Validation of automated post-adjustments of HDR prostate brachytherapy treatment plans by quantitative measures and oncologist observer study.

PURPOSE: The aim was to evaluate a postprocessing optimization algorithm's ability to improve the spatial properties of a clinical treatment plan while preserving the target coverage and the dose to the organs at risk. The goal was to obtain a more homogenous treatment plan, minimizing the need for manual adjustments after inverse treatment planning. MATERIALS AND METHODS: The study included 25 previously treated prostate cancer patients. The treatment plans were evaluated on dose-volume histogram parameters established clinical and quantitative measures of the high dose volumes. The volumes of the four largest hot spots were compared and complemented with a human observer study with visual grading by eight oncologists. Statistical analysis was done using ordinal logistic regression. Weighted kappa and Fleiss' kappa were used to evaluate intra- and interobserver reliability. RESULTS: The quantitative analysis showed that there was no change in planning target volume (PTV) coverage and dose to the rectum. There were significant improvements for the adjusted treatment plan in: V150% and V200% for PTV, dose to urethra, conformal index, and dose nonhomogeneity ratio. The three largest hot spots for the adjusted treatment plan were significantly smaller compared to the clinical treatment plan. The observers preferred the adjusted treatment plan in 132 cases and the clinical in 83 cases. The observers preferred the adjusted treatment plan on homogeneity and organs at risk but preferred the clinical plan on PTV coverage. CONCLUSIONS: Quantitative analysis showed that the postadjustment optimization tool could improve the spatial properties of the treatment plans while maintaining the target coverage.

Dosimetric impact of a robust optimization approach to mitigate effects from rotational uncertainty in prostate intensity-modulated brachytherapy.

BACKGROUND: Intensity-modulated brachytherapy (IMBT) is an emerging technology for cancer treatment, in which radiation sources are shielded to shape the dose distribution. The rotatable shields provide an additional degree of freedom, but also introduce an additional, directional, type of uncertainty, compared to conventional high-dose-rate brachytherapy (HDR BT). PURPOSE: We propose and evaluate a robust optimization approach to mitigate the effects of rotational uncertainty in the shields with respect to planning criteria. METHODS: A previously suggested prototype for platinum-shielded prostate 169 Yb-based dynamic IMBT is considered. We study a retrospective patient data set (anatomical contours and catheter placement) from two clinics, consisting of six patients that had previously undergone conventional 192 Ir HDR BT treatment. The Monte Carlo-based treatment planning software RapidBrachyMCTPS is used for dose calculations. In our computational experiments, we investigate systematic rotational shield errors of ±10° and ±20°, and the same systematic error is applied to all dwell positions in each scenario. This gives us three scenarios, one nominal and two with errors. The robust optimization approach finds a compromise between the average and worst-case scenario outcomes. RESULTS: We compare dose plans obtained from standard models and their robust counterparts. With dwell times obtained from a linear penalty model (LPM), for 10° errors, the dose to urethra ( D 0.1 c c $D_{0.1cc}$ ) and rectum ( D 0.1 c c $D_{0.1cc}$ and D 1 c c $D_{1cc}$ ) increase with up to 5% and 7%, respectively, in the worst-case scenario, while with the robust counterpart, the corresponding increases were 3% and 3%. For all patients and all evaluated criteria, the worst-case scenario outcome with the robust approach had lower deviation compared to the standard model, without compromising target coverage. We also evaluated shield errors up to 20° and while the deviations increased to a large extent with the standard models, the robust models were capable of handling even such large errors. CONCLUSIONS: We conclude that robust optimization can be used to mitigate the effects from rotational uncertainty and to ensure the treatment plan quality of IMBT.

Technical note: Evaluation of a spatial optimization model for prostate high dose-rate brachytherapy in a clinical treatment planning system.

