Sarcoma cell-specific radiation sensitization by titanate scrolled nanosheets: insights from physicochemical analysis and transcriptomic profiling.

This study aimed to explore the potential of metal oxides such as Titanate Scrolled Nanosheets (TNs) in improving the radiosensitivity of sarcoma cell lines. Enhancing the response of cancer cells to radiation therapy is crucial, and one promising approach involves utilizing metal oxide nanoparticles. We focused on the impact of exposing two human sarcoma cell lines to both TNs and ionizing radiation (IR). Our research was prompted by previous in vitro toxicity assessments, revealing a correlation between TNs' toxicity and alterations in intracellular calcium homeostasis. A hydrothermal process using titanium dioxide powder in an alkaline solution produced the TNs. Our study quantified the intracellular content of TNs and analyzed their impact on radiation-induced responses. This assessment encompassed PIXE analysis, cell proliferation, and transcriptomic analysis. We observed that sarcoma cells internalized TNs, causing alterations in intracellular calcium homeostasis. We also found that irradiation influence intracellular calcium levels. Transcriptomic analysis revealed marked disparities in the gene expression patterns between the two sarcoma cell lines, suggesting a potential cell-line-dependent nano-sensitization to IR. These results significantly advance our comprehension of the interplay between TNs, IR, and cancer cells, promising potential enhancement of radiation therapy efficiency.

High dose (54 Gy) pre-operative helical tomotherapy for retroperitoneal liposarcoma: Results of a phase II multicenter study.

PURPOSE: To evaluate efficacy and feasibility of high-dose intensity-modulated radiotherapy (RT) with pre-operative helical tomotherapy, delivering 54 Gy/30 fractions in patients with retroperitoneal liposarcomas (RPLS). MATERIALS AND METHODS: Patients with operable, biopsy-proven, RPLS were included in this phase II multicenter study (ClinicalTrials.gov: NCT01841047). The primary objectives were to analyze loco-regional relapse free survival (LRFS), overall survival (OS) and toxicities, graded according to CTCAE V3.0. RESULTS: From April 2009 to September 2013, 48 patients were included. Histological types were: 20 well differentiated and 28 dedifferentiated liposarcomas. Median clinical target volume (CTV) was 2570 cc (range, 230-8734 cc). The radio-surgical schedule was completed as planned in all patients apart from one. A monobloc wide excision was achieved for all patients. Surgical margins were R0 (16; 34%), R1 (28; 60%), R2 (2; 4%) or missing (1, 2%).With a median follow-up of 5.5 years, 3-year LRFS rate was 74.2% (95%CI: [59.1%; 84.5%]). At 5 years, cumulative incidence of loco-regional relapse for well differentiated and dedifferentiated RPLS was 10% and 18%, respectively. The 5-year OS was 73.9% [95%CI: 58.7-84.3%]. During RT, the most common grade 3-4 adverse events were hematological (N = 20; 41.6%). After surgery and during follow-up, 17 patients (35.4%) presented a grade 3-4 toxicity. Two patients (4.1%) died due to a duodenal toxicity. Nine second cancers were observed. CONCLUSION: From this phase II trial of preoperative RT in RPLS patients, the dose level proposed cannot be considered safe, leading to non-negligible toxicity and second cancers rates. Our results, combined with STRASS-1 study, suggest that the ideal indication of RT for patients with RPLS still remains to be determined.

Changes in intra-nuclear mechanics in response to DNA damaging agents revealed by time-domain Brillouin micro-spectroscopy.

How DNA damage and repair processes affect the biomechanical properties of the nucleus interior remains unknown. Here, an opto-acoustic microscope based on time-domain Brillouin spectroscopy (TDBS) was used to investigate the induced regulation of intra-nuclear mechanics. With this ultrafast pump-probe technique, coherent acoustic phonons were tracked along their propagation in the intra-nucleus nanostructure and the complex stiffness moduli and thicknesses were measured with an optical resolution. Osteosarcoma cells were exposed to methyl methanesulfonate (MMS) and the presence of DNA damage was tested using immunodetection targeted against damage signaling proteins. TDBS revealed that the intra-nuclear storage modulus decreased significantly upon exposure to MMS, as a result of the chromatin decondensation and reorganization that favors molecular diffusion within the organelle. When the damaging agent was removed and cells incubated for 2 h in the buffer solution before fixation the intra-nuclear reorganization led to an inverse evolution of the storage modulus, the nucleus stiffened. The same tendency was measured when DNA double-strand breaks were caused by cell exposure to ionizing radiation. TDBS microscopy also revealed changes in acoustic dissipation, another mechanical probe of the intra-nucleus organization at the nano-scale, and changes in nucleus thickness during exposure to MMS and after recovery.

