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The purpose of this study was to evaluate the performance of a commercially available 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 25 min 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 maintaining 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. PACS numbers: 87.56.nk, 87.56.bd.

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.

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.

To establish an inverse planning set of parameters (class solution) to boost dominant intra-prostatic lesion (DIL) defined by MRI/MRSI.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).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.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.

The robustness of treatment planning to prostatic edema for three different isotopes ({sup 125}I, {sup 103}Pd, and {sup 131}Cs) 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 {sup 125}I, {sup 131}Cs, and {sup 103}Pd, respectively. For each isotope, three dose distribution schemes were used to impose different protection levels to the urethra: V{sub 120}=0%, V{sub 150}=0%, and V{sub 150}=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 {sup 125}I isotope, limiting the urethra V{sub 120} to 0% leads to a prostate D{sub 90} under 140 Gy for initial edema values above 1.5. Planning with urethra V{sub 150} at 0% provides a good response to the edema; the prostate D{sub 90} remains higher than 140 Gymore » for edema values up to 1.8 and a half-life of 30 days or less. For {sup 103}Pd, the prostate D{sub 90} is under 97% of the prescription dose for approximately 66%, 40%, and 30% of edema values for urethra V{sub 120}=0%, V{sub 150}=0%, and V{sub 150}=30%, respectively. Similar behavior is seen for {sup 131}Cs 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 {sup 125}I 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.« less

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.

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.

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 R10 ng/ml, and/or Gleason score R7, 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 (ORZ3.6, 95%CIZ[0.96–13.5], PZ0.058). 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. q 2005 Published by Elsevier Ireland Ltd. Radiotherapy and Oncology 75 (2005) 318–324.

Purpose: To develop and optimize a technique for inverse treatment planning based solely on magnetic resonance imaging (MRI) during high-dose-rate brachytherapy for prostate cancer. Methods and Materials: Phantom studies were performed to verify the spatial integrity of treatment planning based on MRI. Data were evaluated from 10 patients with clinically localized prostate cancer who had undergone two high-dose-rate prostate brachytherapy boosts under MRI guidance before and after pelvic radiotherapy. Treatment planning MRI scans were systematically evaluated to derive a class solution for inverse planning constraints that would reproducibly result in acceptable target and normal tissue dosimetry. Results: We verified the spatial integrity of MRI for treatment planning. MRI anatomic evaluation revealed no significant displacement of the prostate in the left lateral decubitus position, a mean distance of 14.47 mm from the prostatic apex to the penile bulb, and clear demarcation of the neurovascular bundles on postcontrast imaging. Derivation of a class solution for inverse planning constraints resulted in a mean target volume receiving 100% of the prescribed dose of 95.69%, while maintaining a rectal volume receiving 75% of the prescribed dose of

Purpose To dose escalate selected regions inside the prostate without compromising the dose coverage of the prostate and the protection to the urethra, rectum, and bladder for prostate cancer patients treated with high-dose-rate brachytherapy. Methods and materials Magnetic resonance imaging combined with magnetic resonance spectroscopy imaging was used to differentiate between normal and malignant prostate and define cancer-validated dominant intraprostatic lesions (DIL) on 10 patients. The DILs were then contoured on the planning scans (CT or MRI based, 5 patients each), and our inverse planning dose optimization algorithm (called IPSA) was used to generate dose distributions for 3 different boost levels. Dose–volume histograms of the target and each organ at risk were compared with optimized plans without DIL boost. Results Combined MRI/magnetic resonance spectroscopic imaging identified 2 DILs in 8/10 of the 10 patients studied and a single DIL in the remaining 2 patients. The average prostate dose coverage V100 was 97% (σ = 1.0%). When the minimum DIL dose requested was 120% of the prescribed dose, the average DIL V120 was 97.1% (σ = 1.8%). For a boost value of 150%, the average V150 ranged from 77.8% to 86.1%, depending on the upper limit of the dose constraints. The bladder V50 increased by 1%, independently of the boost levels. The absolute increases in V50 for the rectum varied from 1% to 3%, depending on the boost level. The urethra V120 were increased by 13.4% and 32.5% for the lowest and highest boost levels, respectively. Conclusion The DIL dose can be escalated to a minimum of 120% while the entire prostate is treated simultaneously, without increasing the dose to surrounding normal tissues. Higher boost levels between 150% and 170% are feasible, but with slightly larger doses delivered to the rectum and urethra.

