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Is it necessary to eliminate the posterior dose margin in prostate brachytherapy to achieve an acceptably low risk of late rectal morbidity?

PURPOSE: The use of a posterior dose margin in (125)I prostate brachytherapy is controversial. The posterior margin is often eliminated to lower the risk of late rectal morbidity (Radiation Therapy Oncology Group protocols 9805 and P-0019), but this may compromise the posterior prostate dose coverage. The purpose of this work is to determine whether it is necessary to eliminate the posterior margin to achieve an acceptably low risk of Grade 2 (bleeding/ulceration) late rectal morbidity. METHODS AND MATERIALS: The present work is an extension of a previous study in which we reported the probability of Grade 2 late rectal morbidity (bleeding/ulceration) as a function of the maximum rectal dose. Here, we define the relationship between the maximum rectal dose and the width of the posterior dose margin. From this relationship, and the probability of late morbidity determined earlier, we assessed the probability of late rectal morbidity as a function of the width of the posterior dose margin. The present work was based on the preplans of 15 permanent (125)I prostate seed implants having volumes ranging from 19 to 78 cm(3). All used peripheral loading with (125)I sources in the range 0.35-0.45 mCi. The maximum rectal dose was taken to be the isodose line coincident with the posterior edge of the prostate. The maximum rectal dose and the corresponding margin width were determined from the isodose distribution. The sensitivity of the relationship between the maximum rectal dose and the margin width to the prostate volume, the seed density, and the distance of the most posterior seeds from the posterior edge of the prostate was investigated. RESULTS: The maximum rectal dose is directly proportional to the margin width. This relationship is relatively insensitive to the prostate volume and the seed density, but is sensitive to the location of the posterior seeds relative to the posterior edge of the gland. Moving the seeds from 5 mm to 3 mm from the edge typically increased the maximum rectal dose by 17%. With the posterior seeds 3 mm from the edge, the maximum rectal doses that corresponded to 1 mm, 2 mm, 3 mm, 4 mm, and 5 mm margins were 187 +/- 6 Gy, 222 +/- 8 Gy, 257 +/- 11 Gy, 292 +/- 14 Gy, and 327 +/- 17 Gy, respectively. The corresponding probabilities that a patient will experience late rectal morbidity are < or =1%, < or =2%, < or =3%, < or =5%, and < or =7%, respectively. CONCLUSIONS: Our results indicate that a 2-3-mm posterior dose margin can be used in prostate brachytherapy with a relatively low (2-3%) risk of Grade 2 (bleeding/ulceration) late rectal morbidity, provided the sources in the posterior row are implanted at least 3 mm from the edge of the prostate. A practical guideline is to keep the maximum rectal dose below 150% of the target dose.

Brachytherapy↗

Individualized dose titration of growth hormone (GH) during GH replacement in hypopituitary adults.

OBJECTIVE: Until now, GH treatment in GH-deficient adults has employed dose schedules of GH based on body weight or body surface area and has ignored individual responsiveness to GH. This trial has studied the effects of an individualized GH dose adjusted to match a combination of clinical response, normalization of serum IGF-I concentration and body composition. DESIGN AND PATIENTS: Two closely-matched groups, each comprising 30 GH-deficient adults, 38 men and 22 women aged 48 years, were treated with GH for 12 months. The high dose (HD) group received a target dose of 12 micrograms/kg per day and the individualized dose (ID) group received an initial daily GH dose of 0.17 or 0.33 mg per day (0.5 and 1 IU, respectively), independent of body weight, with dose adjustments thereafter. MEASUREMENTS: Serum concentrations of IGF-I, lipoprotein(a), insulin, calcium, intact PTH, osteocalcin and blood glucose were measured. Body composition was determined according to a 4-compartment model using total body potassium and tritiated water as input variables. Total body nitrogen was measured by in vivo neutron activation and total body bone mineral content by dual energy X-ray absorptiometry. RESULTS: At 12 months, the daily dose of GH was 0.55 +/- 0.03 mg and 0.45 +/- 0.03 mg in the HD and ID groups, respectively (P < 0.05). In the HD group, the mean serum IGF-I increased to levels well above the predicted level, while in the ID group the mean serum IGF-I normalized. Side-effects were experienced by 70% of the subjects in the HD group and by 30% in the ID group (P < 0.001). A similar response to GH in terms of body composition, glucose homeostasis, lipoprotein(a) and blood pressure was obtained in both treatment groups. However, the treatment response in terms of serum calcium, intact PTH and osteocalcin was more marked in the HD group. CONCLUSIONS: Similar efficacy, with a lower dose of GH and fewer side-effects, was obtained by considering individual responsiveness to GH as compared to higher doses of GH adjusted to match body weight.

