Motion and uncertainty in radiotherapy is traditionally handled via margins. The clinical target volume (CTV) is expanded to a larger planning target volume (PTV), which is irradiated to the prescribed dose. However, the PTV concept has several limitations, especially in proton therapy. Therefore, robust and probabilistic optimization methods have been developed that directly incorporate motion and uncertainty into treatment plan optimization for intensity modulated radiotherapy (IMRT) and intensity modulated proton therapy (IMPT). Thereby, the explicit definition of a PTV becomes obsolete and treatment plan optimization is directly based on the CTV. Initial work focused on random and systematic setup errors in IMRT. Later, inter-fraction prostate motion and intra-fraction lung motion became a research focus. Over the past ten years, IMPT has emerged as a new application for robust planning methods. In proton therapy, range or setup errors may lead to dose degradation and misalignment of dose contributions from different beams -a problem that cannot generally be addressed by margins. Therefore, IMPT has led to the first implementations of robust planning methods in commercial planning systems, making these methods available for clinical use. This paper first summarizes the limitations of the PTV concept. Subsequently, robust optimization methods are introduced and their applications in IMRT and IMPT planning are reviewed.Abstract. Motion and uncertainty in radiotherapy is traditionally handled via 31 margins. The clinical target volume (CTV) is expanded to a larger planning target 32 volume (PTV), which is irradiated to the prescribed dose. However, the PTV 33 concept has several limitations, especially in proton therapy. Therefore, robust and 34 probabilistic optimization methods have been developed that directly incorporate 35 motion and uncertainty into treatment plan optimization for intensity modulated 36 radiotherapy (IMRT) and intensity modulated proton therapy (IMPT). Thereby, the 37 explicit definition of a PTV becomes obsolete and treatment plan optimization is 38 directly based on the CTV. Initial work focused on random and systematic setup errors 39 in IMRT. Later, inter-fraction prostate motion and intra-fraction lung motion became 40 a research focus. Over the past 10 years, IMPT has emerged as a new application for 41 robust planning methods. In proton therapy, range or setup errors may lead to dose 42 degradation and misalignment of dose contributions from different beams a problem 43 Robust radiotherapy planning 2 that cannot generally be addressed by margins. Therefore, IMPT has led to the first 44 implementations of robust planning methods in commercial planning systems, making 45 these methods available for clinical use. This paper first summarizes the limitations 46 of the PTV concept. Subsequently, robust optimization methods are introduced and 47 their applications in IMRT and IMPT planning are reviewed. 48 1. Introduction 49Radiotherapy aims at delivering curative doses of radiation ...

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Background Tumor segmentation of glioma on MRI is a technique to monitor, quantify and report disease progression. Manual MRI segmentation is the gold standard but very labor intensive. At present the quality of this gold standard is not known for different stages of the disease, and prior work has mainly focused on treatment-naive glioblastoma. In this paper we studied the inter-rater agreement of manual MRI segmentation of glioblastoma and WHO grade II-III glioma for novices and experts at three stages of disease. We also studied the impact of inter-observer variation on extent of resection and growth rate. Methods In 20 patients with WHO grade IV glioblastoma and 20 patients with WHO grade II-III glioma (defined as non-glioblastoma) both the enhancing and non-enhancing tumor elements were segmented on MRI, using specialized software, by four novices and four experts before surgery, after surgery and at time of tumor progression. We used the generalized conformity index (GCI) and the intra-class correlation coefficient (ICC) of tumor volume as main outcome measures for inter-rater agreement. Results For glioblastoma, segmentations by experts and novices were comparable. The inter-rater agreement of enhancing tumor elements was excellent before surgery (GCI 0.79, ICC 0.99) poor after surgery (GCI 0.32, ICC 0.92), and good at progression (GCI 0.65, ICC 0.91). For non-glioblastoma, the inter-rater agreement was generally higher between experts than between novices. The inter-rater agreement was excellent between experts before surgery (GCI 0.77, ICC 0.92), was reasonable after surgery (GCI 0.48, ICC 0.84), and good at progression (GCI 0.60, ICC 0.80). The inter-rater agreement was good between novices before surgery (GCI 0.66, ICC 0.73), was poor after surgery (GCI 0.33, ICC 0.55), and poor at progression (GCI 0.36, ICC 0.73). Further analysis showed that the lower inter-rater agreement of segmentation on postoperative MRI could only partly be explained by the smaller volumes and fragmentation of residual tumor. The median interquartile range of extent of resection between raters was 8.3% and of growth rate was 0.22 mm/year. Conclusion Manual tumor segmentations on MRI have reasonable agreement for use in spatial and volumetric analysis. Agreement in spatial overlap is of concern with segmentation after surgery for glioblastoma and with segmentation of non-glioblastoma by non-experts.

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