Final Safety and Health-Related Quality of LIfe Results of the Phase 2/3 Act.In.Sarc Study With Preoperative NBTXR3 Plus Radiation Therapy Versus Radiation Therapy in Locally Advanced Soft-Tissue Sarcoma.

PURPOSE: Act.In.Sarc (NCT02379845) demonstrated that the first-in-class radioenhancer NBTXR3, activated by preoperative radiation therapy (RT), doubled the rate of pathologic complete response after resection compared with preoperative RT alone in adult patients with locally advanced soft tissue sarcoma of the extremity or trunk wall (16.1% vs 7.9%, P = .045), and more patients achieved R0 resections (77.0% vs 64.0%, P = .042). These are the toxicity and health-related quality of life (HRQoL) results. METHODS AND MATERIALS: Act.In.Sarc randomized eligible patients 1:1 to either NBTXR3 (single intratumoral injection, volume equivalent to 10% of baseline tumor volume, at 53.3 g/L) activated by external-beam RT (arm A) or external-beam RT alone (arm B) (50 Gy in 25 fractions), followed by surgery in both arms. Here, we report the safety analyses in the all-treated population with a long-term follow-up of at least 2 years, and HRQoL in the intention-to-treat full analysis set. RESULTS: During the on-treatment period, serious adverse events (SAEs) of all grades related to NBTXR3 occurred in 10.1% (9/89) of patients (arm A), and SAEs related to RT occurred in 5.6% (5/89) (arm A) versus 5.6% (5/90) (arm B); postsurgery hospitalization owing to SAEs occurred in 15.7% (14/89) (arm A) versus 24.4% (22/90) (arm B). During the follow-up period, posttreatment SAEs (regardless of relationship) occurred in 13.5% (12/89) (arm A) versus 24.4% (22/90) (arm B). NBTXR3 did not negatively affect HRQoL; during the follow-up period, there was an improvement in most mean Toronto extremity salvage, EuroQoL 5-dimension (EQ-5D), EQ5D02-EQ visual analog scale, reintegration to normal living index, and musculoskeletal tumor rating scale scores. CONCLUSIONS: NBTXR3 did not negatively affect safety or HRQoL. Long-term safety results reinforce the favorable benefit-risk ratio of NBTXR3 plus RT.

Spatial mechanistic modeling for prediction of the growth of asymptomatic meningiomas.

BACKGROUND AND OBJECTIVE: Mathematical modeling of tumor growth draws interest from the medical community as they have the potential to improve patients' care and the use of public health resources. The main objectives of this work are to model the growth of meningiomas - slow-growing benign tumors requiring extended imaging follow-up - and to predict tumor volume and shape at a later desired time using only two times examinations. METHODS: We develop two variants of a 3D partial differential system of equations (PDE) which yield after a spatial integration systems of ordinary differential equations (ODE) that relate tumor volume with time. Estimation of models parameters is a crucial step to obtain a personalized model for a patient that can be used for descriptive or predictive purposes. As PDE and ODE systems share the same parameters, they are both estimated by fitting the ODE systems to the tumor volumes obtained from MRI examinations acquired at different times. A population approach allows to compensate for sparse sampling times and measurement uncertainties by constraining the variability of the parameters in the population. RESULTS: Description capabilities of the models are investigated in 39 patients with benign asymptomatic meningiomas who had had at least three surveillance MRI examinations. The two models can fit to the data accurately and more realistically than a naive linear regression. Prediction performances are validated for 33 patients using a population approach. Mean relative errors in volume predictions are less than 10% with ODE systems versus 12.5% with the naive linear model using only two times examinations. Concerning the shape, the mean Sørensen-Dice coefficients are 85% with the PDE systems in a subset of 10 representative patients. CONCLUSIONS: Our strategy - based on personalization of mathematical model - provides a good insight on meningioma growth and may help decide whether to extend the follow-up or to treat the tumor.

