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PubMed2004

Occupational exposure limits in the context of solvent mixtures, consumption of ethanol, and target tissue dose.

Individuals are exposed to mixtures, and never to single chemicals. Depending on the composition of the elements of mixtures, significant toxicological interactions between the components may occur. These interactions are complex and often difficult to predict, ranging from synergistic to additive and subadditive interactions. The nature of the interactions needs to be evaluated as the target tissue dose of the active form of each chemical. PBPK modeling is an effective tool for determining the target tissue dose and evaluating these interactions when data are available for model development. Some of the interactions are pharmacokinetic in nature, affecting the disposition of other chemicals in the body. Other interactions can be pharmacodynamic in nature, altering the effects that other chemicals have on the organism. For many organic solvents, these interactions occur principally at the level of the metabolizing enzyme, cytochrome P-450 2E1 (CYP2E1). Many solvents are known to induce or inhibit CYP2E1, or both. Mixtures may be comprised of concomitant exposures to chemicals or from components encountered separately on-the-job, off-the-job, through the diet, and otherwise. Examples of mixtures where the exposure to separate components occurs off the job will be discussed, with special emphasis on ethanol consumption as a modifier of solvent pharmacokinetics. The present practice of the linear extrapolation of the toxicity of individual mixture components in the interpretation of occupational exposure limits will also be critiqued.

Alcohol Drinking↗

PubMed2005

Optimal dose and target trough level in cyclosporine and tacrolimus conversion in renal transplantation as evaluated by lymphocyte drug sensitivity and pharmacokinetic parameters.

We evaluated the relative clinical potency of cyclosporine (CyA) and tacrolimus (Tac) using pharmacodynamic and pharmacokinetic parameters of the drug to obtain the most suitable converting dose and target trough level. The relative pharmacodynamic potency was examined by the mean ratio of drug concentrations giving 50% inhibition of blastogenesis of lymphocytes (IC50) in 66 chronic renal failure patients. The relative potency estimated from clinical pharmacokinetic parameters was examined by the mean ratio of each pharmacokinetic parameter value of CyA versus Tac. The pharmacokinetic parameters were estimated by 12-hour monitoring of drug blood concentrations in seven CyA patients and seven Tac patients. The mean IC50 ratio of CyA and Tac (CyA/Tac of IC50) was 25.1. The mean area under the concentration-time curve (AUC) ratio (CyA/Tac of AUC) was 25.5, the mean trough level (C(min)) ratio (CyA/Tac of C(min)) was 13.2, and the mean dose per body weight ratio was 25.2. The relative potency estimated from AUC that is the most reliable pharmacokinetic parameter for the estimation of clinical efficacy of calcineurin inhibitors appeared to agree with the relative pharmacodynamic potency estimated from IC50. The data suggest that TAC 25-fold more potent than CyA, which represents a suitable converting dose ratio, and that target trough level of CyA is about 13-fold greater than Tac based on CyA/Tac of C(min). We conclude that these relative values may be useful to estimate the suitable dose and target trough levels to convert between CyA and Tac.

Area Under Curve↗

PubMed2002

Radioiodine therapy in Graves' disease based on tissue-absorbed dose calculations: effect of pre-treatment thyroid volume on clinical outcome.

