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Background and purpose To evaluate clinical results and safety of a dose adaptive protocol based on tumor volume coverage and critical structure constraints, for the treatment of skull base chordomas. Material and methods Between May 2006 and October 2012, 106 patients with skull base chordoma were treated by combined photon and proton irradiation. Prescribed dose levels were 68.4, 70.2, 72 and 73.8 Gy(RBE) in once daily fractionation of 1.8 Gy(RBE). Dose level and dosimetric constraints to organs at risk depended on postoperative residual Gross Tumor Volume (GTV) coverage. Local control (LC) and overall survival (OS) were evaluated using the Kaplan–Meier method. Results With a median follow-up of 61 months, the 2-year, 4-year, and 5-year LC rates were 88.6%, 78.3%, and 75.1%, respectively. GTV > 25 mL ( p  = 0.034 , HR = 2.22; 95%CI 1.06–4.62) was an independent unfavorable prognostic factor of LC. The 2-year, 4-year, and 5-year OS rates were 99%, 90.2%, and 88.3%, respectively. Grade 3–5 late toxicity was observed in 7 patients, resulting in 93% 5-year freedom from high-grade toxicity. Conclusions This study suggests that the probability of LC of skull base chordomas depends on postoperative GTV. The dose adaptive protocol achieves acceptable local control. Future studies should investigate whether further dose escalation to doses in excess of 74 Gy(RBE) would achieve better results. [ABSTRACT FROM AUTHOR]

Purpose: To detect the presence of hypoxic tissue, which is known to increase the radioresistant phenotype, by its uptake of fluoromisonidazole (18F) (FMISO) using hybrid positron emission tomography/computed tomography (PET/CT) imaging, and to compare it with the glucose-avid tumor tissue imaged with fluorodeoxyglucose (18F) (FDG), in residual postsurgical skull base chordoma scheduled for radiotherapy. Patients and Methods: Seven patients with incompletely resected skull base chordomas were planned for high-dose radiotherapy (dose ≥70 Gy). All 7 patients underwent FDG and FMISO PET/CT. Images were analyzed qualitatively by visual examination and semiquantitatively by computing the ratio of the maximal standardized uptake value (SUVmax) of the tumor and cerebellum (T/C R), with delineation of lesions on conventional imaging. Results: Of the eight lesion sites imaged with FDG PET/CT, only one was visible, whereas seven of nine lesions were visible on FMISO PET/CT. The median SUVmax in the tumor area was 2.8 g/mL (minimum 2.1; maximum 3.5) for FDG and 0.83 g/mL (minimum 0.3; maximum 1.2) for FMISO. The T/C R values ranged between 0.30 and 0.63 for FDG (median, 0.41) and between 0.75 and 2.20 for FMISO (median,1.59). FMISO T/C R >1 in six lesions suggested the presence of hypoxic tissue. There was no correlation between FMISO and FDG uptake in individual chordomas (r = 0.18, p = 0.7). Conclusion: FMISO PET/CT enables imaging of the hypoxic component in residual chordomas. In the future, it could help to better define boosted volumes for irradiation and to overcome the radioresistance of these lesions. No relationship was founded between hypoxia and glucose metabolism in these tumors after initial surgery. [Copyright &y& Elsevier]

Purpose: To present the results of uveal melanomas treated at Nice Teaching Hospital. Methods and Materials: This retrospective study included 886 consecutive patients referred to our clinic for the treatment of uveal melanomas by proton beam radiotherapy from June 1991 to December 2007. Survival rates were determined by using Kaplan-Meier estimates, and prognostic factors were evaluated using the log-rank test or Cox model. Results: The number (percent total) of subjects staged according to the TNM classification system (6th edition) of malignant tumors included 39 stage T1 (4.4%), 420 stage T2 (47.40%), 409 stage T3 (46.16%), and 18 stage T4 (2.03%) patients. The median follow-up was 63.7 months. The Kaplan-Meier overall survival rate at 5 years according to the sixth edition TNM classification was 92% for T1, 89% for T2, 67% for T3, and 62% for T4; and at 10 years, 86% for T1, 78% for T2, 43% for T3, and 41% for T4. Five factors were found to be associated with an increased death rate: advanced age, tumor thickness, largest tumor basal diameter, tumor volume, and tumor volume-to-eyeball volume ratio. The metastasis-free survival rates were 88.3 % at 5 years and 76.4 % at 10 years. The local control rates were 93.9% at 5 years and 92.1% at 10 years. The ocular conservation rates were 91.1% at 5 years and 87.3% at 10 years. Conclusions: We report the results of a large series of patients treated for uveal melanomas with a very long follow-up. Despite the large tumor volume treated, our results were similar to previously published findings relating to proton beam therapy. [ABSTRACT FROM AUTHOR]

