiting the urethra V120 to 0% leads to a prostate D90 under 140 Gy for initial edema values above 1.5. Planning with urethra V150 at 0% provides a good response to the edema; the prostate D90 remains higher than 140 Gy for edema values up to 1.8 and a half-life of 30 days or less. For 103Pd, the prostate D90 is under 97% of the prescription dose for approximately 66%, 40%, and 30% of edema values for urethra V120 = 0%, V150 = 0%, and V150 = 30%, respectively. Similar behavior is seen for 131Cs and the center of the prostate becomes "cold" for almost all edema scenarios. The magnitude of the edema following prostate brachytherapy, as well as the half-life of the isotope used and that of the edema resorption, all have important impacts on the dose distribution. The 125I isotope with its longer half-life is more robust to prostatic edema. Setting up good planning objectives can provide an adequate compromise between organ doses and robustness. This is even more important since seed misplacements will contribute to further degrade dose coverage.

Inverse planning simulated annealing for magnetic resonance imaging-based intracavitary high-dose-rate brachytherapy for cervical cancer.

PURPOSE: To develop a technique using exclusively magnetic resonance imaging (MRI) to perform dwell position identification, targets and organs at risk delineation, and to apply inverse planning dose optimization to high-dose-rate brachytherapy for cervical cancer. METHODS AND MATERIALS: We included 15 consecutive women treated with high-dose-rate (HDR) brachytherapy for cervical cancer. All patients underwent MRI after placement of tandem and ring applicator containing a gadodiamide-filled dummy marker. This technique allowed direct visualization of the source pathway and precise definition of the intra-applicator source positions. For each patient, we delineated gross target volume (GTV), high-risk clinical target volume (HR-CTV), and organs at risk on MRI, according to the European Gynecological GEC-ESTRO Working Group definitions. We performed inverse planning simulated annealing (IPSA) and analyzed the dose-volume histograms with the following endpoints: D(90), D(100), and V(100) for GTV and HR-CTV; D0.1 cc, D1 cc, D2 cc for bladder, rectum, and bowel; and dose at Point A. RESULTS: The intra-applicator source pathway was easily visualized on MRI using the gadodiamide-filled marker. IPSA provided excellent target coverage. The mean D(90) and V(100) for HR-CTV were 103+/-5% and 92+/-3%, respectively. IPSA provided excellent bladder sparing. D1 cc and D2 cc of bladder were 73+/-10% and 67+/-10%, respectively. CONCLUSIONS: We developed a novel technique that allows direct visualization of the intra-applicator source pathway on MRI. Using this technique, we successfully performed inverse planning directly from MRI.

Class solution in inverse planned HDR prostate brachytherapy for dose escalation of DIL defined by combined MRI/MRSI.

PURPOSE: To establish an inverse planning set of parameters (class solution) to boost dominant intra-prostatic lesion (DIL) defined by MRI/MRSI. METHODS: For 15 patients, DIL were contoured on CT or MR images and a class solution was developed to boost the DIL under the dosimetric requirements of the RTOG-0321 protocol. To determine the maximum attainable level of boost for each patient, 5 different levels were considered, at least 110%, 120%, 130%, 140% and 150% of the prescribed dose. The maximum attainable level was compared to the plan without boost using cumulative dose volume histogram (DVH). RESULTS: DIL dose escalation was feasible for 11/15 patients under the requirements. The planning target volume (PTV) dose was slightly increased, while the DIL dose was significantly increased without any violation of requirements. With slight adjustments of the dose constraint parameters, the dose escalation was feasible for 13/15 patients under requirements. CONCLUSION: Using a class solution, a dose escalation of the MRI/MRSI defined DIL up to 150% while complying with RTOG dosimetric requirements is feasible. This HDR brachytherapy approach to dose escalation allows a significant dose increase to the tumor while maintaining an acceptable risk of complications.

Optimization of HDR brachytherapy dose distributions using linear programming with penalty costs.