This study was performed with three aims. The first was to analyse the effectiveness of radioiodine therapy in Graves' disease patients with and without goitres under conditions of mild iodine deficiency using several tissue-absorbed doses. The second aim was to detect further parameters which might be predictive for treatment outcome. Finally, we wished to determine the deviation of the therapeutically achieved dose from that intended. Activities of 185-2,220 MBq radioiodine were calculated by means of Marinelli's formula to deliver doses of 150, 200 or 300 Gy to the thyroids of 224 patients with Graves' disease and goitres up to 130 ml in volume. Control of hyperthyroidism, change in thyroid volume and thyrotropin-receptor antibodies were evaluated 15+/-9 months after treatment for each dose. The results were further evaluated with respect to pre-treatment parameters which might be predictive for therapy outcome. Thyroidal radioiodine uptake was measured every day during therapy to determine the therapeutically achieved target dose and its coefficient of variation. There was a significant dose dependency in therapeutic outcome: frequency of hypothyroidism increased from 27.4% after 150 Gy to 67.7% after 300 Gy, while the frequency of persistent hyperthyroidism decreased from 27.4% after 150 Gy to 8.1% after 300 Gy. Patients who became hypothyroid had a maximum thyroid volume of 42 ml and received a target dose of 256+/-80 Gy. The coefficient of variation for the achieved target dose ranged between 27.7% for 150 Gy and 17.8% for 300 Gy. When analysing further factors which might influence therapeutic outcome, only pre-treatment thyroid volume showed a significant relationship to the result of treatment. It is concluded that a target dose of 250 Gy is essential to achieve hypothyroidism within 1 year after radioiodine therapy in Graves' disease patients with goitres up to 40 ml in volume. Patients with larger goitres might need higher doses.

Absorption↗

PubMed2004

On a hybrid method in dose finding studies.

OBJECTIVES: Combination of multiple testing and modeling techniques in dose-response studies. Use of hypotheses tests to assess the significance of the dose-response signal associated with a given candidate dose-response model. Estimation of target dose(s) following the previous model selection step. Illustration of the method with a real data example. METHODS: We assume a set of candidate models potentially reflecting the data generating process. The appropriateness of each individual model is evaluated in terms of contrast tests, where each set of contrast weights describes a specific dose-response shape. Optimum contrast weights are computed, which maximize the non-centrality parameters associated with the contrast tests. A reference set of appropriate candidate models is obtained while controlling the familywise error rate. A single model is then selected from this reference set using standard model selection criteria. The final step is devoted to dose finding by applying inverse regression techniques. This is illustrated for estimating the minimum effective dose. RESULTS: The method is as powerful as competing standard dose-response tests to detect an overall dose-related trend. In addition, the possibility is given to estimate one or more target doses of interest. The analysis of a real data example confirms the advantages of the proposed hybrid method. CONCLUSIONS: Combining multiple testing and modeling techniques leads to a powerful tool, which uses the advantages of both approaches: Rigid error control at the significance testing step and flexibility at the dose estimation step. The method can be extended to handle more general linear models including covariates and factorial treatment structures.

Clinical Trials as Topic↗

PubMed2000

Persistently positive cultures and outcome in invasive neonatal candidiasis.

BACKGROUND: A persistently positive culture >24 h after starting antibiotic therapy has been correlated with adverse outcome in several invasive bacterial infections, but few reports address persistent positivity and outcome in infections caused by fungi and other pathogens that replicate more slowly and therefore may succumb less quickly to therapy. METHODS: To assess whether positive culture >24 h after achieving target doses (amphotericin > or =0.5 mg/kg/day or fluconazole > or =6 mg/kg/day) of systemic antifungal therapy predicts focal infectious complication(s) or death from infection, we compared neonatal intensive care unit infants who had persistent (P+) or nonpersistent (P-) positive cultures with invasive candidiasis (clinical signs of infection and recovery of Candida from a normally sterile site) at this center from January 1, 1981, through June 30, 1999. Infants who died < or = 24 h after attaining target dosing, recovered without therapy, had a focal infectious complication already present at the time target dosing was achieved or were diagnosed with invasive candidiasis only postmortem were excluded. RESULTS: We identified 58 P+ (29, 12 and 7 had positive cultures for >7, >14 and > or =21 days, respectively) and 38 P- infants. No differences were found between P+ and P- for birth weight; gestational age; gender; onset age; central vascular catheters; necrotizing enterocolitis, surgery or bacterial sepsis; or duration of parenteral nutrition, antibiotics, tracheal intubation or postnatal steroids. P+ were more likely to have blood or cerebrospinal fluid involvement (68 vs. 45%, P = 0.03). Distribution of Candida species was similar (albicans in 53 vs. 63% for P+ vs. P-). P+ were significantly more likely to develop later "fungus ball" uropathy (16 of 56 vs. 2 of 32, P = 0.01), to develop renal infiltration (11 of 56 vs. 1 of 32, P = 0.03) and to die from invasive candidiasis (11 of 58 vs. 0 of 38, P = 0.003) than P-. P+ were also more likely to develop endocarditis, abscess, ventriculitis and invasive dermatitis, although P > 0.05. Focal complication increased as duration of P+ increased (48, 55, 67 and 71% at >1, >7, >14 and > or =21 days, P = 0.06). When comparing only those with positive blood and/or cerebrospinal fluid culture, similar patterns were observed, although only death and focal complication or death from invasive candidiasis attained significance. CONCLUSIONS: These observations suggest that in neonatal invasive candidiasis: (1) cultures usually remain positive >24 h after attaining target antifungal doses; (2) aggressive imaging for focal complications may be reserved for infants with persistently positive cultures after several days of antifungal therapy at target doses or have signs strongly suggestive of focal complication; (3) focal complications and/or death from candidiasis increase with persistence; (4) focal complications increase with duration of persistence; (5) serial culture of infected site(s) helps predict outcome and the need for aggressive surveillance and intervention for focal complications.

