Aymeri Huchet

PLASMA Flt-3 LIGAND CONCENTRATION CORRELATED WITH RADIATION-INDUCED BONE MARROW DAMAGE DURING LOCAL FRACTIONATED RADIOTHERAPY

PURPOSE To determine whether variations in the plasma Flt-3 ligand (FL) concentration after radiotherapy (RT) may serve as a biomarker for radiation-induced bone marrow damage. METHODS AND MATERIALS Twenty-seven patients were followed during RT. The irradiated bone marrow volume was determined. The blood cell counts and plasma FL concentrations were evaluated before and after RT. The expression of membrane-bound FL and mRNA expression were also defined in circulating blood cells. RESULTS We found a negative correlation between the plasma FL concentration and the number of circulating white blood cells and platelets during RT. Moreover, the overall amount of FL in the blood of patients during RT correlated directly with both the cumulated radiation dose and the proportion of irradiated bone marrow. CONCLUSIONS We demonstrated that the variations in plasma FL concentration directly reflect the radiation-induced bone marrow damage during fractionated local RT. We suggest a possible use for FL monitoring as a means to predict the occurrence of Grade 3-4 leukopenia or thrombocytopenia during the course of RT.

Methotrexate and temozolomide versus methotrexate, procarbazine, vincristine, and cytarabine for primary CNS lymphoma in an elderly population: an intergroup ANOCEF-GOELAMS randomised phase 2 trial

BACKGROUND No standard chemotherapy regimen exists for primary CNS lymphoma, reflecting an absence of randomised studies. We prospectively tested two promising methotrexate-based regimens, one more intensive and a milder regimen, for primary CNS lymphoma in the elderly population, who account for most patients. METHODS In this open-label, randomised phase 2 trial, done in 13 French institutions, we enrolled immunocompetent patients who had neuroimaging and histologically confirmed newly diagnosed primary CNS lymphoma, were aged 60 years and older, and had a Karnofsky performance scale score of 40 or more. Participants were stratified by Karnofsky performance scale score (<60 vs ≥60) and treating institution and randomly assigned (1:1) to receive methotrexate (3·5 g/m(2)) with temozolomide (150 mg/m(2)) or methotrexate (3·5 g/m(2)), procarbazine (100 mg/m(2)), vincristine (1·4 mg/m(2)), and cytarabine (3 mg/m(2)). Neither regimen included radiotherapy; both included prophylactic G-CSF and corticosteroids. The primary endpoint was 1-year progression-free survival. Analysis was intent to treat, in a non-comparative phase 2 trial design. This study is registered with ClinicalTrials.gov, number NCT00503594. FINDINGS Between July 16, 2007, and March 25, 2010, 98 patients were enrolled, of whom 95 were randomly assigned and analysed; 48 to methotrexate with temozolomide and 47 to methotrexate, procarbazine, vincristine, and cytarabine. 1-year progression-free survival was 36% (95% CI 22-50) in the methotrexate, procarbazine, vincristine, and cytarabine group and 36% (22-50) in the methotrexate with temozolomide group; median progression-free survival was 9·5 months (95% CI 5·3-13·8) versus 6·1 months (3·8-11·9), respectively. Objective responses were noted in 82% (95% CI 68-92) of patients in the methotrexate, procarbazine, vincristine, and cytarabine group versus 71% (55-84) of patients in the methotrexate with temozolomide group. Median overall survival was 31 months (95% CI 12·2-35·8) in the methotrexate, procarbazine, vincristine, and cytarabine group and 14 months (8·1-28·4) in the methotrexate with temozolomide group. No differences were noted in toxic effects between the two groups. The most common grades 3 and 4 toxicities in both groups were liver dysfunction (21 [4%] in the the methotrexate and temozolomide group and 18 [38%] in the methotrexate, procarbazine, vincristine, and cytarabine group), lymphopenia (14 [29%] and 14 [30%]), and infection (six [13%] and seven [15%]). To date, 33 (69%) patients in the methotrexate and temozolomide group have died, versus 31 (55%) in the methotrexate, procarbazine, vincristine and cytarabine group. Quality-of-life evaluation (QLQ-C30 and BN20) showed improvements in most domains (p=0·01-0·0001) compared with baseline in both groups. Prospective neuropsychological testing showed no evidence of late neurotoxicity. INTERPRETATION In this study of two different methotrexate-based combination regimens in elderly patients, the efficacy endpoints tended to favour the methotrexate, procarbazine, vincristine, and cytarabine group. Both regimens were associated with similar, moderate toxicity, but quality of life improved with time, suggesting pursuing treatment in these poor prognosis patients is worthwhile. New alternatives are needed to improve response duration in this population. FUNDING Schering-Plough/Merck and French Government.