Adolescent↗

The effects of the phytoestrogen genistein on the postnatal development of the rat.

The present studies report the effects on neonatal rats of oral exposure to genistein during the period from birth to postnatal day (PND) 21 to generate data for use in assessing human risk following oral ingestion of genistein. Failure to demonstrate significant exposure of the newborn pups via the mothers milk led us to subcutaneously inject genistein into the pups over the period PND 1-7, followed by daily gavage dosing to PND 21. The targeted doses throughout were 4 mg/kg/day genistein (equivalent to the average exposure of infants to total isoflavones in soy milk) and a dose 10 times higher than this (40 mg/kg genistein). The dose used during the injection phase of the experiment was based on plasma determinations of genistein and its major metabolites. Diethylstilbestrol (DES) at 10 micro g/kg was used as a positive control agent for assessment of changes in the sexually dimorphic nucleus of the preoptic area (SDN-POA). Administration of 40 mg/kg genistein increased uterus weights at day 22, advanced the mean day of vaginal opening, and induced permanent estrus in the developing female pups. Progesterone concentrations were also decreased in the mature females. There were no effects in females dosed with 4 mg/kg genistein, the predicted exposure level for infants drinking soy-based infant formulas. There were no consistent effects on male offspring at either dose level of genistein. Although genistein is estrogenic at 40 mg/kg/day, as illustrated by the effects described above, this dose does not have the same repercussions as DES in terms of the organizational effects on the SDN-POA.

Administration, Oral↗

A systematic review of phase-II trials of thalidomide monotherapy in patients with relapsed or refractory multiple myeloma.

The activity of thalidomide in relapsed or refractory multiple myeloma is widely accepted but not yet demonstrated in a randomised-controlled trial. A systematic review of the published clinical trials of these patients could reduce the possible bias of single phase-II studies. A systematic search identified 42 communications reporting on 1674 patients. Thirty-two trials used an escalating dosing regimen and four a fixed dose regimen (one dose with 50 mg/d, three doses with 200 mg/d). The target dose in the dose escalating trials was 800 mg/d in 17 trials, 400-600 mg/d in 10 and 200 mg/d in one trial. The intention-to-treat population for efficacy was 1629 patients with a median age of 62 years. The complete and partial (>50% reduction in monoclonal protein) response rate was 29.4% (95%-confidence interval, 27-32%). The rates for minor responses or stable disease were 13.8% (12-16%) and 11.0% (9-13%). Progressive disease was reported in 9.9% (8-11%). The median overall survival from all trials was reported at 14 months. Severe adverse events (grade III-IV) included somnolence 11%, constipation 16%, neuropathy 6%, rash 3%, thrombo-embolism 3%, cardiac 2%. In conclusion, thalidomide monotherapy achieved complete and partial responses in 29.4% of patients with relapsed or refractory multiple myeloma.

