Purpose or ObjectiveGlioblastoma (GBM) is a highly aggressive malignant brain tumour with a median overall survival of only 15 months.After postoperative chemoradiotherapy, most recurrences occur within or at the margin of the treatment volume.The standard clinical target volume (CTV) is typically defined as an isotropic 2 cm expansion around the surgical cavity and the area of contrast enhancement.This isotropic margin is not taking into account the preferential tumour growth along the white matter tracts of the brain.Diffusion tensor imaging (DTI) MRI can be used to model white matter tracts.The aim of this phase 1 feasibility study is to evaluate DTI-MRI diffusion growth models in the biological CTV definition of GBM. Material and MethodsAdult GBM patients referred for postoperative RT were included, and underwent an additional pre-treatment DTI-MRI; actual treatment wasn't altered.The standard CTV was defined as described above, respecting anatomical barriers.DTI-MRI was used to create two biological CTVs, iso-volumetric to the standard CTV, using anisotropic margins based on tensor directionality of γ0 (bCTVγ0) and γ20 (bCTVγ20; higher γ meaning a higher assumed probability of tumour spread along white matter tracts).The similarity of the CTV and the bCTVs was assessed using the Dice similarity score (DSC; 0=no overlap, 1=complete overlap).Treatment effect was assessed by 3-monthly MRI and described by RANO criteria.Progression was defined as central, in-field/marginal and distant with respective ≥95%, 20-95%, or <20% of the recurrence volume (RV) located within the D95%.Only patients with an infield/marginal or distant recurrence were selected for comparison of the bCTVs to the RV.The overlap or minimal distance between the bCTVs and the delineated RV was calculated. ResultsBetween 10/2016 and 06/2018 38 patients were included.One patient went off-study and one was lost to follow-up, leaving 36 for analyses.Gross total resection was performed in 42% of patients, and 89% completed irradiation to 60 Gy in 30 fractions (Table ).At a median follow-up of 9.5 (range 3-21) months, 23 patients had disease progression; 2 clinical, 19 central, 1 infield/marginal, 2 distant.The median PFS was 7.0 (range 4.5-9.5)months.The mean DSC between CTV and bCTVγ0 was 0.75 (range 0.65-0.85),and CTV and bCTVγ20 was 0.72 (range 0.62-0.81)(bCTVγ0 vs bCTVγ20 p<0.001).For patient 1 with a non-central recurrence the CTV/bCTVγ0/bCTVγ20 overlapped with the RV by 87/90/89% (Figure).For patient 2 the CTV/bCTVγ0/bCTVγ20 overlapped with the RV by 19/21/25%.For patient 3 (no overlap) the shortest distance from the CTV/bCTVγ0/bCTVγ20 to the RV was 4.6/3.6/3.3 cm.

Whole brain radiotherapy (WBRT) has been the radiation treatment of choice for patients with primary central nervous system lymphoma (PCNSL). Neurocognitive functions (NCFs) decline is surely one of the main significant complications which may occur. It has been widely shown that neurocognitive decline is mainly caused by the radiation-induced injury to the hippocampus. The conformal hippocampal avoidance during the course of WBRT might provide meaningful NCFs preservation. Our study aims to investigate the correlation between the site of (Primary Central Nervous System Lymphoma) PCNSL lesions and the hippocampal region in order to explore the feasibility of routinely sparing of the hippocampus during a WBRT to prevent neurocognitive decline. Patients (> 18 years, ECOG <4) with pathologically proven PCNSL and MRI image pre-treatment were retrospectively reviewed. All patients had received high-dose of methotrexate (HD-MTX) before WBRT. T1-weighted, post-contrast axial MR image sets obtained prior to cranial irradiation were imported on Varian Eclipse treatment planning system, version 11 (Varian Medical Systems) and registered with the simulation CT. The hippocampus as well as each PCNSL lesions were contoured. Three dimensional envelopes surrounding the hippocampus were generated adding 5, 10, and 15 mm and the distance of brain lesions were recorded as <5 mm, 5 to <10 mm, 10 to <15 mm, and >15 mm from the hippocampus. The minimum margin of 5 mm was taken into account for systematic setup error and dose fall-off between whole brain clinical target volume and the hippocampus. Thirty-eight patients were treated between 2005 and 2018 and 36 pts with 57 lesions were eligible for this study. PCNSL lesions’ locations were: deep brain structures (26%), parietal lobe (23%), frontal lobe (19%), temporal lobe (14%), occipital lobe (7%), brainstem (5%), other sites (6%). Nine patients were affected by multiple lesions. In 18/57 lesions (31.6%) the distance from the hippocampus region was less than 5 mm and seven of them (12.3%) involved the hippocampus. Lesions over 15 mm from the hippocampus were observed in 30 cases (52.6%), while only the 15,8% was between 5 and 15 mm. These data show that routinely sparing of the hippocampus region is not recommended. Anyway, it should be considered in selected patients, when the spatial distribution of PCNSL is far more than 5 mm from the lesion.