Purpose: The objective is to evaluate the prostate volume change and its dosimetric consequences after the insertion of catheters for high-dose-rate brachytherapy. Methods and Materials: For 13 consecutive patients, a spiral CT scan was acquired before each of the 2 fractions, separated on average by 20 hours. The coordinates of the catheters were obtained on 3 axial CT slices corresponding to apex, mid portion, and base portion of the prostate. A mathematical expansion model was used to evaluate the change of prostate volumes between the 2 fractions. It is based on the difference in the cube of the average distance between the centroid and catheter positions. The variation of implant dose–volume histograms between fractions was computed for plans produced by either inverse planning based on simulated annealing or geometric optimization. Results: The average magnitude of either increase or reduction in prostate volume was 7.8% (range, 2–17%). This volume change corresponds to an average prostate radius change of only 2.5% (range, 0.7–5.4%). For 5 patients, the prostate volume increased on average by 9% (range, 2–17%), whereas a reduction was observed for 8 patients by an average of 7% (range, 2–13%). More variation was observed at the prostate base than at mid or apex gland. The comparison of implant dose–volume histograms showed a small reduction of V100 receiving the prescription dose, with an average of 3.5% (range, 0.5–12%) and 2.2% (range, 1–6%) for inverse planning based on our simulated annealing and geometric optimization plans, respectively. Conclusion: Small volume change was observed between treatment fractions. This translates into small changes in dose delivered to the prostate volume.

PURPOSE: An inverse planning simulated annealing (IPSA) algorithm for optimization of high- dose-rate (HDR) brachytherapy has been previously described. In this study, IPSA is compared with geometrical optimization (GO) for prostate brachytherapy. METHODS AND MATERIALS: Using CT data collected from 10 patients, treatment plans were prepared using GO and IPSA. The clinical target volume (CTV) and critical organs (CO) including bladder, rectum, and urethra were contoured using Plato Version 14.2.1 (Nucletron Corp., Veenendaal, The Netherlands). Implant catheters were digitized using the CT planning system. All dwell positions outside of the CTV were turned off. Two optimized plans were generated for each implant using GO and IPSA. The same set of dose constraints were used for all inverse planning calculations and no manual adjustment of the dwell weight was used. Two prescription methods were used. Using the first method, coverage was prioritized: the prescription dose was normalized to the isodose volume that covers 98% of the CTV (V100 98% of CTV). The dose volume histograms (DVH) of CO were generated for comparison. Using the second method, sparing was prioritized: the prescription dose was normalized such that no urethra volume received 150% of the prescription dose (V150-urethra 0 cc). The DVH of CTV and CO were generated, and the homogeneity index (HI) and conformal index (COIN) were calculated for comparison and compared using the Wilcoxon matched-pairs test. RESULTS: Using the coverage-prioritized method, the difference in V80-bladder dose was not statistically significant (p 0.09; median: IPSA 0.62 cc, GO 1.05 cc). The V80-rectum ranged from 0.20-4.8 cc, and 0.05-1.4 cc using GO and IPSA, respectively. IPSA's V80-rectum was significantly lower (p 0.005; median: IPSA 0.38 cc, GO 1.31 cc). V150-urethra ranged from 0.02-0.75 cc and 0.0-0.01 cc using GO and IPSA, respectively. The V150-urethra was significantly lower using IPSA (p 0.005; median: IPSA 0.00 cc, GO 0.33 cc). Using the sparing prioritized method, the V100-prostate ranged from 30-97% and 95-100% using GO and IPSA, respectively. This difference was statistically significant (p 0.008). The HI and COIN were statistically higher using IPSA (p 0.005). CONCLUSION: Anatomy-based inverse optimization using IPSA is superior to dwell-position- based optimization using GO as it: (1) Improves target coverage and conformality while sparing normal structures, (2) Improves dose homogeneity within the target, and (3) Minimizes volume of non-contoured normal tissue irradiated. Routine application of three-dimensional brachytherapy planning and anatomy-based inverse dwell time optimization is recommended. 2004 American Brachytherapy Society. All rights reserved.

