Whole brain irradiation with hippocampal sparing and dose escalation on multiple brain metastases: Local tumour control and survival.

PURPOSE: Hippocampal-avoidance whole brain radiotherapy (HA-WBRT) for multiple brain metastases may prevent treatment-related cognitive decline, compared to standard WBRT. Additionally, simultaneous integrated boost (SIB) on individual metastases may further improve the outcome. Here, we present initial data concerning local tumour control (LTC), intracranial progression-free survival (PFS), overall survival (OS), toxicity and safety for this new irradiation technique. METHODS AND MATERIALS: Twenty patients, enrolled between 2011 and 2013, were treated with HA-WBRT (30 Gy in 12 fractions, D98% to hippocampus ≤ 9 Gy) and a SIB (51 Gy) on multiple (2-13) metastases using a volumetric modulated arc therapy (VMAT) approach based on 2-4 arcs. Metastases were evaluated bidimensionally along the two largest diameters in contrast-enhanced three-dimensional T1-weighed MRI. RESULTS: Median follow-up was 40 weeks. The median time to progression of boosted metastases has not been reached yet, corresponding to a LTC rate of 73%. Median intracranial PFS was 40 weeks, corresponding to a 1-year PFS of 45.3%. Median OS was 71.5 weeks, corresponding to a 1-year OS of 60%. No obvious acute or late toxicities grade > 2 (NCI CTCAE v4.03) were observed. Dmean to the bilateral hippocampi was 6.585 Gy ± 0.847 (α/ß = 2 Gy). Two patients developed a new metastasis in the area of hippocampal avoidance. CONCLUSION: HA-WBRT (simultaneous integrated protection, SIP) with SIB to metastases is a safe and tolerable regime that shows favorable LTC for patients with multiple brain metastases, while it has the potential to minimize the side-effect of cognitive deterioration.

A teaching intervention in a contouring dummy run improved target volume delineation in locally advanced non-small cell lung cancer: Reducing the interobserver variability in multicentre clinical studies.

INTRODUCTION: Interobserver variability in the definition of target volumes (TVs) is a well-known confounding factor in (multicentre) clinical studies employing radiotherapy. Therefore, detailed contouring guidelines are provided in the prospective randomised multicentre PET-Plan (NCT00697333) clinical trial protocol. This trial compares strictly FDG-PET-based TV delineation with conventional TV delineation in patients with locally advanced non-small cell lung cancer (NSCLC). Despite detailed contouring guidelines, their interpretation by different radiation oncologists can vary considerably, leading to undesirable discrepancies in TV delineation. Considering this, as part of the PET-Plan study quality assurance (QA), a contouring dummy run (DR) consisting of two phases was performed to analyse the interobserver variability before and after teaching. MATERIALS AND METHODS: In the first phase of the DR (DR1), radiation oncologists from 14 study centres were asked to delineate TVs as defined by the study protocol (gross TV, GTV; and two clinical TVs, CTV-A and CTV-B) in a test patient. A teaching session was held at a study group meeting, including a discussion of the results focussing on discordances in comparison to the per-protocol solution. Subsequently, the second phase of the DR (DR2) was performed in order to evaluate the impact of teaching. RESULTS: Teaching after DR1 resulted in a reduction of absolute TVs in DR2, as well as in better concordance of TVs. The Overall Kappa(κ) indices increased from 0.63 to 0.71 (GTV), 0.60 to 0.65 (CTV-A) and from 0.59 to 0.63 (CTV-B), demonstrating improvements in overall interobserver agreement. CONCLUSION: Contouring DRs and study group meetings as part of QA in multicentre clinical trials help to identify misinterpretations of per-protocol TV delineation. Teaching the correct interpretation of protocol contouring guidelines leads to a reduction in interobserver variability and to more consistent contouring, which should consequently improve the validity of the overall study results.

11C-Choline PET/pathology image coregistration in primary localized prostate cancer.

PURPOSE: The aim of this study was to develop a methodology for the comparison of pathology specimens after prostatectomy (post-S) with PET images obtained before surgery (pre-S). This method was used to evaluate the merit of (11)C-choline PET/CT for delineation of gross tumour volume (GTV) in prostate cancer (PC). METHODS: In 28 PC patients, (11)C-choline PET/CT was performed before surgery. PET/CT data were coregistered with the pathology specimens. GTV on PET images (GTV-PET) was outlined automatically and corrected manually. Tumour volume in the prostate (TVP) was delineated manually on the pathology specimens. Based on the coregistered PET/pathology images, the following parameters were assessed: SUVmax and SUVmean in the tumoral and nontumoral prostate (NP), GTV-PET (millilitres) and TVP (millilitres). RESULTS: PET/pathology image coregistration was satisfactory. Mean SUVmax in the TVP was lower than in the NP: 5.0 and 5.5, respectively (p = 0.093). Considering the entire prostate, SUVmax was located in the TVP in two patients, in the TVP and NP in 12 patients and exclusively in NP in 14 patients. Partial overlap the TVP and GTV-PET was seen in 71% of patients, and complete overlap in 4%. CONCLUSION: PET/pathology image coregistration can be used for evaluation of different imaging modalities. (11)C-Choline PET failed to distinguish tumour from nontumour tissue.