Prostate cancer is increasingly treated with high-dose-rate (HDR) brachytherapy, a type of radiotherapy in which a radioactive source is guided through catheters temporarily implanted in the prostate. Clinicians must set dwell times for the source inside the catheters so the resulting dose distribution minimizes deviation from dose prescriptions that conform to patient-specific anatomy. The primary contribution of this paper is to take the well-established dwell times optimization problem defined by Inverse Planning by Simulated Annealing (IPSA) developed at UCSF and exactly formulate it as a linear programming (LP) problem. Because LP problems can be solved exactly and deterministically, this formulation provides strong performance guarantees: one can rapidly find the dwell times solution that globally minimizes IPSA's objective function for any patient case and clinical criteria parameters. For a sample of 20 prostates with volume ranging from 23 to 103 cc, the new LP method optimized dwell times in less than 15 s per case on a standard PC. The dwell times solutions currently being obtained clinically using simulated annealing (SA), a probabilistic method, were quantitatively compared to the mathematically optimal solutions obtained using the LP method. The LP method resulted in significantly improved objective function values compared to SA (P = 1.54 x 10(-7)), but none of the dosimetric indices indicated a statistically significant difference (P < 0.01). The results indicate that solutions generated by the current version of IPSA are clinically equivalent to the mathematically optimal solutions.

Class solution for inversely planned permanent prostate implants to mimic an experienced dosimetrist.

The purpose of this paper is to present a method for the selection of inverse planning parameters and to establish a set of inverse planning parameters (class solution) for the inverse planning included in a commercial permanent prostate implant treatment planning system. The manual planning of more than 750 patients since 1996 led to the establishment of general treatment planning rules. A class solution is tuned to fulfill the treatment planning rules and generate equivalent implants. For ten patients, the inverse planning is compared with manual planning performed by our experienced physicist. The prostate volumes ranged from 17 to 51 cc and are implanted with low activity 1-125 seeds. Dosimetric indices are calculated for comparison. The inverse planning needed about 15 s for each optimization (400 000 iterations on a 2.5 GHz PC). In comparison, the physicist needed about 20 min to perform each manual plan. A class solution is found that consistently produces dosimetric indices equivalent or better than the manual planning. Moreover, even with strict seed placement rules, the inverse planning can produce adequate prostate dose coverage and organ at risk protection. The inverse planning avoids implant with seeds outside of the prostate and too close to the urethra. It also avoids needles with only one seed and needles with three consecutive seeds. This reduces the risk of complication due to seed misplacement and edema. The inverse planning also uses a smaller number of needles, reducing the cause of trauma. The quality of the treatment plans is independent of the gland size and shape. A class solution is established that consistently and rapidly produces equivalent dosimetric indices as manual planning while respecting severe seed placement rules. The class solution can be used as a starting point for every patient, dramatically reducing the time needed to plan individual patient treatments. The class solution works with inverse preplanning, intraoperative inverse preplanning, and intraoperative real-time planning. This technology is not intended to replace the physicist but to accelerate the planning process, making intraoperative treatment planning more effective.

Optimization of dose distribution for HDR brachytherapy of the prostate using Attraction-Repulsion Model.

PURPOSE: To optimize dose distribution for high-dose-rate brachytherapy for prostate cancer, we have developed a new algorithm named Attraction-Repulsion Model (ARM). In this study, we compared the ARM with geometric optimization (GO). METHODS AND MATERIALS: The ARM was used to optimize the dose distribution by finding the best dwell time combination. ARM requires grids inside the clinical target volume (CTV) and critical organs. These grids generate attraction or repulsion based on specific dose constraints. After calculations were performed repeatedly until the attraction and repulsion forces reached equilibrium, the optimal dwell time distribution was established. We compared the ARM with GO for 10 patients using dose-volume histograms. RESULTS: The CTV ranged from 23 to 48 cc, and the CTV V150 ranged from 52% to 79%, and 23% to 44% for GO and ARM, respectively. This indicates that the dose homogeneity indices, as well as the conformal indices, were higher for ARM than for GO. The urethra V150 was 0-99% and 0-1% for GO and ARM, respectively. CONCLUSION: The ARM proved to be superior to GO in minimizing the dose to normal structures and in improving dose homogeneity for the target while reducing the dose to normal tissues.

