Toxicity and efficacy of re-irradiation of high-grade glioma in a phase I dose- and volume escalation trial

Introduction The purpose of this study was to evaluate the safety and efficacy of PET and MRI guided re-irradiation of recurrent high-grade glioma (HGG) and to assess the impact of radiotherapy dose, fractionation and irradiated volume. Material and methods Patients with localized, recurrent HGG (grades III-IV) and no other treatment options were eligible for a prospective phase I trial. Gross tumor volumes for radiotherapy were defined using T1-contrast enhanced MRI and 18F-fluoro-ethyl tyrosine PET. Radiotherapy was delivered using volumetric modulated arc therapy with a 2-mm margin. The dose prescription of four consecutive groups was (1) 35 Gy/10fr., (2) 42 Gy/10fr., (3) 29.5 Gy/5fr. and (4) 35 Gy/10fr. to larger tumor volumes (100–300 cm3), respectively. Results Thirty-one patients were treated of which 81% had glioblastoma. The median progression-free survival was 2.8 months (95%CI: 2.1–3.5) and the median overall survival was 7.0 months (95%CI: 3.5–10.5). Early side effects were mild and included headache and fatigue. Seven patients were progression-free beyond 10 weeks and were evaluable for late toxicity. Among these patients, three (43%) suffered late adverse events which included radionecrosis and irreversible white matter changes. Conclusion Re-irradiation showed limited efficacy and 43% of patients achieving disease control suffered late toxicity that was manageable but not negligible

Impact of [18F]-fluoro-ethyl-tyrosine PET imaging on target definition for radiation therapy of high-grade glioma

Background.We sought to assess the impact of amino-acid 18F-fluoro-ethyl-tyrosine (FET) positron emission tomography (PET) on the volumetric target definition for radiation therapy of high-grade glioma versus the current standard using MRI alone. Specifically, we investigated the influence of tumor grade, MR-defined tumor volume, and the extent of surgical resection on PET positivity. Methods. Fifty-four consecutive high-grade glioma patients (World Health Organization grades III–IV) with confirmed histology were scanned using FET-PET/CT and T1 and T2/fluid attenuated inversion recovery MRI. Gross tumor volume and clinical target volumes (CTVs) were defined in a blinded fashion based on MRI and subsequently PET, and volumetric analysis was performed. The extent of the surgical resection was reviewed using postoperative MRI. Results. Overall, for90 % of the patients, the PET-positive volumes were encompassed by T1 MRI with contrast-defined tumor plus a 20-mm margin. The tumor volume defined by PET was larger for glioma grade IV (P,.001) and smaller for patients with more ex-tensive surgical resection (P .004). The margin required to be added to the MRI-defined tumor in order to fully encompass the FET-PET positive volume tended to be larger for grade IV tumors (P .018). Conclusion. With an unchanged CTV margin and by including FET-PET for gross tumor volume definition, the CTV will increase mod-erately for most patients, and quite substantially for a minority of patients. Patients with grade IV gliomawere found to be the primar

Prognostic value of ¹⁸F-FET PET imaging in re-irradiation of high-grade glioma:Results of a phase I clinical trial

Background and purpose Positron emission tomography (PET) provides quantitative metabolic information and potential biomarkers of treatment outcome. We aimed to determine the prognostic value of early 18F-fluoroethyl-tyrosine (18F-FET) PET scans acquired during re-irradiation for recurrent high-grade glioma (HGG). Material and methods A phase I clinical trial of re-irradiation of HGG was carried out. MRI and 18F-FET PET were used for target delineation and follow-up. Images were acquired at baseline, during radiotherapy and 4 weeks post-treatment and compared by measuring the metabolically active biological tumor volume (BTV) and maximal activity (Tmax/B). Correlations with outcomes were assessed by multivariate Cox regression analysis. Results Thirty-one patients were included and all patients have died. The median overall survival was 7.0 mos. Both baseline BTV and baseline MRI volume (necrotic/cystic cavities subtracted) were prognostic for overall survival (OS) in multivariate analysis (HR = 1.3 p < 0.01 and HR = 1.3 p < 0.01, respectively). Early changes in BTV and Tmax/B were observed but they carried no independent prognostic information. Conclusions Baseline biological tumor volume (BTV) defined by 18F-FET PET was prognostic for OS in multivariate analysis, as was MRI volume (necrotic/cystic cavities subtracted). Tumor volume may aid in identifying patients whose life expectancy is too short to warrant re-irradiation