Amphotericin B↗

PubMed2004

Remote titration of carvedilol for heart failure patients by advanced practice nurses.

BACKGROUND: beta-blockers (BB) in the treatment of heart failure (HF) are frequently underprescribed and underdosed, perhaps because of recommendations for office visits at each dose change. In previous work, we demonstrated the feasibility of remote telephonically assisted BB titration and found favorable effects on morbidity, time to target dose, and low withdrawal rates. In the current expanded evaluation, we reasoned that a structured remote telephonic titration protocol would achieve outcomes comparable to US Carvedilol Trials in regard to optimal dose, titration time, and morbidity. METHODS: Seventy HF patients were initiated on BB therapy (carvedilol). Before therapy, patients were instructed on BB side effects, pulse taking, and weight monitoring. Patients reported weights, vital signs, and symptoms 3 times per week by phone. Advanced practice nurses counseled, educated, and reminded patients to increase their dose every 2 weeks until target doses were reached. RESULTS: A total of 96% reached a therapeutic dose (6.25 mg twice daily). Moreover, 71% of patients reached target doses of 25 mg twice weekly in approximately 8 weeks. No HF hospitalizations occurred during remote titration. CONCLUSIONS: The use of advanced practice nurses, titration protocols, and telemanagement technologies may improve the number of HF patients initiated and treated with appropriate doses of BB.

Adrenergic beta-Antagonists↗

PubMed2002

Radioiodine therapy and thyrostatic drugs and iodine.

Radioiodine therapy is now the most common definite treatment for persistent hyperthyroidism. The outcome of radioiodine therapy depends mainly on the absorbed energy dose in the diseased thyroid tissue. The administered activity and the resulting target dose in the thyroid depend on both the biokinetics of radioiodine and the actual therapeutic effect of radioiodine in the thyroid. Thyrostatic drugs have a major influence on the kinetics of radioiodine in the thyroid and may additionally have a radioprotective effect. Pre-treatment with thyrostatic medication lowers the effective half-life and uptake of radioiodine. This can reduce the target dose in the thyroid and have a negative influence on the outcome of the therapy. Discontinuation of medication shortly before radioiodine administration can increase the absorbed energy dose in the thyroid without increasing the whole-body exposure to radiation as much as would a higher or second radioiodine administration. Furthermore, administration of non-radioactive iodine-127 2-3 days after radioiodine administration can also increase the effective half-life of radioiodine in the thyroid. Thus, improving the biokinetics of radioiodine will allow lower activities to be administered with lower effective doses to the rest of the body, while achieving an equally effective target dose in the thyroid.

Antithyroid Agents↗

PubMed2005

Dialysis dose as a determinant of adequacy.