A Novel Radiomics-Based Tumor Volume Segmentation Algorithm for Lung Tumors in FDG-PET/CT after 3D Motion Correction-A Technical Feasibility and Stability Study.

Positron emission tomography (PET) provides important additional information when applied in radiation therapy treatment planning. However, the optimal way to define tumors in PET images is still undetermined. As radiomics features are gaining more and more importance in PET image interpretation as well, we aimed to use textural features for an optimal differentiation between tumoral tissue and surrounding tissue to segment-target lesions based on three textural parameters found to be suitable in previous analysis (Kurtosis, Local Entropy and Long Zone Emphasis). Intended for use in radiation therapy planning, this algorithm was combined with a previously described motion-correction algorithm and validated in phantom data. In addition, feasibility was shown in five patients. The algorithms provided sufficient results for phantom and patient data. The stability of the results was analyzed in 20 consecutive measurements of phantom data. Results for textural feature-based algorithms were slightly worse than those of the threshold-based reference algorithm (mean standard deviation 1.2%-compared to 4.2% to 8.6%) However, the Entropy-based algorithm came the closest to the real volume of the phantom sphere of 6 ccm with a mean measured volume of 26.5 ccm. The threshold-based algorithm found a mean volume of 25.0 ccm. In conclusion, we showed a novel, radiomics-based tumor segmentation algorithm in FDG-PET with promising results in phantom studies concerning recovered lesion volume and reasonable results in stability in consecutive measurements. Segmentation based on Entropy was the most precise in comparison with sphere volume but showed the worst stability in consecutive measurements. Despite these promising results, further studies with larger patient cohorts and histopathological standards need to be performed for further validation of the presented algorithms and their applicability in clinical routines. In addition, their application in other tumor entities needs to be studied.

4D-CT-based motion correction of PET images using 3D iterative deconvolution.

OBJECTIVES: Positron emission tomography acquisition takes several minutes representing an image averaged over multiple breathing cycles. Therefore, in areas influenced by respiratory movement, PET-positive lesions occur larger, but less intensive than they actually are, resulting in false quantitative assessment. We developed a motion-correction algorithm based on 4D-CT without the need to adapt PET-acquisition. METHODS: The algorithm is based on a full 3D iterative Richardson-Lucy-Deconvolution using a point-spread-function constructed using the motion information obtained from the 4D-CT. In a motion phantom study (3 different hot spheres in background activity), optimal parameters for the algorithm in terms of number of iterations and start image were estimated. Finally, the correction method was applied to 3 patient data sets. In phantom and patient data sets lesions were delineated and compared between motion corrected and uncorrected images for activity uptake and volume. RESULTS: Phantom studies showed best results for motion correction after 6 deconvolution steps or higher. In phantom studies, lesion volume improved up to 23% for the largest, 43% for the medium and 49% for the smallest sphere due to the correction algorithm. In patient data the correction resulted in a significant reduction of the tumor volume up to 33.3 % and an increase of the maximum and mean uptake of the lesion up to 62.1 and 19.8 % respectively. CONCLUSION: In conclusion, the proposed motion correction method showed good results in phantom data and a promising reduction of detected lesion volume and a consequently increasing activity uptake in three patients with lung lesions.

Local control and overall survival after frameless radiosurgery: A single center experience.

INTRODUCTION: Stereotactic radiosurgery (SRS) has been increasingly advocated for 1-3 small brain metastases. The goal of this study was to evaluate the clinical results in patients with brain metastases treated with LINAC-based SRS using a thermoplastic mask (non-invasive fixation system) and Image-Guided Radiotherapy (IGRT). MATERIAL AND METHODS: In this single-institution study 48 patients with 77 brain metastases were treated between February 2012 and January 2014. The prescribed dose was 20 Gy or 18 Gy as a single fraction. SRS was performed with a True Beam STX Novalis Radiosurgery LINAC (Varian Medical Systems). The verification of positioning was done using the BrainLAB ExacTrac ® X-ray 6D system and cone-beam CT. RESULTS: In 69 of 77 treated brain metastases (90%) the follow-up was documented on MR imaging performed every 3 months. Mean follow-up time was 10.86 months. Estimated 1-year local control was 83%, using the Kaplan-Meier method. In 7/69 brain metastases (10%) local failure (LF) was diagnosed. Median progression free survival (PFS) was 3.73 months, largely due to distant brain relapse. A GTV of ≤2.0 cm3 was significantly associated with a better PFS than a GTV >2.0 cm3. Extracranial stable disease and GTV ≤2.5 cm³ were significant predictors of OS.We observed 2 cases of radiation necrosis diagnosed by histology after surgical resection. No other cases of severe side effects (CTACE ≥ 3) were observed. CONCLUSION: LINAC-based frameless SRS with the BrainLAB Mask using the BrainLAB ExacTrac ® X-ray 6D system for patient positioning is well tolerated, safe and leads to favorable crude local control of 90%. In our experience, local control after frameless (ringless) SRS is as good as ring-based SRS reported in literature. Without invasive head fixation, radiotherapy is more comfortable for patients.