Local and Metastatic Relapse Features in Patients After a Primary Soft Tissue Sarcoma: Advocating for a Better-Tailored Follow-Up.

Background: No consensus exists on how to follow patients after complete remission of a primary Soft Tissue Sarcoma (STS). Studying relapse features could help tailor guidelines for follow-up. Patients and Methods: Patients in complete remission after initial management of a localized STS at Institut Bergonié who presented a first local and/or metastatic relapse between January 1995 and July 2015 were eligible. Characteristics of relapse diagnosis were retrospectively collected. Results: 359 patients met inclusion criteria. 197 and 187 patients presented a local relapse and a metastatic relapse, respectively. In group 1 (limbs/trunk wall) and 2 (trunk/gynecological/other location), local relapse was diagnosed on clinical symptoms in 89 and 44% of cases, first detected by the patient himself in 68.5 and 34% of cases, and outside a planned visit in 67 and 36% of cases, respectively. In patients with metastatic relapse, diagnosis was made during a planned visit in 63% of cases, and by imaging in 62% of cases. Median survival after relapse was not different whether the first local relapse was diagnosed clinically or by imaging (44 [95%CI: 28-69.8] vs. 57 months [95%CI: 33.9-84.5], p = 0.35) but was longer if diagnosis of metastatic relapse was made on planned chest-CT scan rather than chest X-ray (58 [95%CI: 35.5-103.9] vs. 25 months [95%CI: 16.5-32.6], p < 0.05). Conclusion: Patient's education for regular clinical examination can be recommended for follow-up of local relapses after a primary STS of the limbs or superficial trunk. Modeling studies aiming at better understanding and predicting tumor biology to improve tailoring STS patients' follow-up are warranted.

NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial.

BACKGROUND: Pathological complete response to preoperative treatment in adults with soft-tissue sarcoma can be achieved in only a few patients receiving radiotherapy. This phase 2-3 trial evaluated the safety and efficacy of the hafnium oxide (HfO2) nanoparticle NBTXR3 activated by radiotherapy versus radiotherapy alone as a pre-operative treatment in patients with locally advanced soft-tissue sarcoma. METHODS: Act.In.Sarc is a phase 2-3 randomised, multicentre, international trial. Adults (aged ≥18 years) with locally advanced soft-tissue sarcoma of the extremity or trunk wall, of any histological grade, and requiring preoperative radiotherapy were included. Patients had to have a WHO performance status of 0-2 and a life expectancy of at least 6 months. Patients were randomly assigned (1:1) by an interactive web response system to receive either NBTXR3 (volume corresponding to 10% of baseline tumour volume at a fixed concentration of 53·3 g/L) as a single intratumoural administration before preoperative external-beam radiotherapy (50 Gy in 25 fractions) or radiotherapy alone, followed by surgery. Randomisation was stratified by histological subtype (myxoid liposarcoma vs others). This was an open-label study. The primary endpoint was the proportion of patients with a pathological complete response, assessed by a central pathology review board following European Organisation for Research and Treatment of Cancer guidelines in the intention-to-treat population full analysis set. Safety analyses were done in all patients who received at least one puncture and injection of NBTXR3 or at least one dose of radiotherapy. This study is registered with ClinicalTrials.gov, number NCT02379845, and is ongoing for long-term follow-up, but recruitment is complete. FINDINGS: Between March 3, 2015, and Nov 21, 2017, 180 eligible patients were enrolled and randomly assigned and 179 started treatment: 89 in the NBTXR3 plus radiotherapy group and 90 in the radiotherapy alone group. Two patients in the NBTXR3 group and one patient in the radiotherapy group were excluded from the efficacy analysis because they were subsequently discovered to be ineligible; thus, a total of 176 patients were analysed for the primary endpoint in the intention-to-treat full analysis set (87 in the NBTXR3 group and 89 in the radiotherapy alone group). A pathological complete response was noted in 14 (16%) of 87 patients in the NBTXR3 group and seven (8%) of 89 in the radiotherapy alone group (p=0·044). In both treatment groups, the most common grade 3-4 treatment-emergent adverse event was postoperative wound complication (eight [9%] of 89 patients in the NBTXR3 group and eight [9%] of 90 in the radiotherapy alone group). The most common grade 3-4 adverse events related to NBTXR3 administration were injection site pain (four [4%] of 89) and hypotension (four [4%]) and the most common grade 3-4 radiotherapy-related adverse event was radiation skin injury in both groups (five [6%] of 89 in the NBTXR3 group and four [4%] of 90 in the radiotherapy alone group). The most common treatment-emergent grade 3-4 adverse event related to NBTXR3 was hypotension (six [7%] of 89 patients). Serious adverse events were observed in 35 (39%) of 89 patients in the NBTXR3 group and 27 (30%) of 90 patients in the radiotherapy alone group. No treatment-related deaths occurred. INTERPRETATION: This trial validates the mode of action of this new class of radioenhancer, which potentially opens a large field of clinical applications in soft-tissue sarcoma and possibly other cancers. FUNDING: Nanobiotix SA.

