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PubMed2004

Feasibility of optimizing the dose distribution in lung tumors using fluorine-18-fluorodeoxyglucose positron emission tomography and single photon emission computed tomography guided dose prescriptions.

The information provided by functional images may be used to guide radiotherapy planning by identifying regions that require higher radiation dose. In this work we investigate the dosimetric feasibility of delivering dose to lung tumors in proportion to the fluorine-18-fluorodeoxyglucose activity distribution from positron emission tomography (FDG-PET). The rationale for delivering dose in proportion to the tumor FDG-PET activity distribution is based on studies showing that FDG uptake is correlated to tumor cell proliferation rate, which is shown to imply that this dose delivery strategy is theoretically capable of providing the same duration of local control at all voxels in tumor. Target dose delivery was constrained by single photon emission computed tomography (SPECT) maps of normal lung perfusion, which restricted irradiation of highly perfused lung and imposed dose-function constraints. Dose-volume constraints were imposed on all other critical structures. All dose-volume/function constraints were considered to be soft, i.e., critical structure doses corresponding to volume/function constraint levels were minimized while satisfying the target prescription, thus permitting critical structure doses to minimally exceed dose constraint levels. An intensity modulation optimization methodology was developed to deliver this radiation, and applied to two lung cancer patients. Dosimetric feasibility was assessed by comparing spatially normalized dose-volume histograms from the nonuniform dose prescription (FDG-PET proportional) to those from a uniform dose prescription with equivalent tumor integral dose. In both patients, the optimization was capable of delivering the nonuniform target prescription with the same ease as the uniform target prescription, despite SPECT restrictions that effectively diverted dose from high to low perfused normal lung. In one patient, both prescriptions incurred similar critical structure dosages, below dose-volume/function limits. However, in the other patient, critical structure dosage from the nonuniform dose prescription exceeded dose-volume/function limits, and greatly exceeded that from the uniform dose prescription. Strict compliance to dose-volume/ function limits would entail reducing dose proportionality to the FDG-PET activity distribution, thereby theoretically reducing the duration of local control. Thus, even though it appears feasible to tailor lung tumor dose to the FDG-PET activity distribution, despite SPECT restrictions, strict adherence to dose-volume/function limits could compromise the effectiveness of functional image guided radiotherapy.

Algorithms↗

PubMed2006

A sensitivity-guided algorithm for automated determination of IMRT objective function parameters.

Optimizing intensity-modulated radiotherapy (IMRT) plans involves tradeoffs that balance normal-tissue objectives against each other and against tumor objectives. Adjusting the parameters that determine the appropriate contributions of individual anatomic structures to the objective functions through trial and error is time consuming and may not produce the best achievable plans. We have developed a sensitivity-guided parameter optimization (SGPO) method to assist in the automatic determination of parameters to drive the IMRT optimization to better achieve, or even exceed, specified planning goals. The method is based on the trade-off relationships among multiple objectives: In a globally optimal plan (or within a convex subspace of the plan objectives), any attempt to improve the achievement of goals for a structure will result in sacrificing the goals for at least one other structure. However, different objectives may have different sensitivities to the overall goal of an IMRT plan. For instance, changes in dose distribution, hence the subscore corresponding to an objective for a given normal structure, may minimally impact the target dose distribution. Stated differently, the target coverage is insensitive to the changes in dose distribution of the specific normal structure. A lung cancer treatment plan designed with the SGPO method was used to demonstrate that IMRT plans could be designed to favor a structure with the highest target sensitivity and spare the structures with the least target sensitivity without compromising the target coverage. Using one case each of prostate and paranasal sinus cancers, we also demonstrated that several alternative optimal solutions could be designed with the SGPO algorithm favoring different structures. Finally, we applied the method to eight oropharyngeal cancer cases to obtain objective function parameters that satisfied the Radiation Therapy Oncology Group RTOG-H-0022 protocol. The eight plans optimized using the computer-generated objective function parameters met the protocol's scoring criteria with no or only minor protocol violations. Our preliminary study indicates that the SGPO method may be an effective and practical way to improve IMRT planning.

Artificial Intelligence↗

PubMed2006

Decomposition analysis of differential dose volume histograms.