BACKGROUND: Spatial properties of a dose distribution, such as volumes of contiguous hot spots, are of clinical importance in treatment planning for high dose-rate brachytherapy (HDR BT). We have in an earlier study developed an optimization model that reduces the prevalence of contiguous hot spots by modifying a tentative treatment plan. PURPOSE: The aim of this study is to incorporate the correction of hot spots in a standard inverse planning workflow and to validate the integrated model in a clinical treatment planning system. The spatial function is included in the objective function for the inverse planning, as opposed to in the previous study where it was applied as a separate post-processing step. Our aim is to demonstrate that fine-adjustments of dose distributions, which are often performed manually in today's clinical practice, can be automated. METHODS: A spatial optimization function was introduced in the treatment planning system RayStation (RaySearch Laboratories AB, Stockholm, Sweden) via a research interface. A series of 10 consecutive prostate patients treated with HDR BT was retrospectively replanned with and without the spatial function. RESULTS: Optimization with the spatial function decreased the volume of the largest contiguous hot spot by on average 31%, compared to if the function was not included. The volume receiving at least 200% of the prescription dose decreased by on average 11%. Target coverage, measured as the fractions of the clinical target volume (CTV) and the planning target volume (PTV) receiving at least the prescription dose, was virtually unchanged (less than a percent change for both metrics). Organs-at-risk received comparable or slightly decreased doses if the spatial function was included in the optimization model. CONCLUSIONS: Optimization of spatial properties such as the volume of contiguous hot spots can be integrated in a standard inverse planning workflow for brachytherapy, and need not be conducted as a separate post-processing step.

Emerging technologies in brachytherapy.

Brachytherapy is a mature treatment modality. The literature is abundant in terms of review articles and comprehensive books on the latest established as well as evolving clinical practices. The intent of this article is to part ways and look beyond the current state-of-the-art and review emerging technologies that are noteworthy and perhaps may drive the future innovations in the field. There are plenty of candidate topics that deserve a deeper look, of course, but with practical limits in this communicative platform, we explore four topics that perhaps is worthwhile to review in detail at this time. First, intensity modulated brachytherapy (IMBT) is reviewed. The IMBT takes advantage ofanisotropicradiation profile generated through intelligent high-density shielding designs incorporated onto sources and applicators such to achieve high quality plans. Second, emerging applications of 3D printing (i.e. additive manufacturing) in brachytherapy are reviewed. With the advent of 3D printing, interest in this technology in brachytherapy has been immense and translation swift due to their potential to tailor applicators and treatments customizable to each individual patient. This is followed by, in third, innovations in treatment planning concerning catheter placement and dwell times where new modelling approaches, solution algorithms, and technological advances are reviewed. And, fourth and lastly, applications of a new machine learning technique, called deep learning, which has the potential to improve and automate all aspects of brachytherapy workflow, are reviewed. We do not expect that all ideas and innovations reviewed in this article will ultimately reach clinic but, nonetheless, this review provides a decent glimpse of what is to come. It would be exciting to monitor as IMBT, 3D printing, novel optimization algorithms, and deep learning technologies evolve over time and translate into pilot testing and sensibly phased clinical trials, and ultimately make a difference for cancer patients. Today's fancy is tomorrow's reality. The future is bright for brachytherapy.

An audit of high dose-rate prostate brachytherapy treatment planning at six Swedish clinics.

PURPOSE: High dose-rate prostate brachytherapy has been implemented in Sweden in the late 1980s and early 1990s in six clinics using the same schedule: 20 Gy in two fractions combined with 50 Gy in 25 fractions with external beam radiation therapy. Thirty years have passed and during these years, various aspects of the treatment process have developed, such as ultrasound-guided imaging and treatment planning system. An audit was conducted, including a questionnaire and treatment planning, which aimed to gather knowledge about treatment planning methods in Swedish clinics. MATERIAL AND METHODS: A questionnaire and a treatment planning case (non-anatomical images) were sent to six Swedish clinics, in which high-dose-rate prostate brachytherapy is performed. Treatment plans were compared using dosimetric indices and equivalent 2 Gy doses (EQD2). Treatment planning system report was used to compare dwell positions and dwell times. RESULTS: For all the clinics, the planning aim for the target was 10.0 Gy, but the volume to receive the dose differed from 95% to 100%. Dose constraints for organs at risk varied with up to 2 Gy. The dose to 90% of target volume ranged from 10.0 Gy to 11.1 Gy, equivalent to 26.0 Gy EQD2 and 31.3 Gy EQD2, respectively. Dose non-homogeneity ratio differed from 0.18 to 0.32 for clinical target volume (CTV) in treatment plans and conformity index ranged from 0.52 to 0.59 for CTV. CONCLUSIONS: Dose constraints for the organs at risk are showing a larger variation than that reflected in compared treatments plans. In all treatment plans in our audit, at least 10 Gy was administered giving a total treatment of 102 Gy EQD2, which is in the upper part of the prescription doses published in the GEC/ESTRO recommendations.