High performance modelling of the transport of energetic particles for photon radiotherapy.

This work consists of the validation of a new Grid Based Boltzmann Solver (GBBS) conceived for the description of the transport and energy deposition by energetic particles for radiotherapy purposes. The entropic closure and a compact mathematical formulation allow our code (M1) to calculate the delivered dose with an accuracy comparable to the Monte-Carlo (MC) codes with a computational time that is reduced to the order of few minutes without any special processing power requirement. A validation protocol with heterogeneity inserts has been defined for different photon sources. The comparison with the MC calculated depth-dose curves and transverse profiles of the beam at different depths shows an excellent accuracy of the M1 model.

Helical tomotherapy of spinal chordomas: French Multicentric, retrospective study of a cohort of 30 cases.

PURPOSE: To evaluate the efficacy and toxicity of helical tomotherapy (HT) in the management of spine chordomas when proton therapy is unavailable or non-feasible. METHODS AND MATERIALS: Between 2007 and 2013, 30 patients with biopsy-proven chordomas were treated by HT in five French institutions. Information regarding local control (LC), overall survival (OS), progression-free survival (PFS) and metastasis-free survival (MFS) was collected. Clinical efficacy, toxicity and treatment quality were evaluated. RESULTS: Two-year actuarial LC, OS, PFS and MFS were 69.9%, 96.7%, 61.2% and 76.4%, respectively. HT treatments were well tolerated and no Grade 4-5 toxicities were observed. HT permitted the delivery of a mean dose of 68 Gy while respecting organ at risk (OAR) dose constraints, in particular in the spinal cord and cauda equina. CONCLUSIONS: This multicentric, retrospective study demonstrated the feasibility of HT in the treatment of spine chordomas, in the absence of hadron therapy.

First-in-Human Study Testing a New Radioenhancer Using Nanoparticles (NBTXR3) Activated by Radiation Therapy in Patients with Locally Advanced Soft Tissue Sarcomas.

Purpose: This phase I study aimed to determine the recommended dose (RD), safety profile, and feasibility of a procedure combining intratumoral injection of hafnium oxide nanoparticles (NBTXR3; a radioenhancer) and external beam radiotherapy (EBRT) for preoperative treatment of adults with locally advanced soft tissue sarcoma (STS).Experimental Design: Patients had a preoperative indication of EBRT for STS of the extremity or trunk. Baseline tumor volume (TV) was calculated by MRI. NBTXR3 was injected percutaneously into tumors at 53.3 g/L. Dose escalation was based on four levels equivalent to 2.5%, 5%, 10%, and 20% of baseline TV. NBTXR3 was visualized in the tumor 24 hours postinjection, and EBRT was initiated (50 Gy over 5 weeks). Surgery was performed 6 to 8 weeks after EBRT completion.Results: Twenty-two patients completed NBTXR3 injection, EBRT, and surgery and were followed for a median 22 months (range, 6-40). At NBTXR3 20% of TV, two dose-limiting toxicities occurred: injection-site pain and postoperative scar necrosis. The RD was defined as 10%. No leakage of NBTXR3 into surrounding tissues occurred; intratumor NBTXR3 levels were maintained during radiotherapy. At the RD, median tumor shrinkage was 40% (range 71% shrinkage, 22% increase); median percentage of residual viable tumor cells was 26% (range, 10%-90%). Patients receiving 20% of TV demonstrated pathologic complete responses. Seven grade 3 adverse events occurred, which were reversible.Conclusions: A single intratumoral injection of NBTXR3 at 10% of TV with preoperative EBRT was technically feasible with manageable toxicity; clinical activity was observed. Clin Cancer Res; 23(4); 908-17. ©2016 AACR.