Purpose: Commercially available optimization schemes generally result in an undesirable dose distribution, because of the particular shapes of tumors extending laterally from the tandem. Dose distribution is therefore manually obtained by adjusting relative dwell time values until an acceptable solution is found. The objective of this work is to present the clinical application of an inverse planning dose optimization tool for the automatic determination of source dwell time values in the treatment of interstitial gynecologic templates. Methods and Materials: In cases where the tumor extends beyond the range of the tandem-ovoid applicator, catheters as well as the tandem are inserted into the paravaginal and parametrial region in an attempt to cover the tumor volume. CT scans of these patients are then used for CT-based dose planning. Dose distribution is obtained manually by varying the relative dwell times until adequate dose coverage is achieved. This manual planning is performed by an experienced physician. In parallel, our in-house inverse planning based on simulated annealing is used to automatically determine which of all possible dwell positions will become active and to calculate the dwell time values needed to fulfill dose constraints applied to the tumor volume and to each organ at risk. To compare the results of these planning methods, dose‐volume histograms and isodose distributions were generated for the target and each organ at risk. Results: This procedure has been applied for the dose planning of 12 consecutive interstitial gynecologic templates cases. For all cases, once the anatomy was contoured, the routine of inverse planning based on simulated annealing found the solution to the dose constraints within 1 min of CPU time. In comparison, manual planning took more than 45 min. The inverse planning‐ generated plans showed improved protection to organs at risk for the same coverage compared to manual planning. Conclusion: This inverse planning tool reduced the planning time significantly and produced improved plans with reduced dose to the organs at risk. Furthermore, the inverse planning approach improves the physician’s control over treatment. The focus becomes the physician’s prescription to the target and his or her compromise due to dose to normal structures. © 2002 Elsevier Science Inc. Brachytherapy, Gynecologic, Inverse planning, Simulated annealing, IPSA.

~Received 7 August 2000; accepted for publication 26 February 2001!An anatomy-based dose optimization algorithm is developed to automatically and rapidly producea highly conformal dose coverage of the target volume while minimizing urethra, bladder, andrectal doses in the delivery of an high dose-rate~HDR! brachytherapy boost for the treatment ofprostate cancer. The dwell times are optimized using an inverse planning simulated annealingalgorithm ~IPSA! governed entirely from the anatomy extracted from a CT and by a dedicatedobjective function ~cost function! reflecting clinical prescription and constraints. With this inverseplanning approach, the focus is on the physician’s prescription and constraint instead of on thetechnical limitations. Consequently, the physician’s control on the treatment is improved. Thecapacity of this algorithm to represent the physician’s prescription is presented for a clinical pros-tate case. The computation time ~CPU! for IPSA optimization is less than 1 min ~41 s for 142915iterations! for a typical clinical case, allowing fast and practical dose optimization. The achieve-ment of highly conformal dose coverage to the target volume opens the possibility to deliver ahigher dose to the prostate without inducing overdosage of urethra and normal tissues surroundingthe prostate. Moreover, using the same concept, it will be possible to deliver a boost dose to adelimited tumor volume within the prostate. Finally, this method can be easily extended to otheranatomical sites. © 2001 American Association of Physicists in Medicine.@DOI: 10.1118/1.1368127#Key words: inverse planning, brachytherapy, HDR, prostate, simulated annealingI. INTRODUCTIONThe last decade has seen major changes in the way radiationtreatments are delivered. The century-old objective of radia-tion therapy, i.e., to deliver a curative dose to the target whilepreserving normal tissues, can now be aimed at with a highdegree of sophistication. However, in spite of major im-provements achieved with 3D imaging modalities that allowthe anatomy to be properly defined, brachytherapy treat-ments have not yet fully benefit from these important newpieces of information. The positioning of the seeds for per-manent implant or of catheters for after-loading treatment isnow image guided, greatly improving the localization of theapplicators. At the planning stage, however, the anatomy isusually only indirectly taken into account. For high dose-rate~HDR! brachytherapy, catheters are placed in the target vol-ume and it is assumed that if the dose distribution covers thecatheters, it should also cover the anatomy. Imaging is com-monly used to set the treatment margins, but optimized dosedistributions are based on considerations such as catheter po-sitions and desired dose to a few defined points. This neces-sarily results in an approximation of the shape of theanatomy. For the case of treatment of the prostate, volumeoptimization results in a dose distribution that is essentiallycylindrical in shape. This may represent an ‘‘average’’ pros-tate, but each prostate has a very specific shape. Any ap-proximation of its shape to a geometrical representation willresult in an overdosage of normal tissues surrounding theprostate. The organs at risk in the vicinity of the prostatemay be included in this unnecessarily overdosed region.Recent studies