Optimization in treatment planning of high dose-rate brachytherapy - Review and analysis of mathematical models.

Treatment planning in high dose-rate brachytherapy has traditionally been conducted with manual forward planning, but inverse planning is today increasingly used in clinical practice. There is a large variety of proposed optimization models and algorithms to model and solve the treatment planning problem. Two major parts of inverse treatment planning for which mathematical optimization can be used are the decisions about catheter placement and dwell time distributions. Both these problems as well as integrated approaches are included in this review. The proposed models include linear penalty models, dose-volume models, mean-tail dose models, quadratic penalty models, radiobiological models, and multiobjective models. The aim of this survey is twofold: (i) to give a broad overview over mathematical optimization models used for treatment planning of brachytherapy and (ii) to provide mathematical analyses and comparisons between models. New technologies for brachytherapy treatments and methods for treatment planning are also discussed. Of particular interest for future research is a thorough comparison between optimization models and algorithms on the same dataset, and clinical validation of proposed optimization approaches with respect to patient outcome.

A mathematical optimization model for spatial adjustments of dose distributions in high dose-rate brachytherapy.

High dose-rate brachytherapy is a modality of radiation therapy used for cancer treatment, in which the radiation source is placed within the body. The treatment goal is to give a high enough dose to the tumour while sparing nearby healthy tissue and organs (organs-at-risk). The most common criteria for evaluating dose distributions are dosimetric indices. For the tumour, such an index is the portion of the volume that receives at least a specified dose level (e.g. the prescription dose), while for organs-at-risk it is instead the portion of the volume that receives at most a specified dose level. Dosimetric indices are aggregate criteria and do not consider spatial properties of the dose distribution. Further, there are neither any established evaluation criteria for characterizing spatial properties, nor have such properties been studied in the context of mathematical optimization of brachytherapy. Spatial properties are however of clinical relevance and therefore dose plans are sometimes adjusted manually to improve them. We propose an optimization model for reducing the prevalence of contiguous volumes with a too high dose (hot spots) or a too low dose (cold spots) in a tentative dose plan. This model is independent of the process of constructing the tentative plan. We conduct computational experiments with tentative plans obtained both from optimization models and from clinical practice. The objective function considers pairs of dose points and each pair is given a distance-based penalty if the dose is either too high or too low at both dose points. Constraints are included to retain dosimetric indices at acceptable levels. Our model is designed to automate the manual adjustment step in the planning process. In the automatic adjustment step large-scale optimization models are solved. We show reductions of the volumes of the largest hot and cold spots, and the computing times are feasible in clinical practice.

An extended dose-volume model in high dose-rate brachytherapy - Using mean-tail-dose to reduce tumor underdosage.

PURPOSE: High dose-rate brachytherapy is a method of radiotherapy for cancer treatment in which the radiation source is placed within the body. In addition to give a high enough dose to a tumor, it is also important to spare nearby healthy organs [organs at risk (OAR)]. Dose plans are commonly evaluated using the so-called dosimetric indices; for the tumor, the portion of the structure that receives a sufficiently high dose is calculated, while for OAR it is instead the portion of the structure that receives a sufficiently low dose that is of interest. Models that include dosimetric indices are referred to as dose-volume models (DVMs) and have received much interest recently. Such models do not take the dose to the coldest (least irradiated) volume of the tumor into account, which is a distinct weakness since research indicates that the treatment effect can be largely impaired by tumor underdosage even to small volumes. Therefore, our aim is to extend a DVM to also consider the dose to the coldest volume. METHODS: An improved DVM for dose planning is proposed. In addition to optimizing with respect to dosimetric indices, this model also takes mean dose to the coldest volume of the tumor into account. RESULTS: Our extended model has been evaluated against a standard DVM in ten prostate geometries. Our results show that the dose to the coldest volume could be increased, while also computing times for the dose planning were improved. CONCLUSION: While the proposed model yields dose plans similar to other models in most aspects, it fulfils its purpose of increasing the dose to cold tumor volumes. An additional benefit is shorter solution times, and especially for clinically relevant times (of minutes) we show major improvements in tumour dosimetric indices.