Health-related quality of life in patients with high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study.

BACKGROUND: Temozolomide chemotherapy versus radiotherapy in patients with a high-risk low-grade glioma has been shown to have no significant effect on progression-free survival. If these treatments have a different effect on health-related quality of life (HRQOL), it might affect the choice of therapy. We postulated that temozolomide compromises HRQOL and global cognitive functioning to a lesser extent than does radiotherapy. METHODS: We did a prospective, phase 3, randomised controlled trial at 78 medical centres and large hospitals in 19 countries. We enrolled adult patients (aged ≥18 years) with histologically confirmed diffuse (WHO grade II) astrocytoma, oligodendroglioma, or mixed oligoastrocytoma, with a WHO performance status of 2 or lower, without previous chemotherapy or radiotherapy, who needed active treatment other than surgery. We randomly assigned eligible patients (1:1) using a minimisation technique, stratified by WHO performance status (0-1 vs 2), age (<40 years vs ≥40 years), presence of contrast enhancement on MRI, chromosome 1p status (deleted vs non-deleted vs indeterminate), and the treating medical centre, to receive either radiotherapy (50·4 Gy in 28 fractions of 1·8 Gy for 5 days per week up to 6·5 weeks) or temozolomide chemotherapy (75 mg/m2 daily, for 21 of 28 days [one cycle] for 12 cycles). The primary endpoint was progression-free survival (results published separately); here, we report the results for two key secondary endpoints: HRQOL (assessed using the European Organisation for Research and Treatment of Cancer's [EORTC] QLQ-C30 [version 3] and the EORTC Brain Cancer Module [QLQ-BN20]) and global cognitive functioning (assessed using the Mini-Mental State Examination [MMSE]). We did analyses on the intention-to-treat population. This study is closed and is registered at EudraCT, number 2004-002714-11, and at ClinicalTrials.gov, number NCT00182819. FINDINGS: Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 eligible patients to either radiotherapy (n=240) or temozolomide chemotherapy (n=237). The difference in HRQOL between the two treatment groups was not significant during the 36 months' follow-up (mean between group difference [averaged over all timepoints] 0·06, 95% CI -4·64 to 4·75, p=0·98). At baseline, 32 (13%) of 239 patients who received radiotherapy and 32 (14%) of 236 patients who received temozolomide chemotherapy had impaired cognitive function, according to the MMSE scores. After randomisation, five (8%) of 63 patients who received radiotherapy and three (6%) of 54 patients who received temozolomide chemotherapy and who could be followed up for 36 months had impaired cognitive function, according to the MMSE scores. No significant difference was recorded between the groups for the change in MMSE scores during the 36 months of follow-up. INTERPRETATION: The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low-grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma. FUNDING: Merck Sharp & Dohme-Merck & Co, National Cancer Institute, Swiss Cancer League, National Institute for Health Research, Cancer Research UK, Canadian Cancer Society Research Institute, National Health and Medical Research Council, European Organisation for Research and Treatment of Cancer Cancer Research Fund.

Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033): a randomised, open-label, phase 3 intergroup study.