Long-term outcome after highly advanced single-dose or fractionated radiotherapy in patients with vestibular schwannomas - pooled results from 3 large German centers.

PURPOSE: To evaluate long-term clinical outcome and determine prognostic factors for local-control, hearing preservation and cranial nerve toxicity in 449 patients treated for 451 vestibular schwannomas (VS) with radiosurgery (n=169; 38%) or fractionated stereotactic radiotherapy (FSRT; n=291; 62%). METHODS AND MATERIALS: 245 patients were male (55%), and 204 were female (45%). Median age was 60 years (range 17-88 years). Median tumor diameter was 15mm. For FSRT, a median dose of 57.6Gy in median single doses of 1.8Gy was applied. For SRS, median dose was 13Gy. The median follow-up time was 67 months. RESULTS: Local control was 97% at 36 months, 95% at 60 months, and 94% at 120 months with no difference between FSRT and SRS (p=0.39). "Useful hearing" was present 46%. After RT, "useful hearing" was preserved in 85% of the patients. Loss of useful hearing was observed in the FSRT group in 14%, and in the SRS group in 16% of the patients. For patients treated with SRS ⩽13Gy, useful hearing deterioration was 13%. For trigeminal and facial nerve toxicity, there was no difference between FSRT and SRS. CONCLUSION: Supported by this large multicentric series, both SRS and FSRT can be recommended for the treatment of VS. SRS application is limited by tumor size, and is associated with a steep dose-response-curve. When chosen diligently based on tumor volume, pre-treatment characteristics and volume-dependent dose-prescription in SRS (⩽13Gy), both treatments may be considered equally effective.

Whole brain irradiation with hippocampal sparing and dose escalation on multiple brain metastases: a planning study on treatment concepts.

PURPOSE: To develop a new treatment planning strategy in patients with multiple brain metastases. The goal was to perform whole brain irradiation (WBI) with hippocampal sparing and dose escalation on multiple brain metastases. Two treatment concepts were investigated: simultaneously integrated boost (SIB) and WBI followed by stereotactic fractionated radiation therapy sequential concept (SC). METHODS AND MATERIALS: Treatment plans for both concepts were calculated for 10 patients with 2-8 brain metastases using volumetric modulated arc therapy. In the SIB concept, the prescribed dose was 30 Gy in 12 fractions to the whole brain and 51 Gy in 12 fractions to individual brain metastases. In the SC concept, the prescription was 30 Gy in 12 fractions to the whole brain followed by 18 Gy in 2 fractions to brain metastases. All plans were optimized for dose coverage of whole brain and lesions, simultaneously minimizing dose to the hippocampus. The treatment plans were evaluated on target coverage, homogeneity, and minimal dose to the hippocampus and organs at risk. RESULTS: The SIB concept enabled more successful sparing of the hippocampus; the mean dose to the hippocampus was 7.55±0.62 Gy and 6.29±0.62 Gy, respectively, when 5-mm and 10-mm avoidance regions around the hippocampus were used, normalized to 2-Gy fractions. In the SC concept, the mean dose to hippocampus was 9.8±1.75 Gy. The mean dose to the whole brain (excluding metastases) was 33.2±0.7 Gy and 32.7±0.96 Gy, respectively, in the SIB concept, for 5-mm and 10-mm hippocampus avoidance regions, and 37.23±1.42 Gy in SC. CONCLUSIONS: Both concepts, SIB and SC, were able to achieve adequate whole brain coverage and radiosurgery-equivalent dose distributions to individual brain metastases. The SIB technique achieved better sparing of the hippocampus, especially when a10-mm hippocampal avoidance region was used.

Description of a method: computer generated virtual model for accurate localisation of tumour margins, standardised resection, and planning of radiation treatment in head & neck cancer surgery.

Communication between the surgeon, the pathologist and the radiation oncologist is improved by a virtual model of the final resection combining 3D imaging with computer aided navigation. The pathologist localises any questionable margins and the oncologist plans focussed delivery of radiation to native tissue in an area of complex anatomy.

Increased radioresistance, modelling of carcinogenesis and low-dose risk estimation.

Increased radioresistance for exposures to low-LET radiation with doses exceeding a few hundred milligray is a well established fact for cell inactivation in vitro and in vivo. Cell inactivation and the subsequent replacement by intermediate cells is a possible mechanism for a radiation-induced increase of the number of intermediate cells in carcinogenesis in an irradiated organ. In the present work this mechanism has been implemented in the two-step clonal expansion model for carcinogenesis in the lung in addition to the conventionally assumed radiation-induced initiation. Compared with the original TSCE model, the new model has the same number of parameters and fits the lung cancer incidence data for the atomic bomb survivors slightly better. The resulting estimate of the lung cancer risk after low-dose exposures of persons with an age of 20 or 40 years is similar in the two models; however, it is higher by about an order of magnitude in the new model for an age-at-exposure of 60 years. Age-at-exposure dependence and risk estimates at low dose turn out to be closer to best estimates obtained with a constant-excess-relative-risk model for different age-at-exposure subgroups.