Treatment of brain metastases in small cell lung cancer: Decision-making amongst a multidisciplinary panel of European experts.

BACKGROUND: Brain metastases (BM) are common in patients with small cell lung cancer (SCLC). In recent years, the role of whole brain radiotherapy (WBRT) for brain metastases in lung cancer is being reevaluated, especially in the context of new systemic treatments available for SCLC. With this analysis, we investigate decision-making in SCLC patients with BM among European experts in medical oncology and radiation oncology. METHODS: We analyzed decision-making from 13 medical oncologists (selected by IASLC) and 13 radiation oncologists (selected by ESTRO) specialized in SCLC. Management strategies of individual experts were converted into decision trees and analyzed for consensus. RESULTS AND CONCLUSION: In asymptomatic patients, chemotherapy alone is the most commonly recommended first line treatment. In asymptomatic patients with limited volume of brain metastases, a higher preference for chemotherapy without WBRT among medical oncologists compared to radiation oncologists was observed. For symptomatic patients, WBRT followed by chemotherapy was recommended most commonly. For limited extent of BM in symptomatic patients, some experts chose stereotactic radiotherapy as an alternative to WBRT. Significant variation in clinical decision-making was observed among European SCLC experts for the first line treatment of patients with SCLC and BM.

Significance of the impact of motion compensation on the variability of PET image features.

In lung cancer, quantification by positron emission tomography/computed tomography (PET/CT) imaging presents challenges due to respiratory movement. Our primary aim was to study the impact of motion compensation implied by retrospectively gated (4D)-PET/CT on the variability of PET quantitative parameters. Its significance was evaluated by comparison with the variability due to (i) the voxel size in image reconstruction and (ii) the voxel size in image post-resampling. The method employed for feature extraction was chosen based on the analysis of (i) the effect of discretization of the standardized uptake value (SUV) on complementarity between texture features (TF) and conventional indices, (ii) the impact of the segmentation method on the variability of image features, and (iii) the variability of image features across the time-frame of 4D-PET. Thirty-one PET-features were involved. Three SUV discretization methods were applied: a constant width (SUV resolution) of the resampling bin (method RW), a constant number of bins (method RN) and RN on the image obtained after histogram equalization (method EqRN). The segmentation approaches evaluated were 40[Formula: see text] of SUVmax and the contrast oriented algorithm (COA). Parameters derived from 4D-PET images were compared with values derived from the PET image obtained for (i) the static protocol used in our clinical routine (3D) and (ii) the 3D image post-resampled to the voxel size of the 4D image and PET image derived after modifying the reconstruction of the 3D image to comprise the voxel size of the 4D image. Results showed that TF complementarity with conventional indices was sensitive to the SUV discretization method. In the comparison of COA and 40[Formula: see text] contours, despite the values not being interchangeable, all image features showed strong linear correlations (r > 0.91, [Formula: see text]). Across the time-frames of 4D-PET, all image features followed a normal distribution in most patients. For our patient cohort, the compensation of tumor motion did not have a significant impact on the quantitative PET parameters. The variability of PET parameters due to voxel size in image reconstruction was more significant than variability due to voxel size in image post-resampling. In conclusion, most of the parameters (apart from the contrast of neighborhood matrix) were robust to the motion compensation implied by 4D-PET/CT. The impact on parameter variability due to the voxel size in image reconstruction and in image post-resampling could not be assumed to be equivalent.

Interobserver variability in target volume delineation of hepatocellular carcinoma : An analysis of the working group "Stereotactic Radiotherapy" of the German Society for Radiation Oncology (DEGRO).