BACKGROUND: Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors. METHODS: For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged >40 years, progressive disease, tumour size >5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50·4 Gy; 28 doses of 1·8 Gy once daily, 5 days per week for up to 6·5 weeks) or dose-dense oral temozolomide (75 mg/m2 once daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age (<40 vs ≥40 years), and WHO performance status (0 vs ≥1). Patients, treating physicians, and researchers were aware of the assigned intervention. A planned analysis was done after 216 progression events occurred. Our primary clinical endpoint was progression-free survival, analysed by intention-to-treat; secondary outcomes were overall survival, adverse events, neurocognitive function (will be reported separately), health-related quality of life and neurological function (reported separately), and correlative analyses of progression-free survival by molecular markers (1p/19q co-deletion, MGMT promoter methylation status, and IDH1/IDH2 mutations). This trial is closed to accrual but continuing for follow-up, and is registered at the European Trials Registry, EudraCT 2004-002714-11, and at ClinicalTrials.gov, NCT00182819. FINDINGS: Between Sept 23, 2005, and March 26, 2010, 707 patients were registered for the study. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 patients to receive either radiotherapy (n=240) or temozolomide chemotherapy (n=237). At a median follow-up of 48 months (IQR 31-56), median progression-free survival was 39 months (95% CI 35-44) in the temozolomide group and 46 months (40-56) in the radiotherapy group (unadjusted hazard ratio [HR] 1·16, 95% CI 0·9-1·5, p=0·22). Median overall survival has not been reached. Exploratory analyses in 318 molecularly-defined patients confirmed the significantly different prognosis for progression-free survival in the three recently defined molecular low-grade glioma subgroups (IDHmt, with or without 1p/19q co-deletion [IDHmt/codel], or IDH wild type [IDHwt]; p=0·013). Patients with IDHmt/non-codel tumours treated with radiotherapy had a longer progression-free survival than those treated with temozolomide (HR 1·86 [95% CI 1·21-2·87], log-rank p=0·0043), whereas there were no significant treatment-dependent differences in progression-free survival for patients with IDHmt/codel and IDHwt tumours. Grade 3-4 haematological adverse events occurred in 32 (14%) of 236 patients treated with temozolomide and in one (<1%) of 228 patients treated with radiotherapy, and grade 3-4 infections occurred in eight (3%) of 236 patients treated with temozolomide and in two (1%) of 228 patients treated with radiotherapy. Moderate to severe fatigue was recorded in eight (3%) patients in the radiotherapy group (grade 2) and 16 (7%) in the temozolomide group. 119 (25%) of all 477 patients had died at database lock. Four patients died due to treatment-related causes: two in the temozolomide group and two in the radiotherapy group. INTERPRETATION: Overall, there was no significant difference in progression-free survival in patients with low-grade glioma when treated with either radiotherapy alone or temozolomide chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive effects of different molecular subtypes for future individualised treatment choices. FUNDING: Merck Sharpe & Dohme-Merck & Co, Canadian Cancer Society, Swiss Cancer League, UK National Institutes of Health, Australian National Health and Medical Research Council, US National Cancer Institute, European Organisation for Research and Treatment of Cancer Cancer Research Fund.

Role of Adjuvant Radiation Therapy After Surgery for Abdominal Desmoplastic Small Round Cell Tumors.

PURPOSE: To identify the prognostic role of adjuvant abdominal radiation therapy (RT) on oncologic outcomes as a part of multimodal treatment in the management of desmoplastic small round cell tumor (DSRCT) and to determine its impact according to the quality of surgical resection. METHODS AND MATERIALS: All patients treated for primary abdominal DSRCT in 8 French centers from 1991 to 2014 were included. Patients were retrospectively staged into 3 groups: group A treated with adjuvant RT after cytoreductive surgery, group B without RT after cytoreductive surgery, and group C by exclusive chemotherapy. Peritoneal progression-free survival (PPFS), progression-free survival (PFS), and overall survival (OS) were evaluated. We also performed a direct comparison between groups A and B to evaluate RT after cytoreductive surgery. Radiation therapy was also evaluated according to completeness of surgery: complete cytoreductive surgery (CCS) or incomplete cytoreductive surgery (ICS). RESULTS: Thirty-seven (35.9%), thirty-six (34.9%), and thirty (28.0%) patients were included in groups A, B, and C, respectively. Three-year OS was 61.2% (range, 41.0%-76.0%), 37.6% (22.0%-53.1%), and 17.3% (6.3%-32.8%) for groups A, B, and C, respectively. Overall survival, PPFS, and PFS differed significantly among the 3 groups (P<.001, P<.001, and P<.001, respectively). Overall survival and PPFS were higher in group A (RT group) compared with group B (no RT group) (P=.045 and P=.006, respectively). Three-year PPFS was 23.8% (10.3%-40.4%) for group A and 12.51% (4.0%-26.2%) for group B. After CCS, RT improved PPFS (P=.024), but differences in OS and PFS were not significant (P=.40 and P=.30, respectively). After ICS, RT improved OS (P=.044). A trend of PPFS and PFS increase was observed, but the difference was not statistically significant (P=.073 and P=.076). CONCLUSIONS: Adjuvant RT as part of multimodal treatment seems to confer oncologic benefits for patients treated for abdominal DSRCT after cytoreductive surgery and perioperative chemotherapy.