OBJECTIVE: To explore safety and efficacy of hypofractionated radiotherapy (HyRT) followed by low dose radiation therapy (LDRT) in combination with Temozolomide (TMZ) in adults with newly diagnosed Glioblastoma Multiforme. MATERIAL AND METHODS: Patients (ECOG ≤2, age ≥18 years) with a previous biopsy or a gross residual tumor after surgery were enrolled in this study. Treatment started with HyRT (30 Gy in ten fraction) combined with TMZ (75 mg/m2 for all time of RT) followed by adjuvant TMZ. From the second to third cycle of adjuvant TMZ, LDRT (0.40 Gy twice daily, at least 4 hours apart over 5 consecutive days, every 28 days) was planned. Another 2 cycles were scheduled if neither progression disease nor clinical decrease was observed. Conformal irradiation included the tumor with surgical cavity, plus a 30-mm margin. The primary endpoints were safety, tolerability and toxicity according to Common Terminology Criteria for Adverse Events version 4.0. Response according to RANO Guidelines, Overall Survival, Progression-free survival (PFS) were the secondary endpoints. RESULTS: From June 2008 to January 2012, 20 patients with a median age of 64.5 years were enrolled. All patients received the prescribed dose of 30 Gy. 17 out of twenty received 2 cycles of LDRT and the median total dose was 12 Gy. All toxicities were reversible and only 5 patients presented hematologic G1-2 toxicity. At the end of the fourth cycle, 4 out of 20 patients had partial response, 6 experienced stable disease and 10 patients had progressive disease Median OS and PFS from diagnosis were 14 and 11 months, respectively. Patients who received ≤2 cycles presented a median OS and PFS of 5 and 4 months respectively; when four cycles were administered the median OS was 26 months and PFS was 14 months. CONCLUSIONS: Hypofractionated regimen followed by LD-FRT combined with TMZ is safe and tolerated well. The number of LDFRT's cycles seems to increase the survival in this setting of patients. A new study is ongoing.

PURPOSE: The neurocognitive decline is one of the main limiting factor of whole brain irradiation. This study evaluate the correlation between the site of (Primary Central Nervous System Lymphoma) PCNSL lesions and the hippocampal region in order to explore the feasibility of routinely sparing of the hippocampus during whole-brain radiotherapy (WBRT) to prevent radiation-induced neurocognitive decline. METHODS AND MATERIALS: Patients (>18 years, ECOG <4) with pathologically proven PCNSL and MRI image pre-treatment were retrospectively reviewed. All patients had received high-dose of methotrexate (HD-MTX) before WBRT. T1-weighted, post-contrast axial MR image sets obtained prior to cranial irradiation were imported on Varian Eclipse treatment planning system, version 11 (Varian Medical Systems) and registered with the simulation CT. The hippocampus as well as each PCNSL lesions were contoured. Three dimensional envelopes surrounding the hippocampus were generated adding 5, 10, and 15 mm and the distance of brain lesions were recorded as <5 mm, 5 to <10 mm, 10 to <15 mm, and >15 mm from the hippocampus. The minimum margin of 5 mm was taken account for systematic setup error and dose fall-off between whole brain clinical target volume and the hippocampus. RESULTS: Between 2006 and 2013, 23 patients were treated and 17 pts with 35 lesions were eligible for this study. In this sample PCNSL lesions were positioned: parietal lobe (28,6%), deep brain structures (20%), frontal lobe (17,1%), temporal lobe (14,3%), brainstem (8,6%), other sites (11,4%). Six patients were affected by multiple lesions. In 7/17 patients (41.2%) PCNSL lesion was distant from the hippocampus region less than 5 mm. Eight out 35 lesion (22.8%) were localized within 5 mm of hippocampal region, three of them involved the hippocampus. Over 15 mm of the hippocampus we observed 51,4% (n = 18) of brain lesions, while 11,4% (n = 4) and 14.4% (n = 5) were between 10-15 mm. CONCLUSIONS: These data show that routinely sparing of the hippocampus region is not recommended; it must be considered when the spatial distribution of PCNSL is more than 5 mm.