Clinical Trials, Phase II as Topic↗

Topiramate for migraine prevention in children: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To assess the efficacy and safety of topiramate for the prevention of pediatric migraine with or without aura in a double-blind, randomized, placebo-controlled trial. BACKGROUND: Treatment options for pediatric migraine are currently limited, and no migraine preventive agents are approved for use in children in the United States. Topiramate is an effective migraine preventive therapy in adults, as demonstrated in several large, randomized, placebo-controlled trials. METHODS: One hundred and sixty-two children with migraine (age, 6 to 15 years) were randomized in a 2:1 ratio to receive topiramate (n = 112) or placebo (n = 50). This study was designed to ensure that 150 participants were randomized to study medication. An additional 12 qualified patients were randomized because they had successfully completed the screening phase. The double-blind phase of the trial consisted of a titration period and a maintenance period. Topiramate was initiated at 15 mg/day and titrated over 8 weeks to 2 to 3 mg/kg per day, or maximum tolerated dose, whichever was less (maximum allowed dose was 200 mg/day). The target dose was maintained for 12 weeks. The primary efficacy variable was the change in mean number of migraine days per month (28 days) during the double-blind phase relative to the 4-week prospective baseline phase for each treatment group. RESULTS: Topiramate treatment was associated with a mean reduction over the entire double-blind phase of 2.6 migraine days per month, compared with a mean reduction of 2.0 migraine days per month for placebo (P = .061 topiramate vs. placebo). A significantly greater percentage of topiramate patients (32%) experienced a > or = 75% reduction in mean monthly migraine days compared with placebo (14%, P = .02). Discontinuation rates due to adverse events were low: 6.5% for the topiramate group and 4.0% for the placebo group. The adverse events that occurred most commonly in the topiramate group at an incidence rate greater than in the placebo group were: upper respiratory tract infection, anorexia, weight decrease, gastroenteritis, paresthesia, and somnolence. The mean average daily dose of topiramate during the maintenance period was 2.0 mg/kg per day. CONCLUSIONS: This pilot study suggests that topiramate may be an effective migraine preventive therapy in children. Topiramate was well tolerated in this population. Further randomized studies would be required to definitively establish the efficacy of topiramate for pediatric migraine prevention.

Adolescent↗

A dose-escalation study of weekly topotecan, cisplatin, and gemcitabine front-line therapy in patients with inoperable non-small cell lung cancer.

PURPOSE: To determine the optimal dose of combination topotecan, cisplatin, and gemcitabine in advanced non-small cell lung cancer patients. MATERIALS AND METHODS: This single-center, single-practice, phase I trial enrolled chemotherapy-naïve patients with inoperable stage IIIB/IV disease. Initial treatment was topotecan (0.5-2.0 mg/m(2)), cisplatin (20 mg/m(2)), and gemcitabine (1,000 mg/m(2)) on days 1, 8, and 15 of a 28-day cycle. Dose-limiting thrombocytopenia at week 3 necessitated less frequent gemcitabine dosing (days 1 and 15 of each cycle). Thereafter, topotecan dose escalation proceeded to the target dose of 2 mg/m(2). RESULTS: Thirty patients were enrolled and evaluable for toxicity assessment. Treatment was extremely well tolerated: only one grade 4 adverse event (leukopenia); no hospitalizations for treatment-related toxicities; no fever/neutropenia. Although no dose-limiting toxicities developed, 1.75 mg/m(2) topotecan is considered optimal and recommended for further study because it was well tolerated, active, and did not require dose adjustments or delays in therapy. Eleven of 29 (38%) evaluable patients achieved a partial response. Median survival was 38 weeks (range 4-110 weeks), median progression-free survival was 17 weeks, and the 1-year survival rate was 33%. Two patients remain alive after 108-122 weeks of follow-up. CONCLUSION: A 28-day cycle of topotecan (1.75 mg/m(2) days 1, 8, 15), cisplatin (20 mg/m(2) days 1, 8, 15), and gemcitabine (1,000 mg/m(2) days 1, 15) was a safe and well-tolerated outpatient treatment for advanced non-small cell lung cancer. The favorable preliminary efficacy and safety of this regimen suggest that further study in phase II trials, including quality-of-life end points, is warranted.

Aged↗

Prevention and therapy of radiation-induced bowel discomfort.

In a double-blind randomized placebo-controlled study, including 70 patients treated with radiotherapy of localized malignancies in the pelvis, the effects of prophylactic sucralfate in preventing bowel discomfort were evaluated. Radiotherapy was delivered in a conventional manner with high-energy photons in a total dose of 62-66 Gy (target dose, 1.8-2.2 Gy) during 6.5 weeks. Dose granules of sucralfate or placebo were given 2 weeks after irradiation started and continued for 6 weeks. All analyses were performed blindly. The patients in the sucralfate group had significantly less problems with acute (5 weeks) and chronic (66 weeks) bowel discomfort. The consumption of loperamide was also reduced in the sucralfate group, and the weight decrease was less pronounced. No adverse effects were seen. Thus, sucralfate seems to be beneficial in minimizing the problems of bowel discomfort during and after irradiation of malignancies in the pelvis. These results are discussed in relation to other related observations.