Brain metastases from thyroid carcinoma: a retrospective study of 21 patients.

BACKGROUND: Brain metastases (BM) from differentiated thyroid carcinoma (DTC) are uncommon, and many questions about their management remain unsolved. The objective of this retrospective study was to analyze the characteristics, treatments, and outcomes of patients with BM from DTC. METHODS: Among the 1523 patients with a DTC prospectively recorded in institutional databases between 1989 and 2012, 21 patients (1.4%) with BM were retrospectively retrieved. Patient characteristics, histological findings on initial thyroidectomy specimen, treatments, and time to death were reviewed. Overall survival (OS) was calculated using the Kaplan-Meier method. Survival curves for various subgroups of patients according to baseline characteristics and treatment received were compared. RESULTS: The mean age at initial and BM diagnosis was, respectively, 52.7 and 63.2 years. World Health Organization performance status (PS) at BM diagnosis was good (<2) for 12 patients and poor (≥2) for 9. The initial carcinoma was papillary for 12 patients, follicular for 5, and poorly differentiated for 4. Eighteen patients had other previous and/or synchronous distant metastases: lung (11), bone (10), and others (2 peritoneum, 1 liver, 1 adrenal gland, and 1 uterine cervix). The average interval between the first metastasis and the BM was 3 years (range 0-35.6 years). The mean number and the mean size of BM were, respectively, 2.8 (range 1-10) and 22.5 mm (range 3-44 mm). Surgery was performed for 10 patients and radiotherapy (RT) for 18, with 2 stereotactic radiosurgery (SRS), 2 conformal RT limited to the metastasis, and 15 whole-brain RT. The median OS after BM was 7.1 months. OS at 1 and 2 years were 41.6% and 35.6%. PS and realization of surgery or SRS had an impact on survival, with OS of 27 months when PS <2 versus 3 months when PS ≥2 (p=0.0009), and OS of 11.9 months after surgery or SRS versus 3.6 months in their absence (p=0.04). CONCLUSIONS: BM from thyroid cancer may have an indolent evolution with survival of one to two years or longer for specific groups of patients. Therefore, aggressive treatment options such as neurosurgery and RT should be strongly considered in patients with good PS.

High-dose pre-operative helical tomotherapy (54 Gy) for retroperitoneal liposarcoma.

PURPOSE: To evaluate the feasibility of pre-operative radiotherapy (54 Gy) with Helical Tomotherapy (HT) followed by surgery. METHODS AND MATERIALS: Ten patients with non-metastatic resectable retroperitoneal liposarcomas were treated by pre-operative tomotherapy (54 Gy) and surgery. Clinical and biological toxicities were evaluated on the CTCAEV3.0 scale. For nine patients, delivered tomotherapy plans were compared with retrospectively-planned dynamic intensity-modulated radiotherapy (IMRT) dosimetric studies. RESULTS: No immediate or late Grade>2 toxicities were observed after radiotherapy. Post-operatively, one patient died and three patients experienced Grade 3 toxicity (two digestive and one metabolic). These toxicities disappeared and only two patients presented persistent Grade 1 paresthesia. R0 resection was obtained for four patients, R1 for four, and R2 resection for two. With a median follow-up of 26 months, no local or metastatic relapse was observed. Dosimetric comparisons between HT and retrospectively-planned IMRT demonstrate adequate target volume coverage for both techniques. Gastrointestinal sparing is higher with HT with a D200cc reduced by 5 Gy. Integral dose (ID) was increased in HT. CONCLUSIONS: High dose pre-operative radiotherapy (54 Gy) for retroperitoneal liposarcoma is feasible and mostly well tolerated. Cumulative toxicity and tolerance depend mainly on patient's general status. Image-guided radiation therapy (IGRT) is essential, irrespective of the IMRT technique used. Furthermore, HT offers the possibility of sparing selected areas in such complex volumes.

The updated ESTRO core curricula 2011 for clinicians, medical physicists and RTTs in radiotherapy/radiation oncology.