The intent-to-treat analyses of all patients in the HEMO trial suggested that increases in dose of dialysis as measured by urea Kt/V were of marginal or no benefit when dialysis was provided in a 3 times/wk schedule. The as-treated analysis in the HEMO trial pointed to markedly increased mortality when the delivered dose decreased even slightly below the targeted dose, evidence of a dose-targeting bias. The intent-to-treat HEMO study results suggested a potential interaction between sex and the dose-mortality relationship, and this also has been found in some cross-sectional studies, the cause of which remains unexplained. Whether dialysis dose should continue to be targeted based on urea distribution volume (V), or targeted to a body size measure that is a lower power of body weight (such as body surface area), remains an open question. The lack of benefit of increasing the dialysis dose in a 3 times/wk setting is more understandable if one looks at measures of equivalent continuous solute removal, such as the standard Kt/V. Differences in standard Kt/V in the 2 dose arms of the HEMO trial, for example, were only about 15%. Without going into removal of very large solutes (eg, beta-2-microglobulin), which is discussed elsewhere in this issue, or protein-bound uremic solutes, the only way to provide significantly more dialysis dose may be to move to more frequent dialysis schedules and/or to very long session lengths. Here, benefit may be related as much to better control of salt and water balance as to better removal of uremic toxins.

Female↗

PubMed1995

High dose rate (HDR) brachytherapy technique: for carcinoma of uterine cervix using Nucletron applicators.

This study describes our existing treatment method for high dose rate (HDR) brachytherapy of carcinoma of uterine cervix using Nucletron applicators. Based on our clinical experience with low dose rate (LDR) brachytherapy since 1986, we deliver 40-45Gy by external and 30Gy by internal radiation therapy. The change in regimen using HDR brachytherapy is that internal radiation dose is given in 5 fractions at weekly intervals following external radiotherapy. We have analyzed the dosimetry of 20 patients; total of 100 treatments done at our center using ring-tandem (R-T) and ovoid-tandem (O-T) applicator combinations. Since O-T applicator has more flexibility of using desired tandem length and reduced rectum and bladder dose due to internal shielding inside the ovoids, we have made the transition from R-T to O-T combination of applicator. The dose volume histogram of the isodose curve indicates that there is an increase in isodose volume with the O-T applicator by as much as 1.5 times as compared to R-T applicator. In majority of the treatments, rectum and bladder doses are less than 70% of target dose, however in very few treatments, the bladder dose has increased to more than the target dose, in which case, the applicators were reseated and added more packing or reduced the dose per fraction, for better tolerance of late responding normal tissues. All our dose calculations are checked with an independent calculation method and agreement was obtained with in 5-7% discrepancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Brachytherapy↗

PubMed1993

Dosing of ACE inhibitors in postinfarct protection.

ACE inhibitors improve not only symptoms and signs of heart failure in patients with symptomatic left ventricular dysfunction but also lead to a slower progression of heart failure. In asymptomatic patients with left ventricular dysfunction, the progression to symptomatic heart failure is retarded by ACE inhibitors. As heart failure is preceded in about 80% by myocardial infarctions, trials were designed to influence the development of heart failure after myocardial infarction. It could be shown that therapy with ACE inhibitors ameliorates the progressive left ventricular dilatation and that this effect is translated into a significant increase of life expectancy. Mainly based on the CONSENSUS I study, large doses of ACE inhibitors were used in most subsequent trials. The mean daily doses of enalapril were 18.4 mg in the CONSENSUS I trial and 16.6 and 16.7 mg in both arms of the SOLVD trial. There is a trend towards lower doses of ACE inhibitors, as in the SAVE trial only 79% of the patients taking captopril received the target dose of 150 mg daily. Smaller studies used similar target doses, but a beneficial effect on left ventricular enlargement has been shown with a daily dose of only 75 mg captopril. Based on the hypothesis that the left ventricular enlargement is mainly determined by the activation of the local cardiac renin angiotensin system, even lower, and therefore better tolerated, doses of ACE inhibitors may prove effective. However, studies comparing the effect of different doses of ACE inhibitors on left ventricular remodeling are missing. Consequently, the above-mentioned target doses of ACE inhibitors should be aimed at when treating patients after myocardial infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1996

Planning and delivering high doses to targets surrounding the spinal cord at the lower neck and upper mediastinal levels: static beam-segmentation technique executed with a multileaf collimator.