CYP2D6 is the major enzyme involved in the metabolism of venlafaxine. Subjects with a low CYP2D6 activity have increased plasma concentrations of venlafaxine that may predispose them to cardiovascular side effects. In vitro and in vivo studies showed that diphenhydramine, a nonprescription antihistamine, can inhibit CYP2D6 activity. Therefore, the authors investigated in this study a potential drug interaction between diphenhydramine and venlafaxine. Fifteen male volunteers, nine with the extensive metabolizer (EM) and six with the poor metabolizer (PM) phenotype of CYP2D6, received venlafaxine hydrochloride 18.75 mg orally every 12 hours for 48 hours on two occasions (1 week apart): once alone and once during the concomitant administration of diphenhydramine hydrochloride (50 mg every 12 hours). Blood and urine samples were collected for 12 hours under steady-state conditions. In EMs, diphenhydramine decreased venlafaxine oral clearance from 104+/-60 L/hr to 43+/-23 L/hr (mean +/- SD; p < 0.05) without any effect on renal clearance (4+/-1 L/hr during venlafaxine alone and 4+/-2 L/hr during venlafaxine plus diphenhydramine). In PMs, coadministration of diphenhydramine did not cause significant changes in oral clearance and partial metabolic clearances of venlafaxine to its various metabolites. Diphenhydramine disposition was only slightly affected by genetically determined low CYP2D6 activity or concomitant administration of venlafaxine. In conclusion, diphenhydramine, at therapeutic doses, inhibits CYP2D6-mediated metabolism of venlafaxine in humans. Clinically significant interactions could be encountered during the concomitant administration of diphenhydramine and other antidepressant or antipsychotic drugs that are substrates of CYP2D6.

Background and objective Mexiletine and propafenone are often used concomitantly and are metabolized by the same cytochrome P450 isozymes, namely CYP2D6, CYP1A2, and probably CYP3A4. Our objective was to study the potential pharmacokinetic and electrophysiological interactions between mexiletine and propafenone. Methods Fifteen healthy volunteers, 8 extensive metabolizers and 7 poor metabolizers of CYP2D6, received oral doses of mexiletine 100 mg two times daily from day 1 to day 8 and oral doses of propafenone 150 mg two times daily from day 5 to day 12. Interdose studies were performed at steady-state on mexiletine alone (day 4), mexiletine plus propafenone (day 8), and propafenone alone (day 12). Results In subjects in the extensive metabolizer group, coadministration of propafenone decreased oral clearances of R-(−)-mexiletine (from 41 ± 11 L/h to 28 ± 7 L/h) and S-(+)-mexiletine (from 43 ± 15 L/h to 29 ± 11 L/h) to an extent such that these values were no longer different between the extensive and the poor metabolizer groups. Propafenone coadministration also decreased partial metabolic clearances of mexiletine to hydroxymethylmexiletine, p-hydroxymexiletine, and m-hydroxymexiletine in extensive metabolizers by 71%, 67%, and 73%, respectively. In contrast, propafenone did not alter the kinetics of mexiletine enantiomers in subjects in the poor metabolizer group except for a slight decrease in the formation of hydroxymethylmexiletine. Pharmacokinetic parameters of propafenone were not changed during concomitant administration of mexiletine in subjects of either phenotype. Finally, electrocardiographic parameters (QRS duration, QTc, RR, and PR intervals) were not modified during the combined administration of the drugs. Conclusion Propafenone is a potent CYP2D6 inhibitor that may cause an increase in plasma concentrations of coadministered CYP2D6 substrates. Clinical Pharmacology & Therapeutics (2000) 68, 44–57; doi: 10.1067/mcp.2000.108023