Dose volume histograms are a common tool to assess the value of a treatment plan for various forms of radiation therapy treatment. The purpose of this work is to introduce, validate, and apply a set of tools to analyze differential dose volume histograms by decomposing them into physically and clinically meaningful normal distributions. A weighted sum of the decomposed normal distributions (e.g., weighted dose) is proposed as a new measure of target dose, rather than the more unstable point dose. The method and its theory are presented and validated using simulated distributions. Additional validation is performed by analyzing simple four field box techniques encompassing a predefined target, using different treatment energies inside a water phantom. Furthermore, two clinical situations are analyzed using this methodology to illustrate practical usefulness. A comparison of a treatment plan for a breast patient using a tangential field setup with wedges is compared to a comparable geometry using dose compensators. Finally, a normal tissue complication probability (NTCP) calculation is refined using this decomposition. The NTCP calculation is performed on a liver as organ at risk in a treatment of a mesothelioma patient with involvement of the right lung. The comparison of the wedged breast treatment versus the compensator technique yields comparable classical dose parameters (e.g., conformity index approximately = 1 and equal dose at the ICRU dose point). The methodology proposed here shows a 4% difference in weighted dose outlining the difference in treatment using a single parameter instead of at least two in a classical analysis (e.g., mean dose, and maximal dose, or total dose variance). NTCP-calculations for the mesothelioma case are generated automatically and show a 3% decrease with respect to the classical calculation. The decrease is slightly dependant on the fractionation and on the alpha/beta-value utilized. In conclusion, this method is able to distinguish clinically important differences between treatment plans using a single parameter. This methodology shows promise as an objective tool for analyzing NTCP and doses in larger studies, as the only information needed is the dose volume histogram.

Algorithms↗

PubMed2001

Field size reduction enables iso-NTCP escalation of tumor control probability for irradiation of lung tumors.

PURPOSE: With the mean lung dose (MLD) as an estimator for the normal tissue complication probability (NTCP) of the lung, we assessed whether the probability of tumor control of lung tumors might be increased by dose escalation in combination with a reduction of field sizes, thus increasing target dose inhomogeneity while maintaining a constant MLD. METHODS AND MATERIALS: An 8-MV AP-PA irradiation of a lung tumor, located in a cylindrically symmetric lung-equivalent phantom, was modeled using numerical simulation. Movement of the clinical target volume (CTV) due to patient breathing and setup errors was simulated. The probability of tumor control, expressed as the equivalent uniform dose (EUD) of the CTV, was assessed as a function of field size, under the constraint of a constant MLD. The approach was tested for a treatment of a non-small cell lung cancer (NSCLC) patient using the beam directions of the clinically applied treatment plan. RESULTS: In the phantom simulation it was shown that by choosing field sizes that ensured a minimum dose of 95% in the CTV ("conventional" plan) taking into account setup errors and tumor motion, an EUD of the CTV of 43.8 Gy can be obtained for a prescribed dose of 44.2 Gy. By reducing the field size and thus shifting the 95% isodose surface inwards, the EUD increases to a maximum of 68.3 Gy with a minimum dose in the CTV of 55.2 Gy. This increase in EUD is caused by the fact that field size reduction enables escalation of the prescribed dose while maintaining a constant MLD. Further reduction of the field size results in decrease of the EUD because the minimum dose in the CTV becomes so low that it has a predominant effect on the EUD, despite further escalation of the prescribed dose. For the NSCLC patient, the EUD could be increased from an initial 62.2 Gy for the conventional plan, to 83.2 Gy at maximum. In this maximum, the prescribed dose is 88.1 Gy, and the minimum dose in the CTV is 67.4 Gy. In this case, the 95% isodose surface is conformed closely to the "static" CTV during treatment planning. CONCLUSIONS: Iso-NTCP escalation of the probability of tumor control is possible for lung tumors by reducing field sizes and allowing a larger dose inhomogeneity in the CTV. Optimum field sizes can be derived, having the highest EUD and highest minimum dose in the CTV under condition of a constant NTCP of the lungs. We conclude that the concept of homogeneous dose in the target volume is not the best approach to reach the highest probability of tumor control for lung tumors.