BACKGROUND AND PURPOSE: It remains a technical challenge to limit the dose to the spinal cord below tolerance if, in head and neck or thyroid cancer, the planning target volume reaches to a level below the shoulders. In order to avoid these dose limitations, we developed a standard plan involving Beam Intensity Modulation (BIM) executed by a static technique of beam segmentation. In this standard plan, many machine parameters (gantry angles, couch position, relative beam and segment weights) as well as the beam segmentation rules were identical for all patients. MATERIALS AND METHODS: The standard plan involved: the use of static beams with a single isocenter; BIM by field segmentation executable with a standard Philips multileaf collimator; virtual simulation and dose computation on a general 3D-planning system (Sherouse's GRATIS); heuristic computation of segment intensities and optimization (improving the dose distribution and reducing the execution time) by human intelligence. The standard plan used 20 segments spread over 8 gantry angles plus 2 non-segmented wedged beams (2 gantry angles). RESULTS: The dose that could be achieved at the lowest target voxel, without exceeding tolerance of the spinal cord (50 Gy at highest voxel) was 70-80 Gy. The in-target 3D dose-inhomogeneity was approximately 25%. The shortest time of execution of a treatment (22 segments) on a patient (unpublished) was 25 min. CONCLUSIONS: A heuristic model has been developed and investigated to obtain a 3D concave dose distribution applicable to irradiate targets in the lower neck and upper mediastinal regions. The technique spares efficiently the spinal cord and allows the delivery of higher target doses than with conventional techniques. It can be planned as a standard plan using conventional 3D-planning technology. The routine clinical implementation is performed with commercially available equipment, however, at the expense of extended execution times.

Dose-Response Relationship, Radiation↗

PubMed1990

Quality assurance in radiotherapy by in vivo dosimetry. 2. Determination of the target absorbed dose.

Combined entrance and exit dose measurements were performed with semiconductor detectors on patients, treated for neck and oral cavity malignancies. Transmission measurements showed the important influence of contour inaccuracies and tissue inhomogeneities. In 39.6% (21/53) of the checked contours, the discrepancy between the contour diameter used for routine treatment planning and the actual patient diameter was 1 cm or more, and in this group a systematic tendency for patient diameter underestimation due to the procedure was detected. When the X-ray beam passed through important bone structures such as the mandibular bones or the vertebral body, large discrepancies of 10% and more between the measured and the expected transmission were found. The target absorbed dose was determined from the transmission and entrance dose measurement. A systematic underdosage of about 2% at midline level was found to be due to an inaccuracy in the algorithms of the treatment planning system. Underdosages of 5% or more at midline were detected in more than 20% (47/230) of the measurements. In all cases, the reason for erroneous dose delivery was identified. Entrance dose measurements were previously demonstrated to be useful for the assessment of uncertainties related to treatment machine, patient set-up and treatment planning system (part 1). Transmission measurements (the ratio of the exit to the entrance dose measurement) are shown to be very useful to evaluate uncertainties related to patient data such as contour errors and tissue inhomogeneities as well as to the algorithms of the planning system. The influence of these errors on the target absorbed dose can be estimated and corrections can be applied for each individual patient.

Algorithms↗

PubMed1999

Assessment of a carcinogenic risk for treatment of Graves' ophthalmopathy in dependence on age and irradiation geometry.