Occurrence of a lupus-like syndrome in a significant number of patients treated with procainamide has limited the clinical use of this antiarrhythmic drug. In-vitro studies conducted in our laboratory have demonstrated that CYP2D6 is the major cytochrome P450 isozyme involved in the formation of N-hydroxyprocainamide, a metabolite potentially involved in the drug-induced lupus erythematosus syndrome observed with procainamide. In the current study, we evaluated the role of CYP2D6 activity in the in-vivo oxidation of procainamide in man. Nineteen healthy individuals, 13 with high (extensive metabolizers) and six with low (poor metabolizers) CYP2D6 activity, received a single 500 mg oral dose of procainamide hydrochloride on two occasions, once alone (period 1) and once during the concomitant administration of the selective inhibitor quinidine (50 mg four times daily; period 2). Blood and urine samples were collected over 36 h after drug administration of procainamide and analysed for procainamide and its major metabolites (N-acetylprocainamide, desethylprocainamide, N-acetyl-desethylprocainamide, p-aminobenzoic acid and its N-acetylated derivative, and nitroprocainamide). No differences were observed in the oral and renal clearances of procainamide between extensive metabolizers and poor metabolizers during either study period. However, partial metabolic clearance of procainamide to desethylprocainamide was significantly greater in extensive metabolizers than in poor metabolizers during both periods. Most importantly, the urinary excretion of nitroprocainamide during period 1 was measurable in 7/13 extensive metabolizers but in none of the poor metabolizers. During the concomitant administration of quinidine, nitroprocainamide could not be detected in the urine of any individuals tested. Therefore, our results suggest that CYP2D6 is involved in the in-vivo aliphatic amine deethylation and N-oxidation of procainamide at its arylamine function in man. Further studies are needed to demonstrate whether a low CYP2D6 activity, either genetically determined or pharmacologically modulated, could prevent drug-induced lupus erythematosus syndrome observed during chronic therapy with procainamide.

Cannabinoid CB1 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 hCB1/hCB2 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.

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.

The purpose of this paper is to report the clinical benefits of our in house inverse planning routine (IPSA) for the treatment planning of permanent prostate implant (PPI). IPSA has been designed for 3D image guided brachytherapy treatment planning. The optimization process is guided by dose objectives define for each organ extracted from medical imaging. IPSA takes into account multiple targets (prostate, boost) and multiple organs at risk (urethra, rectum, bladder, etc.). IPSA is setup to maximize the prostate dose coverage while taking into account other clinical objectives like the dose homogeneity and the organs at risk protection. A simulated annealing algorithm optimizes the source and needle positions to fulfill the dose objectives and few source placement rules in less than 1 minute. For ten patients IPSA is compared to conventional manual planning. IPSA is also tested to optimize with different maximum number of needles and different source activity. IPSA needs about 15 seconds for each optimization. In comparison an experienced physicist needs about 20 minutes to perform a manual planning. The prostate volumes range from 17 to 51cc. IPSA consistently and rapidly produces equivalent dosimetric indices as manual planning while respecting severe restrictions on source placement rules. IPSA produces implant without seeds outside of the prostate, without needles with only one seed and without needles with 3 consecutive seeds. This reduces the risk of complication due to seed misplacement and edema. IPSA also uses a smaller number of needles reducing the cause of trauma. IPSA is appropriate for pre-planning, intra-operative pre-planning and intra-operative real-time planning taking into account the implanted sources and needles. This technology is not intended to replace the physicist but to accelerate the planning process making intra-operative treatment planning more effective.

The purpose of this paper is to report the clinical benefits of our in house inverse planning routine (IPSA) for the treatment planning of prostate high dose rate brachytherapy (HDR). IPSA has been designed for 3D image guided brachytherapy treatment planning. The optimization process is guided by dose objectives define for each organ extracted from medical imaging. IPSA takes into account multiple targets (prostate, boost) and multiple organs at risk (urethra, rectum, bladder, etc.). IPSA is setup to maximize the prostate dose coverage while taking into account other clinical objectives like the dose homogeneity and the organs at risk protection. A simulated annealing algorithm optimizes the dwell times to fulfill the dose objectives in less than 1 minute. The dose volume histograms of 30 consecutive prostate cancer patients were computed and analyzed for this study. The prostate volumes range from small to large and the number of implanted catheters vary accordingly. The dosimetric indices are excellent independently of the gland size and shape. IPSA reduced significantly the treatment planning time and produced improved treatment plans with reduced dose to the organs at risk compare to conventional treatment planning methods. This anatomy based optimization achieved conformal dose coverage to the prostate opening the possibility to deliver higher dose to the prostate while reducing the dose deliver to the urethra and normal tissues. Wide adaptation of this technology should improve quality of patient care.

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: D90, D100, and V100 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 D90 and V100 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.

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.

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.