Differentiation of Brain Metastases due to Primary Malignancy and Glioblastomas using Dynamic Susceptibility Contrast-Enhanced MR at 3T

Purpose:To find out differences in cerebral blood volume (CBV) maps derived from dynamic susceptibility contrast-enhanced magnetic resonance imaging (DSCE-MRI) in glioblastomas and cerebral metastases. The main purpose was to compare CBV maps between metastases with different primary malignancies. Furthermore the metastasis group was compared with the glioblastoma group.Method:Conventional imaging and DSCE-MRI using 3T MRI system was performed in 114 patients, 38 glioblastomas and 76 metastases, 32 lung, 12 breast, 12 melanoma, 10 gastrointestinal (GI), and 10 other. CBV values were measured in the solid tumor area, peritumoral edema, area adjacent to peritumoral edema, and in normal apparent white matter in contralateral semioval center. The four subgroups of metastases were compared with one-way ANOVA to determine differences in CBV of significance. CBV values in glioblastomas and metastases were then statistically compared using paired t-test. Receiver -operating characteristic analysis was used to determine optimal cut-off values when parameters showed statistical differences.Results:There were no significantly differences in CBV between the four subgroups of metastases. CBV in the peritumoral edema significantly differentiated metastases from glioblastomas, p=0.0001. CBV cutoff value of 2.3 yielded a sensitivity, specificity, positive predictive value, and negative predictive value of 87, 87, 71, and 91% respectively. Conclusions:Differentiation of glioblastomas and metastases is possible using DSCE-MRI. No statistically significant differences regarding CBV between metastases from lung, breast, melanoma, and GI were detected

A Helical tomotherapy as a robust low-dose treatment alternative for total skin irradiation

Mycosis fungoides is a disease with manifestation of the skin that has traditionally been treated with electron therapy. In this paper, we present a method of treating the entire skin with megavoltage photons using helical tomotherapy (HT), verified through a phantom study and clinical dosimetric data from our first two treated patients. A whole body phantom was fitted with a wetsuit as bolus, and scanned with computer tomography. We accounted for variations in daily setup using virtual bolus in the treatment plan optimization. Positioning robustness was tested by moving the phantom, and recalculating the dose at different positions. Patient treatments were verified with in vivo film dosimetry and dose reconstruction from daily imaging. Reconstruction of the actual delivered dose to the patients showed similar target dose as the robustness test of the phantom shifted 10 mm in all directions, indicating an appropriate approximation of the anticipated setup variation. In vivo film measurements agreed well with the calculated dose confirming the choice of both virtual and physical bolus parameters. Despite the complexity of the treatment, HT was shown to be a robust and feasible technique for total skin irradiation. We believe that this technique can provide a viable option for Tomotherapy centers without electron beam capability

Surface-guided tomotherapy improves positioning and reduces treatment time : A retrospective analysis of 16 835 treatment fractions