In view of the probable carcinogenic risk due to the irradiation of Graves' ophthalmopathy in young patients the effective dose was assessed for two geometries. Adjusting the field to the conical outline of the orbit resulted in appreciable reduction in dose to uninvolved areas such as brain and bone marrow. In Leiden and in Essen the initial target dose was 20 Gy in 10 fractions of 2 Gy. Since 1996 the target dose in Essen was lowered to 10 fractions of 1.6 Gy with equal positive results. The combined effect of field optimization and 20% reduction in target dose has lowered the effective dose from 65 to 34 mSv. The attributable lifetime risk for fatal malignancies of 0.3% as a population average will be considerably reduced when the exposure occurs at older age.

Adult↗

PubMed2005

Impact of a standardized titration protocol with carvedilol in heart failure: safety, tolerability, and efficacy-a report from the GESICA registry.

Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) studied whether a standardized protocol for the initiation and titration of the beta-blocker carvedilol in a multicenter, open-label program would optimize beta-blocker use in heart failure (HF) patients. The program included: (1) the carvedilol initiation and titration period, and (2) long-term follow-up at 6 and 12 months. Of 1299 patients in the registry, 504 were excluded due to current therapy; of the remaining 795 eligible patients, 293 were excluded due to contraindications. Of the included patients with follow-up data (n = 316), 93.3% tolerated carvedilol initiation and 47.7% of the patients reached the target dose of 50 mg/day for a mean dose of 39 mg/day. Rates were comparable in the elderly (n = 83), of which 53% achieved a target dose for a mean dose of 43.08 mg/day. This protocol improved therapy rates and achieved target doses quickly (average of 4 visits). Concomitant medications did not have to be adjusted and there were low withdrawal rates (10%) and hospital admissions (7.2%) for HF. Patients were able to maintain carvedilol therapy at 6 and 12 months. These results indicate that a standardized titration protocol, as used in GESICA, for the initiation and titration of beta-blockers is well tolerated and may improve beta-blocker use in carefully selected heart failure patients.

Adrenergic beta-Antagonists↗

PubMed2004

Outcomes and the quality of care for patients hospitalized with heart failure.

OBJECTIVE: The purpose of this study was to determine whether process quality indicators derived from evidence-based guidelines for heart failure patients were associated with outcome indicators (hospital mortality and readmissions). DESIGN: A retrospective cohort-study among patients discharged with a primary or secondary International Classification of Disease, 10th revision (ICD-10) heart failure code from 1 January to 31 December 1999. SETTING: The study was implemented in three Swiss academic medical centers. STUDY PARTICIPANTS: Records of 1634 patients hospitalized with heart failure were abstracted. Demographic characteristics, risk factors, symptoms and findings at admission, and discharge characteristics were recorded. Main outcome measure. Process quality indicators were derived from evidence-based guidelines, related to appropriate management and treatment of heart failure patients. Hospital mortality was measured in a chart abstraction process. Thirty-day readmissions were calculated using administrative data from hospitals. RESULTS: Among the three hospitals, 1153 patients with heart failure were eligible for this study. Mean age was 75.3 years (standard deviation 12.7) and 45.7% of patients were female. Ventricular function (VF) was determined in 69% of patients. The adjusted odds-ratios (OR) for the VF not determined were 1.74 [95% confidence interval (CI) 1.06-2.84] for hospital mortality and 0.75 (95% CI 0.47-1.18) for 30-day readmissions. Among patients with left ventricular systolic dysfunction and no contraindication to angiotensin-converting enzyme inhibitor (ACEI), 54% were prescribed target-dose ACEI or angiotensin receptor blockers at discharge, 32% received ACEI at less then target dose, and 14% received no ACEI at discharge. Adjusted ORs (95% CI) for readmissions were 0.89 (0.28-2.84) for no ACEI and 1.17 (0.56-2.43) for less than target ACEI compared with target dose. CONCLUSIONS: Among patients with heart failure, the determination of VF was associated with hospital mortality. However, process indicators derived from evidence-based guidelines were not related to early readmissions in three Swiss university hospitals.

Aged↗

PubMed2006

Oral fumaric acid esters for the treatment of active multiple sclerosis: an open-label, baseline-controlled pilot study.