Purpose Magnetic resonance imaging (MRI) provides superior visualization of the prostate and surrounding anatomy, making it the modality of choice for imaging the prostate gland. This pilot study was performed to determine the feasibility and dosimetric quality achieved when placing high-dose-rate prostate brachytherapy catheters under MRI guidance in a standard "closed-bore" 1.5T scanner. Methods and materials Patients with intermediate-risk and high-risk localized prostate cancer received MRI-guided high-dose-rate brachytherapy boosts before and after a course of external beam radiotherapy. Using a custom visualization and targeting program, the brachytherapy catheters were placed and adjusted under MRI guidance until satisfactory implant geometry was achieved. Inverse treatment planning was performed using high-resolution T 2 -weighted MRI. Results Ten brachytherapy procedures were performed on 5 patients. The median percentage of volume receiving 100% of prescribed minimal peripheral dose (V 100 ) achieved was 94% (mean, 92%; 95% confidence interval, 89–95%). The urethral V 125 ranged from 0% to 18% (median, 5%), and the rectal V 75 ranged from 0% to 3.1% (median, 0.3%). In all cases, lesions highly suspicious for malignancy could be visualized on the procedural MRI, and extracapsular disease was identified in 2 patients. Conclusion High-dose-rate prostate brachytherapy in a standard 1.5T MRI scanner is feasible and achieves favorable dosimetry within a reasonable period with high-quality image guidance. Although the procedure was well tolerated in the acute setting, additional follow-up is required to determine the long-term safety and efficacy of this approach.

Purpose: To present an exhaustive dosimetric comparison between three geometric optimization methods and our inverse-planning simulated annealing (IPSA) algorithm, with two different prescriptions for high-dose-rate (HDR) boost of the prostate. The objective of this analysis was to quantify the dosimetric advantages of the IPSA algorithm compared with more standard geometric optimizations. Methods and Materials: Between September 1999 and June 2001, 34 patients were treated to a dose of 40 – 44 Gy by external pelvic fields, followed by an HDR boost of 18 Gy in 3 fractions. The first 4 patients were treated with HDR using geometric optimization, and anatomy-based inverse-planning dose optimization was used for the remaining 30 patients. We retrospectively used the data from these 30 patients to create HDR dose distributions according to five different dose optimization protocols, including our IPSA algorithm. The various geometric optimization procedures differed in the way the dwell positions were activated and plan normalization was performed. Dose–volume histograms from all these plans were analyzed and multiple implant quality indexes extracted. Results: The IPSA algorithm provided better clinical tumor volume prescription dose coverage than did the geometric optimizations. The average prostate volume receiving 100% of the prescribed dose (V100) was 96.3% and 94.5% for IPSA with two different prescriptions compared with 92.1%, 92.6%, and 88.8% for the three geometric optimization schemes. The average urethra V150 value was 0.0% and 0.7% for IPSA with two different prescriptions, and the three geometric optimization protocols generated average values of 22.9%, 33.9%, and 38.8%. The bladder and rectal dose–volume histograms were similar, although the latest version of the IPSA algorithm slightly decreases the dose to these organs at risk because of organ-specific dose constraints included in the objective function. Conclusion: We found that planning an HDR prostate boost could be performed in a fast, secure, and effective manner with the IPSA algorithm. We demonstrated that our inverse-planning algorithm produces superior HDR plans than more conventional geometric optimizations for adenocarcinoma of the prostate. The organs at risk protection included in the objective function is a major feature of the algorithm and should allow us to escalate the HDR dose to the prostate without increasing undesirable side effects. © 2002 Elsevier Science Inc. Brachytherapy, Inverse planning, HDR, Prostate, Dosimetric study.