Purpose: In this study, we have quantified the setup deviation and time gain when using fast surface scanning for daily setup/positioning with weekly megavoltage computed tomography (MVCT) and compared it to daily MVCT. Methods: A total of 16 835 treatment fractions were analyzed, treated, and positioned using our TomoTherapy HD (Accuray Inc., Madison, USA) installed with a Sentinel optical surface scanning system (C-RAD Positioning AB, Uppsala, Sweden). Patients were positioned using in-room lasers, surface scanning and MVCT for the first three fractions. For the remaining fractions, in-room laser was used for setup followed by daily surface scanning with MVCT once weekly. The three-dimensional (3D) setup correction for surface scanning was evaluated from the registration between MVCT and the planning CT. The setup correction vector for the in-room lasers was assessed from the surface scanning and the MVCT to planning CT registration. The imaging time was evaluated as the time from imaging start to beam-on. Results: We analyzed 894 TomoTherapy treatment plans from 2012 to 2018. Of all the treatment fractions performed with surface scanning, 90 % of the residual errors were within 2.3 mm for CNS (N = 284), 2.9 mm for H&N (N = 254), 8.7 mm for thorax (N = 144) and 10.9 for abdomen (N = 134) patients. The difference in residual error between surface scanning and positioning with in-room lasers was significant (P < 0.005) for all sites. The imaging time was assessed as total imaging time per treatment plan, modality, and treatment site and found that surface scanning significantly reduced patient on-couch time compared to MVCT for all treatment sites (P < 0.005). Conclusions: The results indicate that daily surface scanning with weekly MVCT can be used with the current target margins for H&N, CNS, and thorax, with reduced imaging time

Implementing safe and robust Total Marrow Irradiation using Helical Tomotherapy – A practical guide

Total Marrow Irradiation (TMI) with Helical Tomotherapy is a radiotherapy treatment technique that targets bone marrow and sanctuary sites prior to stem cell or bone marrow transplantation (SCT/BMT). TMI is a complex procedure that involves several critical steps that all need to be carefully addressed for a successful implementation, such as dose homogeneity in field junctions, choice of target margins, integrity of treatment and back-up planning. In this work we present our solution for a robust and reproducible workflow throughout the treatment chain and data for twenty-three patients treated to date. Material & Methods: Patients were immobilized in a whole body vacuum cushion and thermoplastic mask. CT-scanning and treatment were performed in two parts with field matching at the upper thigh. Target consisted of marrow containing bone and sanctuary sites. Lungs, kidneys, bowel, heart and liver were defined as organs at risk (OAR). A fast surface scanning system was used to position parts of the body not covered by the imaging system (MVCT) as well as to reduce treatment time. Results: All patients completed their treatment and could proceed with SCT/BMT. Doses to OARs were significantly reduced and target dose homogeneity was improved compared to TBI. Robustness tests performed on field matching and patient positioning support that the field junction technique is adequate. Replacing MVCT with optical surface scanning reduced the treatment time by 25 min per fraction. Conclusion: The methodology presented here has shown to provide a safe, robust and reproducible treatment for Total Marrow Irradiation using Tomotherapy

Transitioning from conventional photon therapy to proton therapy for primary brain tumors

Introduction: Proton radiation therapy (PT) has become a treatment option alongside photon therapy (XRT) for lower-grade gliomas (LGG). In this single-institution retrospective study, we investigate the patient characteristics and treatment outcomes, including pseudo-progression (PsP), for LGG patients selected for PT. Method: Adult patients with grade 2–3 glioma consecutively treated with radiotherapy (RT) from May 2012 to December 2019 were retrospectively included in this cohort study. Tumor characteristics and treatment data were collected. The groups treated with PT and XRT were compared regarding treatment characteristics, side effects, occurrence of PsP, and survival outcomes. PsP was defined as new or growing lesions followed by either decrease or stabilization during a 12 month-period with no treatment. Results: Out of 143 patients meeting the inclusion criteria, 44 were treated with PT, 98 with XRT and one with mixed PT + XRT. The patients receiving PT were younger, had a lower tumor grade, more oligodendrogliomas and received a lower mean brain and brainstem dose. PsP was observed in 21 out of 126 patients, with no difference between XRT and PT (p =.38). The rate of fatigue in immediate connection to RT (zero to three months after) was higher for XRT than for PT (p =.016). The PT patients had a significantly better PFS and OS than the XRT patients (p =.025 and.035), but in multivariate analysis radiation modality was non-significant. Higher average dose to both brain and brainstem was associated with inferior PFS and OS (p <.001). Median follow-up time were 69 months and 26 months for XRT and PT patients, respectively. Conclusion: Contrary to previous studies, there was no difference in risk of PsP for XRT and PT. PT was associated with lower rates of fatigue <3 months after RT. The superior survival outcomes for PT indicates that the patients with the best prognosis were referred to PT