Tonsillectomy in adults with obstructive sleep apnea.

OBJECTIVES/HYPOTHESIS: To study whether tonsillectomy is effective on obstructive sleep apnea (OSA) in adults with large tonsils. STUDY DESIGN: A multicenter prospective interventional study. METHODS: The study comprised 28 patients with OSA, an apnea-hypopnea index of > 10, large tonsils (Friedman tonsil size 3 and 4), and age 18 to 59 years. They were derived from 41 consecutive males and females with large tonsils referred for a suspicion of sleep apnea to the ear, nose, and throat departments in Umeå, Skellefteå, and Sunderbyn in northern Sweden. The primary outcome was the apnea-hypopnea index, measured with polygraphic sleep apnea recordings 6 months after surgery. Secondary outcomes included daytime sleepiness, as measured with the Epworth Sleepiness Scale, and swallowing function, using video-fluoroscopy. RESULTS: The apnea-hypopnea index was reduced from a mean of 40 units per hour (95% confidence interval [CI] 28-51) to seven units per hour (95% CI 3-11), P < 0.001, at the 6-month follow-up after surgery. The apnea-hypopnea index was reduced in all patients and 18 (64%) were cured. The Epworth Sleepiness Scale was reduced from a mean of 11 (95% CI 8-13) to 6.0 (95% CI 4-7), P < 0.001. A swallowing dysfunction was found in seven of eight investigated patients before surgery. Of those, swallowing function improved in five patients after surgery, whereas no one deteriorated. CONCLUSION: Tonsillectomy may be effective treatment for adult patients with OSA and large tonsils. Tonsillectomy may be suggested for adults with OSA and large tonsils. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:2859-2862, 2016.

A linear programming model for optimizing HDR brachytherapy dose distributions with respect to mean dose in the DVH-tail.

PURPOSE: Recent research has shown that the optimization model hitherto used in high-dose-rate (HDR) brachytherapy corresponds weakly to the dosimetric indices used to evaluate the quality of a dose distribution. Although alternative models that explicitly include such dosimetric indices have been presented, the inclusion of the dosimetric indices explicitly yields intractable models. The purpose of this paper is to develop a model for optimizing dosimetric indices that is easier to solve than those proposed earlier. METHODS: In this paper, the authors present an alternative approach for optimizing dose distributions for HDR brachytherapy where dosimetric indices are taken into account through surrogates based on the conditional value-at-risk concept. This yields a linear optimization model that is easy to solve, and has the advantage that the constraints are easy to interpret and modify to obtain satisfactory dose distributions. RESULTS: The authors show by experimental comparisons, carried out retrospectively for a set of prostate cancer patients, that their proposed model corresponds well with constraining dosimetric indices. All modifications of the parameters in the authors' model yield the expected result. The dose distributions generated are also comparable to those generated by the standard model with respect to the dosimetric indices that are used for evaluating quality. CONCLUSIONS: The authors' new model is a viable surrogate to optimizing dosimetric indices and quickly and easily yields high quality dose distributions.

Impact of using linear optimization models in dose planning for HDR brachytherapy.

PURPOSE: Dose plans generated with optimization models hitherto used in high-dose-rate (HDR) brachytherapy have shown a tendency to yield longer dwell times than manually optimized plans. Concern has been raised for the corresponding undesired hot spots, and various methods to mitigate these have been developed. The hypotheses upon this work is based are (a) that one cause for the long dwell times is the use of objective functions comprising simple linear penalties and (b) that alternative penalties, as these are piecewise linear, would lead to reduced length of individual dwell times. METHODS: The characteristics of the linear penalties and the piecewise linear penalties are analyzed mathematically. Experimental comparisons between the two types of penalties are carried out retrospectively for a set of prostate cancer patients. RESULTS: When the two types of penalties are compared, significant changes can be seen in the dwell times, while most dose-volume parameters do not differ significantly. On average, total dwell times were reduced by 4.2%, with a reduction of maximum dwell times by 25%, when the alternative penalties were used. CONCLUSIONS: The use of linear penalties in optimization models for HDR brachytherapy is one cause for the undesired long dwell times that arise in mathematically optimized plans. By introducing alternative penalties, a significant reduction in dwell times can be achieved for HDR brachytherapy dose plans. Although various measures for mitigating the long dwell times are already available, the observation that linear penalties contribute to their appearance is of fundamental interest.