Purpose:Roboticradiation delivery systems can accurately deliver conformal dose distributions for clinical applications throughout the body. Here we describe methods to reduce treatment times for step‐and‐shoot roboticradiation delivery while maintaining the dosimetric quality of the treatment plan. Method and Materials:Treatment delivery time, excluding patient setup, depends primarily on three parameters: beam‐on time, number of positions (called nodes) of the linear accelerator, and the number of beams delivered per node. New optimization techniques reduce treatment time by direct reduction of the number of nodes and beams. These techniques iteratively remove low‐utility nodes and beams from the solution space and optimize the beam weights of the remaining beams. Annealing schedules are developed based on a user‐specified treatment time and the number of nodes in the solution set. The algorithms were evaluated on plans for standard fractionated prostate roboticIMRT, hypo‐fractionated prostate radiosurgery, spine radiosurgery, and lungSBRT.Results: The algorithms reduced treatment delivery times (excluding patient setup time) per fraction by as much as 60% for prostate roboticIMRT, 35% for prostate radiosurgery, 25% for spine radiosurgery, and 50% for lungSBRT. The implementation of the new optimization features allows the user to explore trade‐offs in treatment plan quality and delivery time by generating a family of plans that correspond to varying treatment times. Substantial time reductions were obtained for most cases while maintaining plan quality and meeting established clinical criteria (e.g., RTOG‐0238 for prostate radiotherapy and RTOG‐0618 for lungradiosurgery). Although the number of nodes was reduced, the remaining nodes still encompassed a large non‐coplanar workspace. Conclusion: New optimization techniques are described that significantly reduce delivery times for roboticradiosurgery,SBRT, and IMRTtreatments. Reduced treatment times increase patient throughput and improve patient comfort. Conflict of Interest: The authors are employed by Accuray Incorporated, Sunnyvale, CA.

Introduction: In clinical high dose rate (HDR) brachytherapy for prostate and breast, catheters are generally implanted using a template, without considering precise tumor size and shape. In this work, we present a method to optimize the number and position of catheters before the implantation stage. Methods: A research version of IPSA was modified to gradually remove uniformly distributed catheters on target volume, until the desired number of catheters is reached. Criterion for removal is based on the fraction of total treatment time attributable to each catheter. We have applied this method to a clinical prostate case implanted with 18 catheters and a breast implant of 21 catheters. For prostate case, some chosen catheters were fixed to take into account the low, but essential treatment time needed near the urethra. Results: For the studied prostate case, the cost function value is reduced for optimizations with 18 catheters down to 15, compared with the clinical plan. Bladder and urethra receive lower dose for all plans and rectum V75 is independent of the number of catheters. For the breast case, a plan with 19 catheters leads to a similar cost function value than the clinical case and optimized plans lead to a better skin protection, down to 13 catheters. Conclusion: We have devised a simple and efficient method to optimize the locations and number of catheters which could be extended to all types of interstitial HDR brachytherapy. The results indicate that it is possible to obtain clinically optimal treatment plans with fewer catheters.

Purpose: In brachytherapy, considering the perturbations from the heterogeneities in the planning system will give a better dose conformity for specific sites. The goal of this work is to demonstrate the feasibility of replacing the TG43 analytical approach by a Monte Carlo (MC)dose calculation engine in the optimization process. Method and Materials: The novel method is based on pre‐computed 3D dose kernels. The CT clinical images and the dwell positions (DWP) are loaded from the DICOM‐RT files to create a voxel based simulation of the treatment. MCdose calculation is used to create the dose kernel specific for each possible DWP. Density and tissue compositions are fully taken into account in MC. The Inverse Planning Simulated Annealing (IPSA) algorithm is used for the optimization process. IPSA reads and analyzes the MCdose kernels before the beginning of the optimization process; it replaces the TG43 parameterization. A breast interstitial HDR plan is used to demonstrate the approach. Results: Computation of precise 3D‐kernels is the most time consuming portion and is proportional to the number of DWP. However, the optimization process itself takes the same amount of time as a standard (TG43) optimization. The breast, TG43/MC plan shows an underdosage in the CTV relative to the TG43/TG43 plan by 4.3 % on D90 and 3.2 % on D50. For the surgical bed, the difference is 4.2 % and 3.5 % for D90 and D50 respectively. This was corrected in the MC/MC plan, with a minimal dose increase of the skin.Conclusion:MCoptimization improved the dose conformity. The method presented is straightforward and can be applied to any site and any afterloading process (HDR or PDR) using various type of sources, from Ir‐192 to micro‐XRay devices, as long as a precise MC model is made.