Purpose: Chondrosarcoma is a rare malignant tumor of the cartilage affecting young adults. Surgery, followed by charged-particle irradiation, is considered the reference standard for the treatment of patients with grade I to II skull base chondrosarcoma. The present study was conducted to assess the effect of the quality of surgery and radiation therapy parameters on local control (LC) and overall survival (OS).Methods and Materials: From 1996 to 2013, 159 patients (median age 40 years, range 12-83) were treated with either protons alone or a combination of protons and photons. The median total dose delivered was 70.2 Gy (relative biologic effectiveness [RBE]; range 67-71). Debulking and biopsy were performed in 133 and 13 patients, respectively.Results: With a median follow-up of 77 months (range 2-214), 5 tumors relapsed based on the initial gross tumor volume. The 5- and 10-year LC rates were 96.4% and 93.5%, respectively, and the 5- and 10-year OS rates were 94.9% and 87%, respectively. A total of 16 patients died (13 of intercurrent disease, 3 of disease progression). On multivariate analysis, age <40 years and primary disease status were independent favorable prognostic factors for progression-free survival and OS, and local tumor control was an independent favorable predictor of OS. In contrast, the extent of surgery, dosimetric parameters, and adjacent organs at risk were not prognostic factors for LC or OS.Conclusions: Systematic high-dose postoperative proton therapy for skull base chondrosarcoma can achieve a high LC rate with a low toxicity profile. Maximal safe surgery, followed by high-dose conformal proton therapy, is therefore recommended. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate retrospectively the efficacy of conformal fractionated radiotherapy combining proton and photon beams after primary surgery for treatment of atypical and malignant meningiomas. Patients and Methods: Between September 1999 and October 2006, 24 patients (12 male, 12 female) with histopathologically proven meningioma (atypical 19, malignant 5) received postoperative combined radiotherapy with a 201-MeV proton beam at the Centre Protontherapie d''Orsay and a high-energy photon beam. Six patients underwent gross total resection and 18 a subtotal resection. Median gross tumor volume and clinical target volume were 44.7 cm3 and 153.3 cm3, respectively. Mean total irradiation dose was 65.01 CGE (cobalt gray equivalent), with a mean proton total dose of 34.05 CGE and a mean photon total dose 30.96 CGE. Results: The median (range) follow-up interval was 32.2 (1–72) months. The overall mean local relapse-free interval was 27.2 (10–50) months, 28.3 (10–50) months for atypical meningioma and 23 (13–33) months for malignant meningioma. Ten tumors recurred locally. One-, 2-, 3-, 4-, 5-, and 8- year local control rates for the entire group of patients were 82.9% ± 7.8%, 82.9% ± 7.8%, 61.3% ± 11%, 61.3% ± 11%, 46.7% ± 12.3%, and 46.7% ± 12.3%, respectively. One-, 2-, 3-, 4-, 5-, and 8- year overall survival rates were 100%, 95.5% ± 4.4%, 80.4% ± 8.8%, 65.3% ± 10.6%, 53.2% ± 11.6%, and 42.6% ± 13%, respectively. Survival was significantly associated with total dose. There was no acute morbidity of radiotherapy. One patient developed radiation necrosis 16 months after treatment. Conclusions: Postoperative combination of conformal radiotherapy with protons and photons for atypical and malignant meningiomas is a well-tolerated treatment producing long-term tumor stabilization. [Copyright &y& Elsevier]

Purpose: To compare treatment planning between combined photon–proton planning (CP) and proton planning (PP) for skull base tumors, so as to assess the potential limitations of CP for these tumors. Methods and Materials: Plans for 10 patients were computed for both CP and PP. Prescribed dose was 67 cobalt Gray equivalent (CGE) for PP; 45 Gy (photons) and 22 CGE (protons) for CP. Dose–volume histograms (DVHs) were calculated for gross target volume (GTV), clinical target volume (CTV), normal tissues (NT), and organs at risk (OARs) for each plan. Results were analyzed using DVH parameters, inhomogeneity coefficient (IC), and conformity index (CI). Results: Mean doses delivered to the GTVs and CTVs with CP (65.0 and 61.7 CGE) and PP (65.3 and 62.2 Gy CGE) were not significantly different (p > 0.1 and p = 0.72). However, the dose inhomogeneity was drastically increased with CP, with a mean significant incremental IC value of 10.5% and CP of 6.8%, for both the GTV (p = 0.01) and CTV (p = 0.04), respectively. The CI80% values for the GTV and CTV were significantly higher with PP compared with CP. Compared with CP, the use of protons only led to a significant reduction of NT and OAR irradiation, in the intermediate-to-low dose (≤80% isodose line) range. Conclusions: These results suggest that the use of CP results in levels of target dose conformation similar to those with PP. Use of PP significantly reduced the tumor dose inhomogeneity and the delivered intermediate-to-low dose to NT and OARs, leading us to conclude that this treatment is mainly appropriate for tumors in children. [Copyright &y& Elsevier]