Diarrhea↗

Lamotrigine as adjunct to paroxetine in acute depression: a placebo-controlled, double-blind study.

BACKGROUND: Mood stabilizers appear to be more potent in treating mania than depression. The anticonvulsant lamotrigine has been shown to be effective for bipolar depression. This study examines putative antidepressive properties of lamotrigine in a mainly unipolar routine clinical patient population. METHOD: Forty patients with a depressive episode (DSM-IV criteria) requiring psychiatric intervention received lamotrigine or placebo using a fixed dose escalation scheme with a target dose of 200 mg/day for 9 weeks. Additionally, all patients were treated with paroxetine. Hamilton Rating Scale for Depression (HAM-D) and Clinical Global Impressions scale (CGI) ratings were used to monitor therapeutic efficacy. RESULTS: Adjunctive treatment with lamotrigine did not result in a significant difference in HAM-D total score at the endpoint of the study when compared with paroxetine alone. However, lamotrigine demonstrated significant efficacy on core depressive symptoms as reflected by HAM-D items 1 (depressed mood; p = .0019), 2 (guilt feelings; p = .0011), and 7 (work and interest; p = .049) and the CGI-Severity of Illness scale (p < .0001). Patients receiving lamotrigine had fewer days on treatment with benzodiazepines and fewer withdrawals for treatment failure. Lamotrigine appeared to accelerate the onset of action of the antidepressant. Two patients on lamotrigine treatment developed neutropenia, and 1 developed a benign rash. There was no detectable pharmacokinetic interaction between lamotrigine and paroxetine. CONCLUSION: Lamotrigine might have antidepressive properties in unipolar patients and may accelerate onset of action when given in combination with typical antidepressants.

Acute Disease↗

[Effect of chronic therapy with low dose of angiotensin converting enzyme inhibitors on mortality in patients with left ventricular dysfunction after acute myocardial infarction].

UNLABELLED: Angiotensin converting enzyme inhibitors (ACE-I) used in patients with postinfarction left ventricular dysfunction reduce the risk of death. Some patients do not tolerate high dose of medications which benefit was well documented in multicentre trials. THE AIM OF THIS STUDY: was to evaluate the effect of low doses of ACE-I on mortality rate in patients with ejection fraction (EF) below < or = 35% after acute myocardial infarction (MI) in long-term observation. MATERIAL AND METHODS: Study population consisted of 84 patients (pts) (67 men and 17 women) aged 38-79 (mean age 61 +/- 11) years with post-MI left ventricular dysfunction (EF < or = 35%). Patients were divided into 2 groups according to applied treatment: the group ACE-I (+) - 50 pts who received captopril, enalapril, trandolapril, perindopril or quinapril at doses not exceeding half of target dose in chronic heart failure and the group ACE-I (-) - 34 pts not treated with ACE-I. The end point of this observation was total mortality during 48 month follow-up. RESULTS: During long-term observation 33 from 84 patients died (39%). Mortality from all causes in the group ACE-I (+) was non significantly reduced as compared with the group ACE-I (-) (36% vs. 44%). CONCLUSION: In patients with left ventricular dysfunction (EF < or = 35%) after acute myocardial infarction chronic treatment with low doses of ACE-I do not reduce total mortality rate.

Angiotensin-Converting Enzyme Inhibitors↗

Intensity-modulated radiotherapy versus conventional three-dimensional conformal radiotherapy for boost or salvage treatment of nasopharyngeal carcinoma.