Humans↗

PubMed1990

The carcinogenic activity of commercial grade toluene diisocyanate in rats and mice in relation to the metabolism of the 2,4- and 2,6-TDI isomers.

Groups of 50 F344/N rats of each sex and 50 B6C3F1 mice of each sex were gavaged with corn oil or a mixture of toluene diisocyanate (TDI) in corn oil for 5 days per week for 105 or 106 weeks. Female rats and mice were given doses of 60 or 120 mg/kg body weight, while male rats received 30 or 60 mg/kg, and male mice received 120 or 240 mg/kg. The TDI reacted with the moisture in the corn oil vehicle resulting in doses that were 10% to 23% below the target dose concentrations. The chemical product used was commercial grade TDI, which was an 80%-20% mixture of the 2,4- and 2,6-isomers. Chemical disposition and metabolism studies were conducted with each of the radiolabelled TDI isomers in male rats. Absorption of both of the TDI isomers occurred, with the highest concentrations found in the stomach, cecum, large intestine, and bladder. Excretion occurred via the feces and urine. The major metabolic products from the metabolism of 2,4-TDI were shown to be identical with those from the metabolism of the carcinogen, 2,4-diaminotoluene, whereas the metabolism of the 2,6-TDI isomer yielded one major product, identified as 2,6-bis(acetylamino)toluene. Greater than 10% depression in body weight gain occurred in all dosed groups of rats throughout most of the study. The major non-neoplastic lesions that were observed in both sexes of the TDI-exposed rats were dose-related increases in acute broncho-pneumonia, characterized as chemical pneumonitis, with incidences as high as 50%. In mice mean body weight gain was depressed in dosed male and in high dose females. The principle non-neoplastic lesion in mice that was attributed to chemical treatment was cytomegaly of the kidney tubular epithelium in males. Survival in all groups of dosed rats was significantly lower than in controls. A dose-dependent pattern of mortality did not commence until 70 weeks of exposure, demonstrating that toluene diisocyanate elicited a cumulative toxic response. There was also significantly lower survival in high dose male, but not female mice, by comparison to controls. Despite the reduction of power and sensitivity in the rat studies caused by early mortality, statistically significant increases in tumor incidences were observed in many different target organs. TDI was carcinogenic in F344/N rats, causing subcutaneous fibromas and fibrosarcomas in males and females, pancreatic acinar cell adenomas in males, and pancreatic islet cell adenomas, neoplastic nodules of the liver, and mammary gland tumors in females.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2005

Comparison of end normal inspiration and expiration for gated intensity modulated radiation therapy (IMRT) of lung cancer.

BACKGROUND AND PURPOSE: Gated delivery of radiation during part of the respiration cycle may improve the treatment of lung cancer with intensity modulated radiation therapy (IMRT). In terms of the respiration phase for gated treatment, normal end-expiration (EE) is more stable but normal end-inspiration (EI) increases lung volume. We compare the relative merit of using EI and EE in gated IMRT for sparing normal lung tissue. PATIENTS AND METHODS: Ten patients received EI and EE respiration-triggered CT scans in the treatment position. An IMRT plan for a prescription dose of 70 Gy was generated for each patient and at each respiration phase. The optimization constraints included target dose uniformity, less than 35% of the total lung receiving 20 Gy or more and maximum cord dose <or=45 Gy. We compared planning target volume (PTV) coverage, mean lung dose, percentage of total lung receiving 20 Gy or more (V(20)) and lung normal tissue complication probability (NTCP). RESULTS: For 9 of the 10 patients, cord and lung doses were acceptable and PTV coverage was similar for EE and EI, with lung sparing was equal to or slightly better at EI than at EE. For the 10th patient, lung sparing at EI was significantly better. Patient averaged mean lung dose was 15.4 Gy (range: 7.1-20.4) at EI and 16.3 Gy (range: 6.9-21.9) at EE. The average V(20) was 23.8% (range: 13-36.4) at EI and 25.3% (range: 13-37.3) at EE. The average NTCP at EI was 8 versus 12% at EE. CONCLUSIONS: Dosimetric indices of lung protection for IMRT plans at EI are better than at EE. For 9 out of the 10 patients in our study, this difference is small. Thus other factors such as reproducibility, reliability and duty cycle at normal end expiration may be more critical for selecting treatment breathing phase.