BACKGROUND: Definition of gross tumor volume (GTV) in hepatocellular carcinoma (HCC) requires dedicated imaging in multiple contrast medium phases. The aim of this study was to evaluate the interobserver agreement (IOA) in gross tumor delineation of HCC in a multicenter panel. METHODS: The analysis was performed within the "Stereotactic Radiotherapy" working group of the German Society for Radiation Oncology (DEGRO). The GTVs of three anonymized HCC cases were delineated by 16 physicians from nine centers using multiphasic CT scans. In the first case the tumor was well defined. The second patient had multifocal HCC (one conglomerate and one peripheral tumor) and was previously treated with transarterial chemoembolization (TACE). The peripheral lesion was adjacent to the previous TACE site. The last patient had an extensive HCC with a portal vein thrombosis (PVT) and an inhomogeneous liver parenchyma due to cirrhosis. The IOA was evaluated according to Landis and Koch. RESULTS: The IOA for the first case was excellent (kappa: 0.85); for the second case moderate (kappa: 0.48) for the peripheral tumor and substantial (kappa: 0.73) for the conglomerate. In the case of the peripheral tumor the inconsistency is most likely explained by the necrotic tumor cavity after TACE caudal to the viable tumor. In the last case the IOA was fair, with a kappa of 0.34, with significant heterogeneity concerning the borders of the tumor and the PVT. CONCLUSION: The IOA was very good among the cases were the tumor was well defined. In complex cases, where the tumor did not show the typical characteristics, or in cases with Lipiodol (Guerbet, Paris, France) deposits, IOA agreement was compromised.

Stereotactic body radiotherapy (SBRT) in recurrent or oligometastatic pancreatic cancer : A toxicity review of simultaneous integrated protection (SIP) versus conventional SBRT.

BACKGROUND: Stereotactic body radiotherapy (SBRT) in pancreatic cancer can be limited by its proximity to organs at risk (OAR). In this analysis, we evaluated the toxicity and efficacy of two different treatment approaches in patients with locally recurrent or oligometastatic pancreatic cancer. MATERIALS AND METHODS: According to the prescription method, patients were divided in two cohorts (C1 and C2). The planning target volume (PTV) was created through a 4 mm expansion of the internal target volume. In C2, a subvolume was additionally created, a simultaneous integrated protection (SIP), which is the overlap of the PTV with the planning risk volume of an OAR to which we prescribed a reduced dose. RESULTS: In all, 18 patients were treated (7 with local recurrences, 9 for oligometastases, 2 for both). Twelve of 23 lesions were treated without SIP (C1) and 11 with SIP (C2). The median follow-up was 12.8 months. Median overall survival (OS) was 13.2 (95% confidence interval [CI] 9.8-14.6) months. The OS rates at 6 and 12 months were 87 and 58%, respectively. Freedom from local progression for combined cohorts at 6 and 12 months was 93 and 67% (95% CI 15-36), respectively. Local control was not statistically different between the two groups. One patient in C2 experienced grade ≥3 acute toxicities and 1 patient in C1 experienced a grade ≥3 late toxicity. CONCLUSION: The SIP approach is a useful prescription method for abdominal SBRT with a favorable toxicity profile which does not compromise local control and overall survival despite dose sacrifices in small subvolumes.

Evaluation of PET texture features with heterogeneous phantoms: complementarity and effect of motion and segmentation method.

A major source of error in quantitative PET/CT scans of lung cancer tumors is respiratory motion. Regarding the variability of PET texture features (TF), the impact of respiratory motion has not been properly studied with experimental phantoms. The primary aim of this work was to evaluate the current use of PET texture analysis for heterogeneity characterization in lesions affected by respiratory motion. Twenty-eight heterogeneous lesions were simulated by a mixture of alginate and 18 F-fluoro-2-deoxy-D-glucose (FDG). Sixteen respiratory patterns were applied. Firstly, the TF response for different heterogeneous phantoms and its robustness with respect to the segmentation method were calculated. Secondly, the variability for TF derived from PET image with (gated, G-) and without (ungated, U-) motion compensation was analyzed. Finally, TF complementarity was assessed. In the comparison of TF derived from the ideal contour with respect to TF derived from 40%-threshold and adaptive-threshold PET contours, 7/8 TF showed strong linear correlation (LC) (p < 0.001, r > 0.75), despite a significant volume underestimation. Independence of lesion movement (LC in 100% of the combined pairs of movements, p < 0.05) was obtained for 1/8 TF with U-image (width of the volume-activity histogram, WH) and 4/8 TF with G-image (WH and energy (ENG), local-homogeneity (LH) and entropy (ENT), derived from the co-ocurrence matrix). Their variability in terms of the coefficient of variance ([Formula: see text]) resulted in [Formula: see text](WH) = 0.18 on the U-image and [Formula: see text](WH) = 0.24, [Formula: see text](ENG) = 0.15, [Formula: see text](LH) = 0.07 and [Formula: see text](ENT) = 0.06 on the G-image. Apart from WH (r > 0.9, p < 0.001), not one of these TF has shown LC with C max. Complementarity was observed for the TF pairs: ENG-LH, CONT (contrast)-ENT and LH-ENT. In conclusion, the effect of respiratory motion should be taken into account when the heterogeneity of lung cancer is quantified on PET/CT images. Despite inaccurate volume delineation, TF derived from 40% and COA contours could be reliable for their prognostic use. The TF that exhibited simultaneous added value and independence of lesion movement were ENG and ENT computed from the G-image. Their use is therefore recommended for heterogeneity quantification of lesions affected by respiratory motion.