PURPOSE: To compare intensity-modulated radiotherapy (IMRT) and conventional three-dimensional conformal radiotherapy (3D-CRT) for the boost treatment of new-onset nasopharyngeal carcinoma (NPC) or the salvage treatment of locally recurrent NPC. METHODS AND MATERIALS: Between January 14 and February 23, 2000, 5-field 3D-CRT treatment plans were generated for 14 consecutive NPC patients using the ADAC Pinnacle planning system in Chang Gung Memorial Hospital, Kaohsiung, Taiwan. The planning data of these patients were later transferred to Memorial Sloan-Kettering Cancer Center, where new IMRT plans, also using 5-7 radiation fields were created for each patient using an inverse treatment planning system. The IMRT and 3D-CRT plans were compared for all 14 patients. The relationship between the anatomic shapes and locations of targets and the results of different plans were studied. RESULTS: Target doses were more homogeneous in IMRT plans. The average maximal brainstem dose (D(05), the dose received by 5% of the brainstem volume) decreased from 30.9% of the prescription dose with 3D-CRT to 15.3% and 14.7% with 5- and 7-field IMRT, respectively (p = 0.004 and 0.003, respectively, compared with 3D-CRT, paired Student's t test). Five anatomic factors were found that predicted greater benefits with IMRT. These factors were (1) vertical length of target >7 cm, (2) minimal distance between target and brainstem <0.1 cm, (3) maximal AP overlap of target and brainstem >0.6 cm, (4) maximal AP overlap of target and spinal cord >1 cm, and (5) vertical overlap of target and eyes >0 cm. For the 7 patients with at least 1 of these 5 anatomic factors, the benefits achieved by IMRT planning would have been greater than the benefits for the other 7 patients (p = 0.005, Fisher's exact test). CONCLUSION: For boost or salvage treatment of NPC, lower normal tissue doses and more homogeneous target doses were achieved with IMRT plans. For NPC patients with at least 1 of the 5 anatomic factors, IMRT is highly recommended.

Algorithms↗

Gamma knife surgery for idiopathic trigeminal neuralgia performed using a far-anterior cisternal target and a high dose of radiation.

OBJECT: Gamma knife surgery (GKS) has emerged as a suitable treatment of pharmacologically resistant idiopathic trigeminal neuralgia. The optimal radiation dose and target for this therapy, however, remain to be defined. The authors analyzed the results of GKS in which a high dose of radiation and a distal target was used, to determine the best parameters for this treatment. METHODS: The authors evaluated results in 47 patients who were treated with this approach. All patients underwent clinical and magnetic resonance imaging examinations at 6 weeks, 6 months, and 1 year post-GKS. Fifteen potential prognostic factors associated with favorable pain control were studied. The mean follow-up period was 16 months (range 6-42 months). The initial pain relief was excellent (100% pain control) in 32 patients, good (90-99% pain control) in seven patients, fair (50-89% pain control) in three patients, and poor (< 50% pain control) in five patients. The actuarial curve of pain relief displayed a 59% rate of excellent pain control and a 71% excellent or good pain control at 42 months after radiosurgery. Radiosurgery-induced facial numbness was bothersome for two patients and mild for 18 patients. Three prognostic factors were found to be statistically significant factors for successful pain relief: a shorter distance between the target and the brainstem, a higher radiation dose delivered to the brainstem, and the development of a facial sensory disturbance after radiosurgery. CONCLUSIONS: To optimize pain control and minimize complications of this therapy, we recommend that the nerve be targeted at a distance of 5 to 8 mm from the brainstem.

Adult↗

Feasibility study of helical tomotherapy for total body or total marrow irradiation.

Total body radiation (TBI) has been used for many years as a preconditioning agent before bone marrow transplantation. Many side effects still plague its use. We investigated the planning and delivery of total body irradiation (TBI) and selective total marrow irradiation (TMI) and a reduced radiation dose to sensitive structures using image-guided helical tomotherapy. To assess the feasibility of using helical tomotherapy, (A) we studied variations in pitch, field width, and modulation factor on total body and total marrow helical tomotherapy treatments. We varied these parameters to provide a uniform dose along with a treatment times similar to conventional TBI (15-30 min). (B) We also investigated limited (head, chest, and pelvis) megavoltage CT (MVCT) scanning for the dimensional pretreatment setup verification rather than total body MVCT scanning to shorten the overall treatment time per treatment fraction. (C) We placed thermoluminescent detectors (TLDs) inside a Rando phantom to measure the dose at seven anatomical sites, including the lungs. A simulated TBI treatment showed homogeneous dose coverage (+/-10%) to the whole body. Doses to the sensitive organs were reduced by 35%-70% of the target dose. TLD measurements on Rando showed an accurate dose delivery (+/-7%) to the target and critical organs. In the TMI study, the dose was delivered conformally to the bone marrow only. The TBI and TMI treatment delivery time was reduced (by 50%) by increasing the field width from 2.5 to 5.0 cm in the inferior-superior direction. A limited MVCT reduced the target localization time 60% compared to whole body MVCT. MVCT image-guided helical tomotherapy offers a novel method to deliver a precise, homogeneous radiation dose to the whole body target while reducing the dose significantly to all critical organs. A judicious selection of pitch, modulation factor, and field size is required to produce a homogeneous dose distribution along with an acceptable treatment time. In addition, conformal radiation to the bone marrow appears feasible in an external radiation treatment using image-guided helical tomotherapy.