The robustness of treatment planning to prostatic edema for three different isotopes ({sup 125}I, {sup 103}Pd, and {sup 131}Cs) 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 {sup 125}I, {sup 131}Cs, and {sup 103}Pd, respectively. For each isotope, three dose distribution schemes were used to impose different protection levels to the urethra: V{sub 120}=0%, V{sub 150}=0%, and V{sub 150}=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 {sup 125}I isotope, limiting the urethra V{sub 120} to 0% leads to a prostate D{sub 90} under 140 Gy for initial edema values above 1.5. Planning with urethra V{sub 150} at 0% provides a good response to the edema; the prostate D{sub 90} remains higher than 140 Gymore » for edema values up to 1.8 and a half-life of 30 days or less. For {sup 103}Pd, the prostate D{sub 90} is under 97% of the prescription dose for approximately 66%, 40%, and 30% of edema values for urethra V{sub 120}=0%, V{sub 150}=0%, and V{sub 150}=30%, respectively. Similar behavior is seen for {sup 131}Cs 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 {sup 125}I 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.« less

Purpose: Multiobjective optimizations are performed to evaluate the inverse planning (IP) ability to adjust the dose homogeneity and the urethra protection in HDR brachytherapy of the prostate. Materials and Methods: An IP is an anatomy‐based optimization guided by dose objectives specified for each organ extracted from medical imaging. It selects automatically the active dwell positions and optimizes the dwell times to fulfill the dose objectives. It is setup to maximize the prostate dose coverage while taking into account other clinical objectives like the dose homogeneity and the organs at risk protection. Multiobjective optimizations are performed using the IP for one small (23cc), one intermediate (35cc) and one large (80cc) prostate. 10 inverse plans were generated with different compromises between dose coverage and dose homogeneity. This was performed first with the prostate alone and then with all the organs at risk. In addition, 10 inverse plans were generated with different compromises between dose coverage and urethra protection. 90 DVH were generated and analyzed. Results: When only the prostate is included, the prostate V100 varies from 100% to 97% and the homogeneity index (HI) from 0.06 to 0.68. When all the organs at risk are included, the prostate V100 varies from 97% to 91% and the HI from 0.52 to 0.72. When the urethra protection is increased, the prostate V100 varies from 100% to 89%, the urethra V100 from 100% to 89%, the urethra V120 from 87% to 0% and the urethra V150 from 3% to 0%. Conclusion: For simple cases where only a target is defined, the dose homogeneity is adjustable with the IP. For complex cases where organs at risk are added, this anatomy‐based optimization automatically adjusts the dose homogeneity to protect the urethra. Additional organ protection can be achieved with specific penalty. This research was supported by Nucletron Corporation.

Purpose: To determine the dosimetric impact of the number of catheters used in prostate HDR brachytherapy and to evaluate the possibility of reducing the number currently used clinically. Method and Materials: Our in‐house inverse planning optimizes the catheter positions based on clinical objectives such as prostate dose coverage, dose homogeneity and urethra protection. This optimization displaces straight catheters on a 5 mm grid searching for the best pattern. The number of catheters is fixed, only their positions and the dwell times are optimized. For one prostate, 8 implants were generated with different number of catheters (5, 6, 8, 10, 12, 14, 16 and 18). Results: Implants with more than 10 catheters shows equivalent dosimetric indices with good dose coverage (V100>95%) and low dose delivered to the urethra (V120

High dose rate brachytherapy is a promising radiation treatment modality that uses temporarily implanted catheters to deliver the curative dose directly in the tumor. A programmable robotic device (the afterloader) moves a single tiny radioactive source (192Ir) along the catheters using a flexible cable attached to the source. With this flexible system, a wide variety of dose distributions can be generated from a given implant simply by adjusting the length of time (dwell time) that the source dwells at any location within the implanted catheters (dwell position). The challenge is to select the optimal sequence of dwell times related to the unique clinical situation of each patient. This treatment-planning problem can be formalized as a combinatorial optimization problem. The optimization algorithm presented in this thesis is conceived to perform this task. An inverse planning (IP) approach has been adopted to guide the optimization process. This means that the optimization is guided by clinical objectives described by means of dose constraints specified to each digitized anatomical structure. A simulated annealing (SA) optimization engine has been designed to solve this particular problem in a short time for clinical applications (about 30 s ). This inverse planning by simulated annealing (IPSA) algorithm has been successfully implanted in four institutions: UCSF(1), CHUQ(2), NIH(3), CAV(4). At the moment of writing this thesis, more than 300 patients have been treated at these institutions for a wide variety of anatomical sites. Clinical studies performed by clinicians using IPSA demonstrated that the algorithm produces superior treatment plans from a dosimetric point of view than the conventional method using geometrical optimization. IPSA improves the target dose coverage while minimizing the dose delivered to organs at risk and provides consistent results from one patient to another. Both dosimetric indices and overall procedure time were improved with the clinical introduction of IPSA.