Automating the self-scheduling process of nurses in Swedish healthcare: a pilot study.

Hospital wards need to be staffed by nurses round the clock, resulting in irregular working hours for many nurses. Over the years, the nurses' influence on the scheduling has been increased in order to improve their working conditions. In Sweden it is common to apply a kind of self-scheduling where each nurse individually proposes a schedule, and then the final schedule is determined through informal negotiations between the nurses. This kind of self-scheduling is very time-consuming and does often lead to conflicts. We present a pilot study which aims at determining if it is possible to create an optimisation tool that automatically delivers a usable schedule based on the schedules proposed by the nurses. The study is performed at a typical Swedish nursing ward, for which we have developed a mathematical model and delivered schedules. The results of this study are very promising and suggest continued work along these lines.

Profound antiviral effect of oral administration of MIV-210 on chronic hepadnaviral infection in a woodchuck model of hepatitis B.

MIV-210 is a prodrug of 3'-fluoro-2',3'-dideoxyguanosine with high oral bioavailability in humans and potent activity against hepatitis B virus (HBV). Woodchucks infected with woodchuck hepatitis virus (WHV) represent an accurate model of HBV infection that is utilized for evaluation of the efficacy and safety of novel anti-HBV agents. Oral administration of MIV-210 at 20 or 60 mg/kg of body weight/day induced a rapid virological response in chronically infected woodchucks, reducing serum WHV DNA levels by 4.75 log10 and 5.72 log10, respectively, in 2 weeks. A progressive decline in WHV viremia occurred throughout the 10-week therapy, giving final reductions of 7.23 log10 and 7.68 log10 in the 20- and 60-mg/kg/day groups, respectively. Further, a daily dose of 10 mg/kg decreased the serum WHV load 400-fold after 4 weeks of treatment, and a dose of 5 mg/kg/day was sufficient to maintain this antiviral effect during the following 6-week period. MIV-210 at 20 or 60 mg/kg/day reduced the liver WHV DNA load 200- to 2,500-fold from pretreatment levels and, importantly, led to a 2.0 log10 drop in the hepatic content of WHV covalently closed circular DNA. The treatment with 60 mg/kg/day was well tolerated. Liver biopsy specimens obtained after the 10-week treatment with 20 or 60 mg/kg/day and after the 10-week follow-up showed hepatocyte and mitochondrial ultrastructures comparable to those in the placebo-treated group. It was concluded that MIV-210 is highly effective against chronic WHV infection. These findings, together with the previously demonstrated inhibitory activity of MIV-210 against lamivudine-, adefovir-, and entecavir-resistant HBV variants, make MIV-210 a highly valuable candidate for further testing as an agent against chronic hepatitis B.

ME-609: a treatment for recurrent herpes simplex virus infections.

Studies in conventional murine models of HSV infection use immunologically naive animals. These models thus mimic primary infections rather than recurrent infections in humans. We have, therefore, used a newly developed mouse model that more closely mimics recurrent HSV infection in humans. In this model, the mice are infected, and zosteriform HSV-1 infection develops in the presence of a primed immune response using adoptive transfer of immunity (ATI) as we have described previously. Using the ATI mouse model, it has been shown that a more beneficial therapy for recurrent mucocutaneous HSV infection could be achieved by controlling both the viral replication and the inflammatory response to the virus. Topical treatment was initiated in this model at the time of first occurrence of symptoms and was given three times daily for 4 days. Topical treatment with ME-609 (which contains 5% acyclovir and 1% hydrocortisone) in the ATI mouse model was substantially more efficacious than 5% Zovirax cream, 1% hydrocortisone or no treatment, respectively. The beneficial properties of ME-609 were also found to be superior to those of Zovirax cream when tested in the standard guinea pig model, representing a primary HSV infection. ME-609 represents a novel treatment principle of recurrent HSV infections and the present paper summarizes the preclinical and early clinical experience of ME-609.