INTRODUCTION: In 2007 ESTRO proposed a revision and harmonisation of the core curricula for radiation oncologists, medical physicists and RTTs to encourage harmonised education programmes for the professional disciplines, to facilitate mobility between EU member states, to reflect the rapid development of the professions and to secure the best evidence-based education across Europe. MATERIAL AND METHODS: Working parties for each core curriculum were established and included a broad representation with geographic spread and different experience with education from the ESTRO Educational Committee, local representatives appointed by the National Societies and support from ESTRO staff. RESULTS: The revised curricula have been presented for the ESTRO community and endorsement is ongoing. All three curricula have been changed to competency based education and training, teaching methodology and assessment and include the recent introduction of the new dose planning and delivery techniques and the integration of drugs and radiation. The curricula can be downloaded at http://www.estro-education.org/europeantraining/Pages/EuropeanCurricula.aspx. CONCLUSION: The main objective of the ESTRO core curricula is to update and harmonise training of the radiation oncologists, medical physicists and RTTs in Europe. It is recommended that the authorities in charge of the respective training programmes throughout Europe harmonise their own curricula according to the common framework.

Two-year clinical experience with tomotherapy: the French national cancer institute project on implementing new technology.

The pooled 2-year clinical experience using three tomotherapy units installed in France in 2007 is presented. Treatment indications and protocols were devised for each disease site and were the result of a consensus. A total of 642 patients were treated for central nervous system, head and neck, thoracic, abdominal, and pelvic tumors. Overall, grade 3, 4, and 5 acute toxicity was 10.7%, 0.3%, and 0.2%, respectively. Grade 3 chronic toxicity was 1.2%. There was no grade 4 or 5 chronic toxicity. The use of tomotherapy in a broad clinical practice is safe, and acute and chronic toxicity both are acceptable for all anatomical locations.

[Radiation therapy in France in 2010]. / La radiothérapie en France en 2010.

Radiation therapy contributes, with others therapeutic means, to cure many cancers without mutilation and sparing conservative functions. In France, in 2010, about 180,000 patients underwent external radiation therapy in 177 centers assumed by 660 radiation oncologists. Many progress and changes have been made during the past years with the implementation of new techniques as conformal and intensity modulated techniques. Renewal of innovative treatment machines is rapidly ongoing. Since 2007, after medical accidents, quality and security policies have been improved and coordinated to a national level with the active cooperation of the main institutional and professional partners. The new national "Plan Cancer 2009-2013" leads to improvement for patients to access to innovative and safe treatments and to clinical research.

"Metronomic" chemotherapy in advanced soft tissue sarcomas.

PURPOSE: Angiogenesis plays a crucial role in metastatic progression of soft tissue sarcomas (STS). Endothelial cells are the primary target of metronomic chemotherapy. We report the safety and the efficacy of metronomic chemotherapy in metastatic STS patients. METHODS: The medical charts of 26 metastatic STS patients treated at Institut Bergonie (Bordeaux, France) with metronomic etoposide (100 mg/day orally for 21 consecutive days, repeated every 4 weeks) were reviewed by two independent investigators. RESULTS: Median age was 49. All but three patients received prior treatment with doxorubicin and/or ifosfamide. One patient (4%) had partial response and 11 patients (42%) had stable disease for more than 24 weeks. The 6-month and the 1-year progression-free survival rates were 42% [95% CI: 23; 61] and 23% [95% CI: 7; 39], respectively. The 6-month and the 1-year overall survival rates were 69% [95% CI: 51; 87] and 31% [95% CI: 13; 49], respectively. Two patients experienced grade 4 febrile neutropenia and one of them died of sepsis. CONCLUSION: In this series, metronomic etoposide was associated with significant clinical activity in STS. Further prospective investigations are necessary to identify those patients who are more likely to benefit from this strategy.

Comparison between CT- and FDG-PET-defined target volumes for radiotherapy planning in head-and-neck cancers.

Nine patients with head-and-neck cancer underwent computerized tomography (CT) simulation and [(18)F]-fluorodeoxyglucose positron emission tomography (FDG-PET) to compare the radiotherapy target volumes. The PET volumes were delineated with an automatic segmentation based on the source-to-background ratio. The volume comparison showed a reduction and qualitative discrepancies between the PET- and CT-volumes.