Bone Marrow↗

Intensity modulated radiotherapy with charged particle beams: studies of inverse treatment planning for rotation therapy.

The optimization of intensity modulated radiotherapy (IMRT) for charged particle beams is a necessary prerequisite to evaluate the clinical potential of this treatment modality in comparison to IMRT with high energy photons. A theoretical study for IMRT with charged particle beams delivered by rotation therapy is presented. First, the inverse problem for two-dimensional rotation therapy with arbitrary depth dose curves is formulated. Then a numerical strategy is devised to calculate fluence profiles for the simplified case of arbitrary rotationally invariant dose distributions. This mathematical framework is applied to study various aspects of charged particle IMRT. A central topic of the investigation is the evaluation of dose delivery, based on distal edge tracking (DET) and intensity modulation. The potential of DET-IMRT with charged particle beams is studied in comparison to an optimal, conventional dose delivery technique, which employs the concept of a spread-out Bragg peak (SOBP). Moreover, a comparison to photon IMRT is provided for simple geometric dose patterns. The technique of DET-IMRT for the delivery of a homogeneous target dose is only feasible for targets up to a critical radius, depending on the individual shape of the employed Bragg peak. The irradiation of larger targets requires energy modulation in addition to the range modulation for DET. The accurate placement of the Bragg peak with respect to the target edge is found to be of potential importance. Comparing dose delivery via DET-IMRT with the optimal SOBP technique revealed a significant advantage of DET-IMRT, especially a saved integral dose in target-adjacent healthy tissues of up to 30%, and a reduction of the penumbra at the target edge by almost 50%. A saving in integral dose to healthy tissues by a factor of 2-3 was observed for DET-IMRT in comparison to IMRT with high energy photons.

Biophysical Phenomena↗

Lessons from the Hemodialysis (HEMO) Study: an improved measure of the actual hemodialysis dose.

The Hemodialysis (HEMO) Study is a multicenter, prospective, randomized, 2 x 2 factorial clinical trial designed to evaluate the efficacy of the dose of dialysis delivered ("standard" v "high") and dialysis membrane flux ("low" v "high") in reducing the morbidity and mortality of patients. The study is nearly half complete. Although both patients and investigators are blinded to the overall findings, which will not be available for another 3 years, important data have been generated from which a more accurate expression has been derived for the dose of dialysis received by each patient in the trial. This new expression of the effectiveness of dialysis, eKt/V, is a two-pool approximation derived from the traditional single-pool Kt/V (spKt/V) and time on dialysis. The dialysis prescription for the HEMO Study subjects is individualized to achieve the target dose for each patient and is closely monitored by measuring the more accurate and validated expression of eKt/N. Comparisons of the HEMO Study dose of dialysis with other studies have been confused by this unique expression (eKt/V) of the dialysis dose and adequacy adopted for the HEMO Study. The target eKt/V dose in the "standard" arm of the Study is 1.05 and in the "high" arm is 1.45 per dialysis thrice weekly. Based on data available from 426 subjects randomized to each arm, the target of 1.05 in the "standard" dose of the HEMO Study is equivalent to an spKt/V of 1.32, and that of the "high" dose, 1.67. Thus, volunteers in the "standard" arm of the Study are receiving a tightly controlled and closely monitored dose, which is above the current national mean spKt/V, and above that of the accepted minimum standard spKt/N of 1.2. When completed, the HEMO Study will show whether there are merits of a tightly controlled hemodialysis dose that is consistently delivered over a prolonged period and whether a high dose is beneficial and safe to prescribe.