Descriptive epidemiology of CNS tumors in France: results from the Gironde Registry for the period 2000–2007

An increase in the incidence of CNS tumors has been observed in many countries in the last decades. The reality of this trend has been much debated, as it has happened during a period when computer-assisted tomography and MRI have dramatically improved the detection of these tumors. The Gironde CNS Tumor Registry provides here the first data on CNS tumor incidence and trends in France for all histological types, including benign and malignant tumors, for the period 2000-2007. Incidence rates were calculated globally and for each histological subtype. For trends, a piecewise log-linear model was used. The overall annual incidence rate was found to be 17.6/100 000. Of this rate, 7.9/100 000 were neuroepithelial tumors and 6.0/100 000 were meningiomas. An overall increase in CNS tumor incidence was observed from 2000 to 2007, with an annual percent change (APC) of +2.33%, which was explained mainly by an increase in the incidence of meningiomas over the 8-year period (APC = +5.4%), and also more recently by an increase in neuroepithelial tumors (APC = +7.45% from 2003). The overall increase was more pronounced in women and in the elderly, with an APC peaking at +24.65% in subjects 85 and over. The increase in the incidence rates we observed may have several explanations: not only improvements in registration, diagnosis, and clinical practice, but also changes in potential risk factors.

Effet volume en radiothérapie [II]. Deuxième partie : volume et tolérance des tissus sains

The first part of our work has focused on the relationship between tumor volume and tumor control. Indeed, it is well known that the importance of irradiated volume could be a main parameter of radiation-induced complications. Numerous mathematical models have described the correlation between the irradiated volume and the risk of adverse effects. These models should predict the complication rate of each treatment planning. At the present time late effects have been the most studied. In this report we firstly propose a review of different mathematical models described for volume effect. Secondly, we will discuss whether these theoretical considerations can influence our view of radiation treatment planning optimization.Resume Dans la premiere partie, nous avons evoque la relation entre la taille tumorale et les effets de l’irradiation. Par ailleurs, le volume de tissu sain irradie peut conditionner le risque de complications en radiotherapie. De nombreux modeles mathematiques ont ete appliques a la relation dose–volume–effet afin de predire le risque de complications d’un schema d’irradiation donne. Les modeles les plus developpes concernent les effets tardifs de l’irradiation. Dans un premier temps, pour une meilleure comprehension des mecanismes incrimines dans la relation dose–volume, nous allons faire la revue de la litterature concernant un certain nombre de modeles predictifs. Dans un second temps nous tenterons d’evaluer l’impact de la prise en compte de cet effet volume sur l’optimisation de la planification des traitements par radiations ionisantes.

Unique case of malignant transformation of a vestibular schwannoma after fractionated radiotherapy.

OBJECTIVE Malignant transformation of vestibular schwannoma is considered a rare clinical entity. Radiotherapy, as a treatment option for vestibular schwannoma, is regarded as a potential risk factor for secondary malignancy. Recently, radiotherapy with dose fractionation has been proposed, intended to diminish the risk of radiation-induced neuropathy. CASE PRESENTATION The aim of the present study is to report the first case, to the best of our knowledge, of malignant transformation of a residual vestibular schwannoma 19 years after fractionated radiotherapy, describing its characteristics with regard to those previously reported in the literature. CONCLUSIONS The main purpose of the present work is to state that the knowledge of the iatrogenic potential pitfalls of any technique of radiotherapy in clinical oncology is becoming a necessity. Finally, our report demonstrates that the irradiated patients must be monitored for life because a secondary malignancy may appear after a very long delay.