SBRT for centrally localized NSCLC - What is too central?

PURPOSE: Current guidelines recommend stereotactic body radiotherapy (SBRT) for stage I non-small-cell lung cancer (NSCLC) in medically inoperable patients. There are excellent outcome and toxicity data for SBRT of peripheral lung tumors. However, the discussion on SBRT for centrally located tumors is controversial. This study evaluated current clinical practice regarding SBRT of centrally located lung tumors, to identify common fractionation schedules and commonly accepted contraindications for SBRT. METHODS: A questionnaire consisting of two parts was introduced at the annual meeting of the DEGRO working group on stereotactic radiotherapy, representing centers in Germany and Switzerland. The first part of the questionnaire covered general information about the centers, whereas the second part specifically addressed SBRT of centrally located lung tumors, using case examples of nine primary NSCLC patients. Reconstructions of a contrast enhanced CT, as well as PET-Imaging for each case were demonstrated to the participants. RESULTS: Twenty-six centers participated in the meeting. The majority was academic (73%), participated in interdisciplinary thoracic oncology tumorboards (88%) and offered SBRT for lung tumors (96%). Two centers questioned the indication of SBRT for central lung tumors because of lack of evidence. The majority of centers had experience in SBRT for central lung tumors (88%) and half of the centers reported more than ten cases treated during a median period of five years. Most fractionation schedules used PTV encompassing doses of 48-60 Gy in eight fractions with maximum doses of 125-150%. A clear indication for SBRT treatment was seen by more than 85% of centers in three of the nine patients in whom tumors were small and not closer than 2 cm to the main bronchus. Prior pneumonectomy or immediate adjacency to hilar/mediastinal structures were not considered as contraindications for SBRT. In cases where the tumor exceeded 4 cm in diameter or was located closer than 4 cm to the carina 50-80% of centers saw an indication for SBRT. One case, with a 7 cm tumor reaching to the carina would have been treated with SBRT only by one center. CONCLUSION: Within DEGRO working group on stereotactic radiotherapy, SBRT for small (<4 cm) early stage NSCLC is a common indication, if the minimal distance to the main bronchi is at least 2 cm. The controversy on the treatment of larger and more central tumors will hopefully be solved by ongoing prospective clinical trials.

Automatic quantification of multi-modal rigid registration accuracy using feature detectors.