Aged↗

PubMed2001

Biologic treatment planning for high-dose-rate brachytherapy.

PURPOSE: Interstitial brachytherapy treatment plans are conventionally optimized with respect to total target dose and dose homogeneity, which does not account for the biologic effects of dose rate. In an HDR implant, with a stepping source, the dose rate dramatically changes during the course of treatment, depending on location, as the source moves from dwell position to dwell position. These widely varying dose rates, together with the related sequencing of the dwell positions, may impart different biologic effects at points receiving the same total dose. This study applies radiobiologic principles to account for the potential biologic impact of dose delivery at varying dose rates within an HDR implant. METHODS AND MATERIALS: The model under study uses a generalized version of the linear-quadratic (LQ) cell kill formula to calculate the surviving fraction of cells subjected to HDR irradiation. Using a planar interstitial HDR implant with the dwell times optimized to produce a homogeneous dose distribution along a reference plane parallel to the implant plane, surviving fractions were compared at selected reference points subjected to the same total dose. Biologic effect homogeneity was compared to dose homogeneity by plotting the effects at the reference points. The effects were examined with LQ parameters alpha, beta, and sublethal repair time T(1) varied over a range typical of human cells. RESULTS: In a region in which dose is relatively uniform, surviving fraction for some values of the model parameters are found to vary by as much as an order of magnitude due to differences in the HDR irradiation profiles at different dose points. This effect is more pronounced for shorter repair times and smaller alpha/beta ratios, and increases with increasing total irradiation time. CONCLUSION: Conventional HDR treatment planning currently considers dose distribution as the primary indicator of clinical effect. Our results demonstrate that plans optimized to maximize homogeneity within a target volume may not reflect the effect of the sequential nature of HDR dose delivery on cell kill. Biologic effect modeling may improve our understanding and ability to predict the adverse effects of our treatment, such as fat necrosis and fibrosis. Accounting for irradiation history and repair kinetics in the evaluation of HDR brachytherapy plans may add an important new dimension to our planning capabilities.

Algorithms↗

PubMed1995

Carboplatin (CBDCA)-hexamethylmelamine (HMM)-oral etoposide (VP-16) first-line treatment of ovarian cancer patients with bulky disease: a phase II study.

Hexamethylmelamine (HMM) and oral etoposide (VP-16) have shown to be active against platinum-resistant epithelial ovarian cancer. On this basis a three-drug regimen including carboplatin (CBDCA) plus HMM and oral VP-16 was tested in previously untreated ovarian cancer patients with tumor size > 2 cm. Since October 1991, 29 chemotherapy-naive ovarian cancer patients with tumor larger than 2 cm (20 stage III and 9 stage IV) have been treated for a total of 153 courses. CBDCA was administered i.v. on Day 1. The dose was individualized using the Calvert formula (the target dose was AUC = 5). VP-16 was administered orally at the dose of 50 mg/m2 Days 1-14, HMM at the dose of 150 mg/m2 po Days 14-28. Therapy was repeated every 28 days for a total of 6 courses. In order to avoid severe leukopenia and delays in the treatment administration, G-CSF 5 micrograms/kg/day sc Days 8-14 (or until postnadir recovery of neutrophil count > 10,000/mm3) and Days 22-28 was administered. All patients were evaluable for toxicity. No treatment-related deaths occurred. Myelotoxicity was the main side effect. It was grade 3-4 in a total of 13/29(45%) patients. One patient discontinued treatment after the first course due to HMM-related gastrointestinal toxicity. The actual delivered dose intensity was 89% of the planned dose. At the time of this analysis (April 1994) 26 patients are evaluable for response. Fifteen patients achieved a clinical complete remission and 9 a partial response for a 92% overall response rate. Fourteen patients accepted second-look laparotomy. We observed 11 pathological complete regressions (42%; 95% CI, 21-63). At a median follow-up of 16 months 3 deaths have occurred. Only 2 patients with NED at second-look laparotomy have relapsed. We stopped the accrual since the 95% confidence interval of the pCR-rate observed exceeded 20%. This new first-line regimen seems to be highly effective in patients with poor-prognosis advanced ovarian cancer, although the data are not yet sufficiently mature for a final analysis of time to progression and overall survival.