Blood Urea Nitrogen↗

The probability of correct target dosage: dose-population histograms for deriving treatment margins in radiotherapy.

PURPOSE: To provide an analytical description of the effect of random and systematic geometrical deviations on the target dose in radiotherapy and to derive margin rules. METHODS AND MATERIALS: The cumulative dose distribution delivered to the clinical target volume (CTV) is expressed analytically. Geometrical deviations are separated into treatment execution (random) and treatment preparation (systematic) variations. The analysis relates each possible preparation (systematic) error to the dose distribution over the CTV and allows computation of the probability distribution of, for instance, the minimum dose delivered to the CTV. RESULTS: The probability distributions of the cumulative dose over a population of patients are called dose-population histograms in short. Large execution (random) variations lead to CTV underdosage for a large number of patients, while the same level of preparation (systematic) errors leads to a much larger underdosage for some of the patients. A single point on the histogram gives a simple "margin recipe." For example, to ensure a minimum dose to the CTV of 95% for 90% of the patients, a margin between CTV and planning target volume (PTV) is required of 2.5 times the total standard deviation (SD) of preparation (systematic) errors (Sigma) plus 1.64 times the total SD of execution (random) errors (sigma') combined with the penumbra width, minus 1.64 times the SD describing the penumbra width (sigma(p)). For a sigma(p) of 3.2 mm, this recipe can be simplified to 2.5 Sigma + 0.7 sigma'. Because this margin excludes rotational errors and shape deviations, it must be considered as a lower limit for safe radiotherapy. CONCLUSION: Dose-population histograms provide insight into the effects of geometrical deviations on a population of patients. Using a dose-probability based approach, simple algorithms for choosing margins were derived.

Algorithms↗

Once-daily intravenous busulfan in children prior to stem cell transplantation: study of pharmacokinetics and early clinical outcomes.

We studied the pharmacokinetics and clinical outcome of a new once-daily intravenous area under the curve-targeted dosing scheme for busulfan based on body surface area. Eighteen children undergoing busulfan-based conditioning for allogeneic stem cell transplantation were enrolled. The age of the children ranged from 0.5 to 16 years. For all children, the starting dose was 80 mg/m. Unlimited dose adjustment was allowed to reach the target area under the curve (3800 micromol/l . min). This target area under the curve was determined on the basis of a previous study in our hospital. Pharmacokinetic studies were performed after the first dose. The median area under the curve on day 1 was 2616 (range 1781-5040) micromol/l . min at a dose of 80 mg/m. This resulted in a median dose increment to 114 (range 62-168) mg/m to reach the target area under the curve. In only one patient, the dose was decreased. Donor engraftment was established in 14 out of 18 patients (78%). Two of the four patients were successfully retransplanted. Relapse occurred in two patients (one died, one received additional treatment). Fourteen patients survived with a median follow-up of 1.6 years (1.0-2.2 years). The disease-free survival was 66% (12 of 18 patients). Despite the high systemic peak levels, there was no new unexpected or unusual toxicity. Moderate veno-occlusive disease was seen in one patient only. We conclude that intravenous busulfan in children administered once daily is safe, convenient and feasible, and can be dosed surface-based, independent of age. There was very limited (liver) toxicity, but the rejection rate was relative high, which can be probably overcome by a higher exposure to busulfan. Future investigations should be aimed at further optimizing the target area under the curve of intravenous busulfan for specific patient groups.

Adolescent↗

Intensity-modulated radiation therapy (IMRT) dosimetry of the head and neck: a comparison of treatment plans using linear accelerator-based IMRT and helical tomotherapy.