In radiotherapy, the use of multi-modal images can improve tumor and target volume delineation. Images acquired at different times by different modalities need to be aligned into a single coordinate system by 3D/3D registration. State of the art methods for validation of registration are visual inspection by experts and fiducial-based evaluation. Visual inspection is a qualitative, subjective measure, while fiducial markers sometimes suffer from limited clinical acceptance. In this paper we present an automatic, non-invasive method for assessing the quality of intensity-based multi-modal rigid registration using feature detectors. After registration, interest points are identified on both image data sets using either speeded-up robust features or Harris feature detectors. The quality of the registration is defined by the mean Euclidean distance between matching interest point pairs. The method was evaluated on three multi-modal datasets: an ex vivo porcine skull (CT, CBCT, MR), seven in vivo brain cases (CT, MR) and 25 in vivo lung cases (CT, CBCT). Both a qualitative (visual inspection by radiation oncologist) and a quantitative (mean target registration error-mTRE-based on selected markers) method were employed. In the porcine skull dataset, the manual and Harris detectors give comparable results but both overestimated the gold standard mTRE based on fiducial markers. For instance, for CT-MR-T1 registration, the mTREman (based on manually annotated landmarks) was 2.2 mm whereas mTREHarris (based on landmarks found by the Harris detector) was 4.1 mm, and mTRESURF (based on landmarks found by the SURF detector) was 8 mm. In lung cases, the difference between mTREman and mTREHarris was less than 1 mm, while the difference between mTREman and mTRESURF was up to 3 mm. The Harris detector performed better than the SURF detector with a resulting estimated registration error close to the gold standard. Therefore the Harris detector was shown to be the more suitable method to automatically quantify the geometric accuracy of multimodal rigid registration.

Interactive contour delineation of organs at risk in radiotherapy: Clinical evaluation on NSCLC patients.

PURPOSE: Accurate delineation of organs at risk (OARs) on computed tomography (CT) image is required for radiation treatment planning (RTP). Manual delineation of OARs being time consuming and prone to high interobserver variability, many (semi-) automatic methods have been proposed. However, most of them are specific to a particular OAR. Here, an interactive computer-assisted system able to segment various OARs required for thoracic radiation therapy is introduced. METHODS: Segmentation information (foreground and background seeds) is interactively added by the user in any of the three main orthogonal views of the CT volume and is subsequently propagated within the whole volume. The proposed method is based on the combination of watershed transformation and graph-cuts algorithm, which is used as a powerful optimization technique to minimize the energy function. The OARs considered for thoracic radiation therapy are the lungs, spinal cord, trachea, proximal bronchus tree, heart, and esophagus. The method was evaluated on multivendor CT datasets of 30 patients. Two radiation oncologists participated in the study and manual delineations from the original RTP were used as ground truth for evaluation. RESULTS: Delineation of the OARs obtained with the minimally interactive approach was approved to be usable for RTP in nearly 90% of the cases, excluding the esophagus, which segmentation was mostly rejected, thus leading to a gain of time ranging from 50% to 80% in RTP. Considering exclusively accepted cases, overall OARs, a Dice similarity coefficient higher than 0.7 and a Hausdorff distance below 10 mm with respect to the ground truth were achieved. In addition, the interobserver analysis did not highlight any statistically significant difference, at the exception of the segmentation of the heart, in terms of Hausdorff distance and volume difference. CONCLUSIONS: An interactive, accurate, fast, and easy-to-use computer-assisted system able to segment various OARs required for thoracic radiation therapy has been presented and clinically evaluated. The introduction of the proposed system in clinical routine may offer valuable new option to radiation oncologists in performing RTP.

Impact of consensus contours from multiple PET segmentation methods on the accuracy of functional volume delineation.

PURPOSE: The aim of this study was to evaluate the impact of consensus algorithms on segmentation results when applied to clinical PET images. In particular, whether the use of the majority vote or STAPLE algorithm could improve the accuracy and reproducibility of the segmentation provided by the combination of three semiautomatic segmentation algorithms was investigated. METHODS: Three published segmentation methods (contrast-oriented, possibility theory and adaptive thresholding) and two consensus algorithms (majority vote and STAPLE) were implemented in a single software platform (Artiview®). Four clinical datasets including different locations (thorax, breast, abdomen) or pathologies (primary NSCLC tumours, metastasis, lymphoma) were used to evaluate accuracy and reproducibility of the consensus approach in comparison with pathology as the ground truth or CT as a ground truth surrogate. RESULTS: Variability in the performance of the individual segmentation algorithms for lesions of different tumour entities reflected the variability in PET images in terms of resolution, contrast and noise. Independent of location and pathology of the lesion, however, the consensus method resulted in improved accuracy in volume segmentation compared with the worst-performing individual method in the majority of cases and was close to the best-performing method in many cases. In addition, the implementation revealed high reproducibility in the segmentation results with small changes in the respective starting conditions. There were no significant differences in the results with the STAPLE algorithm and the majority vote algorithm. CONCLUSION: This study showed that combining different PET segmentation methods by the use of a consensus algorithm offers robustness against the variable performance of individual segmentation methods and this approach would therefore be useful in radiation oncology. It might also be relevant for other scenarios such as the merging of expert recommendations in clinical routine and trials or the multiobserver generation of contours for standardization of automatic contouring.