Administration, Oral↗

PubMed2026

Efficacy and Safety of the Kidney Function-Based Finerenone Dosing Strategy Used in FINEARTS-HF.

BACKGROUND: Given that mineralocorticoid receptor antagonists have the potential to impair renal function and induce hyperkalemia, close monitoring of estimated glomerular filtration rate (eGFR) and serum potassium levels is essential to ensure the safe administration of this therapy. OBJECTIVES: In this prespecified analysis, the authors evaluated the efficacy and safety of the kidney function-based finerenone dosing strategy used in the FINEARTS-HF trial. METHODS: In FINEARTS-HF, patients with an eGFR of 25 to 60 mL/min/1.73 m2 at baseline were stratified at randomization to the low-dose group and started on 10 mg of finerenone once daily (titrated to a maximum 20 mg/d) or matching placebo, whereas those with an eGFR >60 mL/min/1.73 m2 at baseline were stratified to the high-dose group and started on 20 mg of finerenone once daily (titrated to a maximum 40 mg/d) or matching placebo. The primary outcome was the composite of total (first and recurrent) heart failure events and cardiovascular death. RESULTS: Among 5,986 (99.8%) analyzable patients, 3,159 were assigned to the higher eGFR/high-dose stratum and 2,827 to the lower eGFR/low-dose stratum group. The mean ± SD achieved dose was 32.3 ± 9.1 mg (finerenone) and 34.4 ± 7.8 mg (placebo) in the higher eGFR/high-dose stratum, and 15.6 ± 4.3 mg (finerenone) and 16.7 ± 4.0 mg (placebo) in the lower eGFR/low-dose stratum. The effect of finerenone on the primary outcome was consistent across the 2 dosing strata (higher eGFR/high-dose stratum: rate ratio: 0.77 [95% CI: 0.63-0.94] vs lower eGFR/low-dose stratum: rate ratio: 0.87 [95% CI: 0.74-1.03]; P for interaction = 0.34). Consistent benefits were observed for the components of the primary outcome and all-cause death. Safety was also consistent between dosing strata, except for hypokalemia, where the reduction in the odds of hypokalemia with finerenone compared to placebo was greater in the higher eGFR/high-dose stratum (P-interaction < 0.01). CONCLUSIONS: In FINEARTS-HF, an eGFR-based dosing strategy allowed effective and safe use of finerenone in patients with heart failure with mildly reduced ejection fraction/ heart failure with preserved ejection fraction with a baseline eGFR as low as 25 mL/min/1.73 m2. We recommend that clinicians implement the trial-validated dosing strategy and incorporate appropriate uptitration to the target dose to ensure optimal therapeutic outcomes. (FINEARTS-HF [Study to Evaluate the Efficacy (Effect on Disease) and Safety of Finerenone in Participants With Heart Failure and Left Ventricular Ejection Fraction (Proportion of Blood Expelled Per Heart Stroke) Greater or Equal to 40%; NCT04435626).

Aged↗

PubMed1996

Combined alpha-beta blockade (doxazosin plus metoprolol) compared with beta blockade alone in chronic congestive heart failure.

There has been growing evidence for the benefits of beta blockers, but alpha blockers have not shown sustained benefits in chronic congestive heart failure (CHF). Thirty patients with moderate to severe CHF (New York Heart Association class II to IV) were sequentially assigned to receive metoprolol 6.25 mg with the alpha-1 antagonist doxazosin 4 mg/day or metoprolol alone. The dose of metoprolol was gradually increased to a target dose of 50 mg orally twice daily. Hemodynamic measurements were obtained before drug therapy, 2 hours after the first dose of combined alpha-beta therapy or metoprolol alone, and after 3 months of continuous treatment. Nuclear ejection fraction, plasma norepinephrine, and submaximal and maximal exercise capacity were also measured before and after chronic therapy. With initial combined drug administration, mean arterial pressure, left ventricular filling pressure, and systemic vascular resistance decreased significantly compared with results after metoprolol alone. However, after 3 months of continuous therapy, both treatment groups showed similar and significant reductions in systemic vascular resistance and heart rate, with significant increases in cardiac index, stroke volume index, stroke work index, ejection fraction, and exercise capacity. Furthermore, the next dose of chronic combined medication no longer showed vasodilating effects. Chronic therapy with fixed-dose doxazosin and increasing doses of metoprolol produced identical effects as those seen in patients receiving metoprolol alone.