An exploratory, prospective, open-label study of fumaric acid esters (FAE, Fumaderm(R)) was conducted in patients with relapsing-remitting multiple sclerosis (RRMS). The study consisted of the following four phases: 6-week baseline, 18-week treatment (target dose of 720 mg/day), 4-week washout, and a second 48-week treatment phase (target dose of 360 mg/day). Ten patients with an Expanded Disability Status Scale (EDSS) score of 2.0-6.0 and at least one gadolinium-enhancing (Gd+) lesion on T1-weighted magnetic resonance imaging (MRI) brain scans participated in the study. Safety was assessed by adverse events (AEs), blood chemistry/hematology, electrocardiogram, and urinalysis. The primary efficacy outcomes were number and volume of Gd+ lesions. Other clinical outcomes included EDSS score, ambulation index (AI), and nine-hole peg test (9-HPT). Effects of FAE on intracellular cytokine profiles, T-cell apoptosis, and soluble adhesion molecules were also assessed. Three patients withdrew during the first 3 weeks of the study because of side effects, non-compliance, and follow-up loss. The most common AEs were gastrointestinal symptoms and flushing; all AEs were reported as mild and reversible. FAE produced significant reductions from baseline in number (P < 0.05) and volume (P < 0.01) of Gd+ lesions after 18 weeks of treatment; this effect persisted during the second treatment phase at half the target dose after the 4-week washout period. EDSS scores, AI, and 9-HPT remained stable or slightly improved from baseline in all patients. Measures of T-cell function demonstrated alterations in cytokines and circulating tumor necrosis factor. The results of this exploratory study suggest that further studies of FAE in patients with MS are warranted.

Administration, Oral↗

PubMed1998

A continuous penalty function method for inverse treatment planning.

Conventional inverse treatment planning attempts to calculate dose distributions that may not be feasible given the specified dose levels to various anatomical structures. A technique for inverse treatment planning has been developed that uses only target dose levels which are easily selectable to be feasible. A nonlinear constrained minimization problem is formulated to reflect the goal of sparing critical organs as much as possible while delivering a certain target dose within specified uniformity. The objective function is the squared dose delivered to critical organs. The constraints require the delivery of certain target dose within specified uniformity and non-negative pencil beam weights. A continuous penalty function method is introduced as a method for solving the large-scale constrained minimization problem. The performance of the continuous penalty function method is optimized by numerical investigation of few numerical integration schemes and a pair of weighting functions which influence the utility of the method. Clinical examples are presented that illustrate several features of the technique. The properties of the continuous penalty function method suggest that it may be a viable alternative to conventional inverse treatment planning.

Biophysical Phenomena↗

PubMed1997

Multiple local minima in radiotherapy optimization problems with dose-volume constraints.

The cause of multiple local minima in beam weight optimization problems subject to dose-volume constraints is analyzed. Three objective functions were considered: (a) maximization of tumor control probability (TCP), (b) maximization of the minimum target dose, and (c) minimization of the mean-squared-deviation of the target dose from the prescription dose. It is shown that: (a) TCP models generally result in strongly quasiconvex objective functions; (b) maximization of the minimum target dose results in a strongly quasiconvex objective function; and (c) minimizing the root-mean-square dose deviation results in a convex objective function. Dose-volume constraints are considered such that, for each region at risk (RAR), the volume of tissue whose dose exceeds a certain tolerance dose (DTol) is kept equal to or below a given fractional level (VTol). If all RARs lack a "volume effect" (i.e., VTol = 0 for all RARs) then there is a single local minimum. But if volume effects are present, then the feasible space is possibly nonconvex and therefore possibly leads to multiple local minima. These conclusions hold for all three objective functions. Hence, possible local minima come not from the nonlinear nature of the objective functions considered, but from the "either this volume or that volume but not both" nature of the volume effect. These observations imply that optimization algorithms for dose-volume constraint types of problems should have effective strategies for dealing with multiple local minima.

Algorithms↗