LungTech, an EORTC Phase II trial of stereotactic body radiotherapy for centrally located lung tumours: a clinical perspective.

Evidence supports stereotactic body radiotherapy (SBRT) as a curative treatment option for inoperable early stage non-small-cell lung cancer (NSCLC) resulting in high rates of tumour control and low risk of toxicity. However, promising results are mainly derived from SBRT of peripheral pulmonary lesions, whereas SBRT for the central tumours can lead to severe radiation sequelae owing to the spatial proximity to the serial organs at risk. Robust data on the tolerance of mediastinal structures to high-dose hypofractionated radiation are limited; furthermore, there are many open questions regarding the efficiency, safety and response assessment of SBRT in inoperable, centrally located early stage NSCLC, which are addressed in a prospective multicentre study [sponsored by the European Organization for Research and Treatment of Cancer (EORTC 22113-08113-LungTech)]. In this review, we summarize the current status regarding SBRT for centrally located early stage NSCLC that leads to the rationale of the LungTech trial. Outline and some essential features of the study with focus on a summary of current experiences in dose/fraction-toxicity coherences after SBRT to the mediastinal structures that lead to LungTech normal tissue constraints are provided.

Influence of experience and qualification on PET-based target volume delineation. When there is no expert--ask your colleague.

BACKGROUND AND PURPOSE: The integration of positron emission tomography (PET) information for target volume delineation in radiation treatment planning is routine in many centers. In contrast to automatic contouring, research on visual-manual delineation is scarce. The present study investigates the dependency of manual delineation on experience and qualification. PATIENTS AND METHODS: A total of 44 international interdisciplinary observers each defined a [(18)F]fluorodeoxyglucose (FDG)-PET based gross tumor volume (GTV) using the same PET/CT scan from a patient with lung cancer. The observers were "experts" (E; n = 3), "experienced interdisciplinary pairs" (EP; 9 teams of radiation oncologist (RO) + nuclear medicine physician (NP)), "single field specialists" (SFS; n = 13), and "students" (S; n = 10). Five automatic delineation methods (AM) were also included. Volume sizes and concordance indices within the groups (pCI) and relative to the experts (eCI) were calculated. RESULTS: E (pCI = 0.67) and EP (pCI = 0.53) showed a significantly higher agreement within the groups as compared to SFS (pCI = 0.43, p = 0.03, and p = 0.006). In relation to the experts, EP (eCI = 0.55) showed better concordance compared to SFS (eCI = 0.49) or S (eCI = 0.47). The intermethod variability of the AM (pCI = 0.44) was similar to that of SFS and S, showing poorer agreement with the experts (eCI = 0.35). CONCLUSION: The results suggest that interdisciplinary cooperation could be beneficial for consistent contouring. Joint delineation by a radiation oncologist and a nuclear medicine physician showed remarkable agreement and better concordance with the experts compared to other specialists. The relevant intermethod variability of the automatic algorithms underlines the need for further standardization and optimization in this field.

Definition of stereotactic body radiotherapy: principles and practice for the treatment of stage I non-small cell lung cancer.

This report from the Stereotactic Radiotherapy Working Group of the German Society of Radiation Oncology (Deutschen Gesellschaft für Radioonkologie, DEGRO) provides a definition of stereotactic body radiotherapy (SBRT) that agrees with that of other international societies. SBRT is defined as a method of external beam radiotherapy (EBRT) that accurately delivers a high irradiation dose to an extracranial target in one or few treatment fractions. Detailed recommendations concerning the principles and practice of SBRT for early stage non-small cell lung cancer (NSCLC) are given. These cover the entire treatment process; from patient selection, staging, treatment planning and delivery to follow-up. SBRT was identified as the method of choice when compared to best supportive care (BSC), conventionally fractionated radiotherapy and radiofrequency ablation. Based on current evidence, SBRT appears to be on a par with sublobar resection and is an effective treatment option in operable patients who refuse lobectomy.