Adrenergic alpha-Antagonists↗

PubMed2003

Pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension.

BACKGROUND: Bosentan, a dual endothelin-receptor antagonist, is registered for the treatment of pulmonary arterial hypertension. Little is known about the effects of bosentan in children. This study was conducted to investigate the pharmacokinetics, safety, and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension. METHODS: In this 2-center, open-label study, 19 pediatric patients with pulmonary arterial hypertension were enrolled and stratified for body weight and epoprostenol use. Patients weighing between 10 and 20 kg, between 20 and 40 kg, or greater than 40 kg received a single dose of 31.25, 62.5, or 125 mg, respectively, on day 1, followed by 4 weeks of treatment with the initial dose. The dose was then up-titrated to the target dose (31.25, 62.5, or 125 mg twice daily). Pharmacokinetic and hemodynamic parameters were obtained at baseline and after 12 weeks of treatment. Six-minute walk distance and cardiopulmonary exercise testing results were measured at baseline and at week 12 in children aged 8 years or older. RESULTS: The variability in exposure among the 3 groups was less than 2-fold after single- and multiple-dose administration. The exposure to bosentan decreased over time in all groups. The covariates body weight, gender, age, and the use of epoprostenol had no significant effect on the pharmacokinetics of bosentan. Bosentan produced hemodynamic improvement and was well tolerated. The mean change from baseline in mean pulmonary artery pressure was -8.0 mm Hg (95% confidence interval, -12.2 to -3.7 mm Hg), and that in pulmonary vascular resistance index was -300 dyne x s x m(2)/cm(5) (95% confidence interval, -576 to -24 dyne x s x m(2)/cm(5)). CONCLUSIONS: The pharmacokinetics of bosentan in pediatric patients with pulmonary arterial hypertension and healthy adults are similar, and treatment with bosentan resulted in hemodynamic improvement. These results suggest that the applied dosing regimens may be appropriate to treat pediatric patients.

Adolescent↗

PubMed1999

Treatment planning for brachytherapy: an integer programming model, two computational approaches and experiments with permanent prostate implant planning.

An integer linear programming model is proposed as a framework for optimizing seed placement and dose distribution in brachytherapy treatment planning. The basic model involves using 0/1 indicator variables to describe the placement or non-placement of seeds in a prespecified three-dimensional grid of potential locations. The dose delivered to each point in a discretized representation of the diseased organ and neighbouring healthy tissue can then be modelled as a linear combination of the indicator variables. A system of linear constraints is imposed to attempt to keep the dose level at each point to within specified target bounds. Since it is physically impossible to satisfy all constraints simultaneously, each constraint uses a variable to either record when the target dose level is achieved, or to record the deviation from the desired level. These additional variables are embedded into an objective function to be optimized. Variations on this model are discussed and two computational approaches--a branch-and-bound algorithm and a genetic algorithm--for finding 'optimal' seed placements are described. Results of computational experiments on a collection of prostate cancer cases are reported. The results indicate that both optimization algorithms are capable of producing good solutions within 5 to 15 min, and that small variations in model parameters can have a measurable effect on the dose distribution of the resulting plans.

Algorithms↗

PubMed2006

Adapting radiotherapy to hypoxic tumours.