PURPOSE: To date, most intensity-modulated radiation therapy (IMRT) delivery has occurred using linear accelerators (linacs), although helical tomotherapy has become commercially available. To quantify the dosimetric difference, we compared linac-based and helical tomotherapy-based treatment plans for IMRT of the oropharynx. METHODS AND MATERIALS: We compared the dosimetry findings of 10 patients who had oropharyngeal carcinoma. Five patients each had cancers in the base of the tongue and tonsil. Each plan was independently optimized using either the CORVUS planning system (Nomos Corporation, Sewickly, PA), commissioned for a Varian 2300 CD linear accelerator (Varian Medical Systems, Palo Alto, CA) with 1-cm multileaf collimator leaves, or helical tomotherapy. The resulting treatment plans were evaluated by comparing the dose-volume histograms, equivalent uniform dose (EUD), dose uniformity, and normal tissue complication probabilities. RESULTS: Helical tomotherapy plans showed improvement of critical structure avoidance and target dose uniformity for all patients. The average equivalent uniform dose reduction for organs at risk (OARs) surrounding the base of tongue and the tonsil were 17.4% and 27.14% respectively. An 80% reduction in normal tissue complication probabilities for the parotid glands was observed in the tomotherapy plans relative to the linac-based plans. The standard deviation of the planning target volume dose was reduced by 71%. In our clinic, we use the combined dose-volume histograms for each class of plans as a reference goal for helical tomotherapy treatment planning optimization. CONCLUSIONS: Helical tomotherapy provides improved dose homogeneity and normal structure dose compared with linac-based IMRT in the treatment of oropharyngeal carcinoma resulting in a reduced risk for complications from focal hotspots within the planning target volume and for the adjacent parotid glands.

Carcinoma, Squamous Cell↗

Impact of IMRT and leaf width on stereotactic body radiotherapy of liver and lung lesions.

PURPOSE: The present study explored the impact of intensity-modulated radiotherapy (IMRT) on stereotactic body RT (SBRT) of liver and lung lesions. Additionally, because target dose conformity can be affected by the leaf width of a multileaf collimator (MLC), especially for small targets and stereotactic applications, the use of a micro-MLC on "uniform intensity" conformal and intensity-modulated SBRT was evaluated. METHODS AND MATERIALS: The present study included 10 patients treated previously with SBRT in our institution (seven lung and three liver lesions). All patients were treated with 3 x 12 Gy prescribed to the 65% isodose level. The actual MLC-based conformal treatment plan served as the standard for additional comparison. In total, seven alternative treatment plans were made for each patient: a standard (actual) plan and an IMRT plan, both calculated with Helax TMS (Nucletron) using a pencil beam model; and a recalculated standard and a recalculated IMRT plan on Helax TMS using a point dose kernel approach. These four treatment plans were based on a standard MLC with 1-cm leaf width. Additionally, the following micro-MLC (central leaf width 3 mm)-based treatment plans were calculated with the BrainSCAN (BrainLAB) system: standard, IMRT, and dynamic arc treatments. For each treatment plan, various target parameters (conformity, coverage, mean, maximal, and minimal target dose, equivalent uniform doses, and dose-volume histogram), as well as organs at risk parameters (3 Gy and 6 Gy volume, mean dose, dose-volume histogram) were evaluated. Finally, treatment efficiency was estimated from monitor units and the number of segments for IMRT solutions. RESULTS: For both treatment planning systems, no significant difference could be observed in terms of target conformity between the standard and IMRT dose distributions. All dose distributions obtained with the micro-MLC showed significantly better conformity values compared with the standard and IMRT plans using a regular MLC. Dynamic arc plans were characterized by the steepest dose gradient and thus the smallest V(6 Gy) values, which were on average 7% smaller than the standard plans and 20% lower than the IMRT plans. Although the Helax TMS IMRT plans show about 18% more monitor units than the standard plan, BrainSCAN IMRT plans require approximately twice the number of monitor units relative to the standard plan. All treatment plans optimized with a pencil beam model but recalculated with a superposition method showed significant qualitative, as well as quantitative, differences, especially with respect to conformity and the dose to organs at risk. CONCLUSION: Standard conformal treatment techniques for SBRT could not be improved with inversely planned IMRT approaches. Dose calculation algorithms applied in optimization modules for IMRT applications in the thoracic region need to be based on the most accurate dose calculation algorithms, especially when using higher energy photon beams.

Algorithms↗