[Stereotactic body radiotherapy for malignant nodules in the lung]. / Extrakranielle stereotaktische Bestrahlung bei Lungenrundherden.

Stereotactic body radiotherapy (SBRT) is a method for the highly precise application of percutaneous high dose radiotherapy of extracranial targets in a limited number of treatment fractions. Due to the excellent local control rates, SBRT is now well established in limited stage lung tumours. In medically inoperable patients SBRT is the method of choice, in high-risk patients and patients who refuse resection, the current literature recommends SBRT as a reasonable therapeutic option. An analysis of the SBRT working group of the German Society for Radiation Oncology showed that the treatment results in Germany are well comparable to international data. The limitations of SBRT lie in the treatment of tumours in the direct neighbourhood of so-called "serial" normal tissues, which is due to the risk of severe late effects of high dose radiation. Therefore these patients should be treated by SBRT, if at all, in the context of respective clinical studies.

Stereotactic ablative radiotherapy for small lung tumors with a moderate dose. Favorable results and low toxicity.

BACKGROUND: Stereotactic ablative body radiotherapy (SBRT, SABR) is being increasingly applied because of its high local efficacy, e.g., for small lung tumors. However, the optimum dosage is still under discussion. Here, we report data on 45 lung lesions [non-small cell lung cancer (NSCLC) or metastases] in 39 patients treated between 2009 and 2010 by SABR. PATIENTS AND METHODS: SABR was performed with total doses of 35 Gy (5 fractions) or 37.5 Gy (3 fractions) prescribed to the 60% isodose line encompassing the planning target volume. Three-monthly follow-up CT scans were supplemented by FDG-PET/CT if clinically indicated. RESULTS: The median follow-up was 17 months. Local progression-free survival rates were 90.5% (all patients), 95.0% (NSCLC), and 81.8% (metastases) at 1 year. At 2 years, the respective local progression-free survival rates were 80.5%, 95.0%, and 59.7%. Overall survival rates were 71.1% (all patients), 65.4% (NSCLC), and 83.3% (metastases) at 1 year. Overall survival rates at 2 years were 52.7%, 45.9%, and 66.7%, respectively. Acute side effects were mild. CONCLUSION: With the moderate dose schedule used, well-tolerated SABR led to favorable local tumor control as in other published series. Standardization in reporting the dose prescription for SABR is needed to allow comparison of different series in order to determine optimum dosage.

Measuring inter-observer agreement in contour delineation of medical imaging in a dummy run using Fleiss' kappa.

BACKGROUND: In medical imaging used for planning of radiation therapy, observers delineate contours of a treatment volume in a series of images of uniform slice thickness. OBJECTIVE: To summarize agreement in contouring between an arbitrary number of observers by a single number, we generalized the kappa index proposed by Zijdenbos et al. (1994). METHODS: Observers characterized voxels by allocating them to one of two categories, inside or outside the contoured region. Fleiss' kappa was used to measure association between n indistinguishable observers. Given the number Vi of voxels contoured by exactly i observers (i = 1, ..., n ), the resulting overall kappa is representable as a ratio of weighted sums of the Vi . RESULTS: Overall kappa was applied to analyze inter-center variations in a multicenter trial on radiotherapy planning in patients with locally advanced lung cancer. A contouring dummy run was performed within the quality assurance program. Contouring was done twice, once before and once after a training program. Observer agreement was enhanced from 0.59 (with a 95% confidence interval (CI) of 0.51-0.67) to 0.69 (95% CI 0.59-0.78). CONCLUSION: By contrast to average pairwise indices, overall kappa measures observer agreement for more than two observers using the full information about overlapping volumes, while not distinguishing between observers. It is particularly adequate for measuring observer agreement when identification of observers is not possible or desirable and when there is no gold standard.