In the current work, the concepts of biologically adapted radiotherapy of hypoxic tumours in a framework encompassing functional tumour imaging, tumour control predictions, inverse treatment planning and intensity modulated radiotherapy (IMRT) were presented. Dynamic contrast enhanced magnetic resonance imaging (DCEMRI) of a spontaneous sarcoma in the nasal region of a dog was employed. The tracer concentration in the tumour was assumed related to the oxygen tension and compared to Eppendorf histograph measurements. Based on the pO(2)-related images derived from the MR analysis, the tumour was divided into four compartments by a segmentation procedure. DICOM structure sets for IMRT planning could be derived thereof. In order to display the possible advantages of non-uniform tumour doses, dose redistribution among the four tumour compartments was introduced. The dose redistribution was constrained by keeping the average dose to the tumour equal to a conventional target dose. The compartmental doses yielding optimum tumour control probability (TCP) were used as input in an inverse planning system, where the planning basis was the pO(2)-related tumour images from the MR analysis. Uniform (conventional) and non-uniform IMRT plans were scored both physically and biologically. The consequences of random and systematic errors in the compartmental images were evaluated. The normalized frequency distributions of the tracer concentration and the pO(2) Eppendorf measurements were not significantly different. 28% of the tumour had, according to the MR analysis, pO(2) values of less than 5 mm Hg. The optimum TCP following a non-uniform dose prescription was about four times higher than that following a uniform dose prescription. The non-uniform IMRT dose distribution resulting from the inverse planning gave a three times higher TCP than that of the uniform distribution. The TCP and the dose-based plan quality depended on IMRT parameters defined in the inverse planning procedure (fields and step-and-shoot intensity levels). Simulated random and systematic errors in the pO(2)-related images reduced the TCP for the non-uniform dose prescription. In conclusion, improved tumour control of hypoxic tumours by dose redistribution may be expected following hypoxia imaging, tumour control predictions, inverse treatment planning and IMRT.

Animals↗

PubMed1995

The estimation of lung dose from mid-perineum ionization chamber measurements in total body irradiations: a quality control check on dose delivery.

A series of patients (eleven males and eight females) receiving total body irradiation prior to bone marrow transplantation was monitored during treatment by recording the dose from an ionization chamber placed between the thighs in the mid-perineal region. The treatment was delivered by opposed lateral 6 MV photon beams. The patient was encompassed by the radiation field with the maximum collimator opening at a distance of 3.49 m from the X-ray focus to the patient mid-line. An analysis was made of the measured dose and the calculated percentage average lung dose for each patient in the series to seek a correlation between measured doses and patients' anatomical data so that estimates of delivered lung doses could be made. Whilst a global factor can be applied to measured dose to predict lung dose, it is concluded that perineal dose measurements distal to the region where dose is prescribed (mean lung dose) are sub-optimal for checks on target dose delivery. Entrance and exit dose measurements at the level of dose prescription (in the thorax) are preferable for more accurate predictions and quality control checks.

Female↗

PubMed1986

Post-treatment fertility in patients with testicular cancer. III. Influence of radiotherapy in seminoma patients.

Sperm analysis and serum hormone measurements (LH, FSH, testosterone) were performed in 29 patients after orchiectomy for seminoma before and after irradiation. Before radiotherapy 14 of 20 orchiectomized patients were azoospermic or had impaired spermatogenesis. A minimum sperm count was found 1 year after radiotherapy with gradual improvement up to 2 years. The recovery of sperm cell production was impaired most in patients with pre-treatment sperm counts less than 3 million/ml. Serum testosterone remained at low normal levels throughout the observation period. The mean serum FSH was increased 1 year after radiotherapy but returned to normal in 50% of patients within 3 years after treatment. This post-treatment increase in FSH was significantly correlated with increased pre-treatment FSH but not with the gonadal dose, which was 1 to 3% of the target dose. Severe disturbances in spermatogenesis, observed 2 to 3 years after radiotherapy for early seminoma, are likely to be the expression of a highly impaired pre-treatment sperm cell production and only to a lesser degree dependent on the irradiation of the remaining testicle.

Adult↗

PubMed2002

On the implementation of dose-volume objectives in gradient algorithms for inverse treatment planning.

A method that allows a straightforward implementation of dose-volume constraints in gradient algorithms for inverse treatment planning is presented. The method is consistent with the penalty function approach, which requires the formulation of an objective function with penalty terms proportional to the magnitudes of constraint violations. Dose constraints with respect to minimum and maximum target dose levels are incorporated in quadratic, dose-penalty terms. Analogously, quadratic volume-penalty terms in the objective function reflect the violation of dose-volume constraints imposing limits on the fractions of healthy organ volumes that can be irradiated above specified dose levels. It has been demonstrated that within the framework of this formulation neither modified objective functions nor finite difference gradient calculations are necessary for the incorporation of gradient minimization algorithms. As an example, a simple steepest descent algorithm is presented along with its application to illustrate prostate and lung cases.