Purpose: This study reports the results of proton beam radiotherapy based on a retrospective series of patients treated for uveal melanoma at the Orsay Center. Methods and Materials: Between September 1991 and September 2001, 1,406 patients with uveal melanoma were treated by proton beam radiotherapy. A total dose of 60 cobalt Gray equivalent (CGE) was delivered in 4 fractions on 4 days. Survival rates were determined using Kaplan–Meier estimates. Prognostic factors were determined by multivariate analysis using the Cox model. Results: The median follow-up was 73 months (range, 24–142 months). The 5-year overall survival and metastasis-free survival rates were 79% and 80.6%, respectively. The 5-year local control rate was 96%. The 5-year enucleation for complications rate was 7.7%. Independent prognostic factors for overall survival were age (p < 0.0001), gender (p < 0.0003), tumor site (p < 0.0001), tumor thickness (p = 0.02), tumor diameter (p < 0.0001), and retinal area receiving at least 30 CGE (p = 0.003). Independent prognostic factors for metastasis-free survival were age (p = 0.0042), retinal detachment (p = 0.01), tumor site (p < 0.0001), tumor volume (p < 0.0001), local recurrence (p < 0.0001), and retinal area receiving at least 30 CGE (p = 0.002). Independent prognostic factors for local control were tumor diameter (p = 0.003) and macular area receiving at least 30 CGE (p = 0.01). Independent prognostic factors for enucleation for complications were tumor thickness (p < 0.0001) and lens volume receiving at least 30 CGE (p = 0.0002). Conclusion: This retrospective study confirms that proton beam radiotherapy ensures an excellent local control rate. Further clinical studies are required to decrease the incidence of postirradiation ocular complications. [Copyright &y& Elsevier]

: PurposeTo evaluate the efficacy and outcome of Linac radiosurgery (RS) as treatment of cerebral arteriovenous malformations (cAVM) in a series of 57 children.: Methods and materialsBetween 1984 and 2000, we used Linac radiosurgery to treat 792 patients with cAVM. This series included 57 children (7.2%) under the age of 15 years at the time of RS (range = 7–15 years, median = 12 years). We were able to evaluate 49 of the children (86%) by angiography, 21 boys and 28 girls (sex ratio = 0.75). First symptoms were: hemorrhage, 34 patients (69.4%); seizures, 6 patients (12.5%); headache, 6 patients (12.5%); and progressive neurologic deficit, 1 patient (2.1%). Nidus size ranged from 5 to 50 mm (median = 20 mm). Nidus volume ranged from 0.6 to 16 cc (median = 3.5 cc). Patient distribution according to Spetzler-Martin grade was as follows: Grade 1, n = 5 (11%); Grade 2, n = 18 (35%); Grade 3, n = 21 (40%,); Grade 4, n = 5 (14%); and Grade 5, n = 0%. Twenty-seven patients (55.1%) had other treatment before RS: embolization, n = 14 (31.1%); neurosurgery, n = 9 (20.5%); embolization and neurosurgery, n = 3 (6.1%). RS was performed with the system used for adults. Patients were seated in a Betti armchair. Circular 15 MV X-ray minibeams (6 to 20 mm) were delivered in coronal arcs by a GECGR Saturne 43 Linac. Planification and dosimetry were carried out using the Associated Target Methodology and Dosigray TPS dosimetric systems. The dose at the peripheral isodose (50–70%) ranged from 18 to 28 Gy. Median and mean doses were 25 Gy and 23.8 Gy. Mono-isocentric planification was used in 25 patients (53.2%) and multi-isocentric in 24 patients (2 to 5 isocenters). The overall follow-up ranged from 7 to 172 months (mean 40 months, median 34 months).: ResultsThe overall rate of obliteration (OR) was 30/49 (61.2%). Mean time to obliteration was 34 months (range = 7 to 172 months). OR varied according to nidus size and volume: OR was 80% for nidus <15 mm, 67% for nidus between 15 and 25 mm, and 42% for nidus >25 mm (p = 0.058). OR was 100% for nidus <1 cc, 73% for nidus between 1 and 4 cc, and 40% for nidus of 4 to 10 cc (p = 0.019). OR according to patient gender was 84.2% for boys and 40% for girls. OR according to minimum dose (Dmin) was 44% for Dmin < 15 Gy (p = 0.01), 89% for D min from 15 to 20 Gy, and 100% for Dmin > 20 Gy (p = 0.01). OR was 62% in nonembolized AVM and 58% in previously embolized AVM (NS). OR according to the number of isocenters was 68.2%, 55.6%, 80%, 50%, and 0% for 1, 2, 3, 4, and 5 isocenters, respectively. After multivariate analysis, only Dmin closely correlated with OR (β = 0.462; SE = 0.244, p = 0.057). Of the 6 patients with seizures before RS, 5 (80%) were seizure-free without medication after RS. One patient died of pneumonia.: MorbidityFour patients (8.2%) had bleeding after RS at 39, 45, 51, and 59 months. No new neurologic deficit was found during the follow-up period. Twenty-nine patients underwent magnetic resonance imaging. Thirteen patients (44.8%) showed no parenchymal changes. Thirteen patients (44.8%) had Grade 2 changes, that is, T2 hypersignals. Two patients (6.9%) had Grade 3 changes, and 1 patient (3.4%) had Grade 4 “necrosis-like” changes.: ConclusionIn our experience, Linac RS has proven to be a safe and effective method to treat cerebral AVM in children <15 years, whether used alone or in association with embolization and/or neurosurgery. [Copyright &y& Elsevier]