3D inverse treatment planning for the tandem and ovoid applicator in cervical cancer.

PURPOSE: Three-dimensional treatment planning systems and inverse planning optimization for brachytherapy are becoming commercially available. Guidelines for target delineation and dose constrictions have not been established using this new software. In this study we describe a method of target delineation for the tandem and ovoids applicator. We then compare inverse planning dose distributions with the traditional methods of prescribing dose. METHODS AND MATERIALS: Target and organ-at-risk volumes were defined using systematic guidelines on 15 patients treated in our department with high-dose-rate brachytherapy for cervical cancer using tandem and ovoids. High-dose-rate distributions were created according to three different dose optimization protocols: inverse planning simulated annealing (IPSA), point A, and point A with a normalization of 2 cc of the bladder receiving 80% of the dose (bladder-sparing method). An uniform cost function for dose constraints was applied to all IPSA generated plans, and no manual optimization was allowed for any planning method. RESULTS: Guidelines for target and structure-at-risk volumes, as well as dose constraint cost functions, were established. Dose-volume histogram analysis showed that the IPSA algorithm indicated no difference in tumor coverage compared with point A optimization while decreasing dose to the bladder and rectum. The IPSA algorithm provided better target volume coverage compared with bladder-sparing method with equivalent doses to the bladder and rectum. CONCLUSION: This study uses a systematic approach for delineating target and organ-at-risk volumes and a uniform cost function for generating IPSA plans for cervical cancer using tandem and ovoids. Compared with conventional dose prescription methods, IPSA provides a consistent method of optimization that maintains or improves target coverage while decreasing dose to normal structures. Image-guided brachytherapy and inverse planning improve brachytherapy dosimetry.

Anatomy-based inverse planning dose optimization in HDR prostate implant: a toxicity study.

BACKGROUND AND PURPOSE: The aim of this study is to evaluate the acute and late complications in patients who have received HDR implant boost using inverse planning, and to determine dose volume correlations. PATIENTS AND METHODS: Between September 1999 and October 2002, 44 patients with locally advanced prostate cancer (PSA>/=10 ng/ml, and/or Gleason score>/=7, and/or Stage T2c or higher) were treated with 40-45 Gy external pelvic field followed by 2--3 fraction of inverse-planned HDR implant boost (6--9.5 Gy /fraction). Median follow-up time was 1.7 years with 81.8% of patients who had at least 12 months of follow up (range 8.6--42.5. Acute and late morbidity data were collected and graded according to RTOG criteria. Questionnaires were used to collect prostate related measures of quality of life, and international prostate symptom score (IPSS) before and after treatment. Dose-volume histograms for prostate, urethra, bladder, penis bulb and rectum were analyzed. RESULTS: The median patient age was 64 years. Of these, 32% were in the high risk group, and 61% in the intermediate risk group. 3 patients (7%) had no adverse prognostic factors. A single grade 3 GU acute toxicity was reported but no grade 3--4 acute GI toxicity. No grade 3--4 late GU or GI toxicity was reported. Acute (late) grade 2 urinary and rectal symptoms were reported in 31.8 (11.4%) and 4.6% (4.6%) of patients, respectively. A trend for predicting acute GU toxicity is seen for total HDR dose of more than 18 Gy (OR=3.6, 95%CI=[0.96--13.5], P=0.058). The evolution of toxicity is presented for acute and late GU/GI toxicity. Erectile dysfunction occurs in approximately 27% of patients who were not on hormonal deprivation, but may be taking sildenafil. The IPSS peaked on averaged 6 weeks post-implant and returned to the baseline at a median of 6 months. CONCLUSIONS: Inverse-planned HDR brachytherapy is a viable option to deliver higher dose to the prostate as a boost without increasing GU or rectal complication. Further HDR dose escalation to the prostate is feasible.