Algorithms↗

PubMed2006

Phase III trial of intraperitoneal therapy with yttrium-90-labeled HMFG1 murine monoclonal antibody in patients with epithelial ovarian cancer after a surgically defined complete remission.

PURPOSE: This was a multinational, open-label, randomized phase III trial comparing yttrium-90-labeled murine HMFG1 (90Y-muHMFG1) plus standard treatment versus standard treatment alone in patients with epithelial ovarian cancer (EOC) who had attained a complete clinical remission after cytoreductive surgery and platinum-based chemotherapy. PATIENTS AND METHODS: In total, 844 International Federation of Gynecology and Obstetrics stage Ic to IV patients were initially screened, of whom 447 patients with a negative second-look laparoscopy (SLL) were randomly assigned to receive either a single dose of 90Y-muHMFG1 plus standard treatment (224 patients) or standard treatment alone (223 patients). Patients in the active treatment arm received a single intraperitoneal dose of 25 mg of 90Y-muHMFG1 (target dose 666 MBq/m2). The primary end point was length of survival; secondary end points included time to relapse and safety. The study had an 80% power to detect a 15% change in survival. RESULTS: After a median follow-up of 3.5 years (range, 1 to 6 years), 70 patients had died in the active treatment arm compared with 61 patients in the control arm. Cox proportional hazards analysis of survival demonstrated no difference between treatment arms. In the study drug arm, 104 patients experienced relapse compared with 98 patients in the standard treatment arm. No difference in time to relapse was observed between the two study arms. Active therapy was associated with occasional grade 3 or 4 thrombocytopenia and neutropenia and grade 1 or 2 GI symptoms, abdominal discomfort, arthralgia, and myalgia. CONCLUSION A single IP administration of 90Y-muHMFG1 to patients with EOC who had a negative SLL after primary therapy did not extend survival or time to relapse.

Adult↗

PubMed1999

Optimized radioiodine therapy of Graves' disease: analysis of the delivered dose and of other possible factors affecting outcome.

The best approach to radioiodine dose selection in the treatment of Graves' hyperthyroidism remains highly controversial. The formula to calculate the individual dose of (131)I to be delivered has been used for half a century and takes into account the thyroid mass, the effective half-life and the maximum uptake of (131)I. The objective of the present study was to evaluate the accuracy of this formula by determining the relationship between the administered dose of (131)I calculated to deliver a target dose of 50Gy to the thyroid and the actual exact organ dose. We further analyzed if therapeutic success, defined by euthyroidism following the individually calculated dose, can be predicted by different pretreatment parameters and particularly by organ dose. One hundred patients with a first episode of Graves' disease and who had received optimal thyroid irradiation after precise dosimetry were retrospectively reviewed. The patients were categorized according to their thyroid function (plasma free thyroxine (T(4)) serum concentration) as eu-, hyper- or hypothyroid during and 1 year after treatment. The relationship between the administered dose and organ dose was assessed by simple regression. We compared free T(4), free tri-iodothyronine, thyroid weight, the number of patients with antithyroperoxidase antibodies and TSH receptor autoantibodies, 24h urinary iodine excretion, (131)I uptake, and the exact dose of (131)I delivered to the thyroid as pretreatment variables. Although we found a correlation between administered dose (mCi) and organ dose (Gy) (r=0.3, P=0.003), the mean coefficient of variation for organ dose was 45%. Individualized radioiodine therapy enabled euthyroidism in 26% of patients and failed in 74% of patients (33% had persistent or recurrent hyperthyroidism and 41% permanent hypothyroidism). (131)I uptake was significantly higher in the hyperthyroidism group in comparison with the euthyroid group. However, organ dose and other pretreatment variables did not differ among the three groups. In conclusion, these results confirm the low performance of individual dosimetry using what are established ratios, since the delivered dose to the gland, although correlated to the intended dose, is highly variable. The finding that other usual pretreatment variables are not different between groups, gives little hope for improving the way of calculating the ideal dose of radioiodine. We suggest to those not yet ready to give a standard or an ablative dose for Graves' hyperthyroidism that they abandon this way to calculate the (131)I dose.

Adult↗