Paediatric brain tumours: A review of radiotherapy, state of the art and challenges for the future regarding protontherapy and carbontherapy.

BACKGROUND AND PURPOSE Brain tumours are the most frequent solid tumours in children and the most frequent radiotherapy indications in paediatrics, with frequent late effects: cognitive, osseous, visual, auditory and hormonal. A better protection of healthy tissues by improved beam ballistics, with particle therapy, is expected to decrease significantly late effects without decreasing local control and survival. This article reviews the scientific literature to advocate indications of protontherapy and carbon ion therapy for childhood central nervous system cancer, and estimate the expected therapeutic benefits. MATERIALS AND METHODS A systematic review was performed on paediatric brain tumour treatments using Medline (from 1966 to March of 2014). To be included, clinical trials had to meet the following criteria: age of patients 18 years or younger, treated with radiation, and report of survival. Studies were also selected according to the evidence level. A secondary search of cited references found other studies about cognitive functions, quality of life, the comparison of photon and proton dosimetry showing potential dose escalation and/or sparing of organs at risk with protontherapy; and studies on dosimetric and technical issues related to protontherapy. RESULTS A total of 7051 primary references published were retrieved, among which 40 clinical studies and 60 papers about quality of life, dose distribution and dosimetry were analysed, as well as the ongoing clinical trials. These papers have been summarized and reported in a specific document made available to the participants of a final 1-day workshop. Tumours of the meningeal envelop and bony cranial structures were excluded from the analysis. Protontherapy allows outstanding ballistics to target the tumour area, while substantially decreasing radiation dose to the normal tissues. There are many indications of protontherapy for paediatric brain tumours in curative intent, either for localized treatment of ependymomas, germ-cell tumours, craniopharyngiomas, low-grade gliomas; or panventricular irradiation of pure non-secreting germinoma; or craniospinal irradiation of medulloblastomas and metastatic pure germinomas. Carbon ion therapy is just emerging and may be studied for highly aggressive and radioresistant tumours, as an initial treatment for diffuse brainstem gliomas, and for relapse of high-grade gliomas. CONCLUSION Both protontherapy and carbon ion therapy are promising for paediatric brain tumours. The benefit of decreasing late effects without altering survival has been described for most paediatric brain tumours with protontherapy and is currently assessed in ongoing clinical trials with up-to-date proton devices. Unfortunately, in 2015, only a minority of paediatric patients in France can receive protontherapy due to the lack of equipment.

Monitoring of residual hematopoiesis after total body irradiation in humans as a model for accidental x-ray exposure: dose-effect and failure of ex vivo expansion of residual stem cells in view of autografting.

PURPOSE To evaluate the residual hematopoiesis at different levels of total body irradiation (TBI) dose in bone marrow (BM) and peripheral blood (PB), and to study the dose-effect relationship on hematopoietic immature and mature progenitors. We also investigated the possibility of expanding ex vivo the residual progenitors exposed to different dose levels of TBI. METHODS AND MATERIALS Eight patients treated for AML (n = 3) and myeloma (n = 5) were included. BM and PB samples were harvested before TBI and after doses of: <or=2 Gy, 2.1-5 Gy, and >5 Gy. Mononuclear cells (MNCs) were assayed for burst-forming unit erythroid (BFU-E), granulocyte-forming unit macrophage (CFU-GM), and long-term culture initiating cells (LTC-ICs). Ex vivo expansion: MNCs (after irradiation and controls) were suspended in long-term cultures and expanded with a combination of five cytokines. RESULTS CD34+ cells were detectable at 10 Gy. We observed a significant decrease of CFU-GM and BFU-E, respectively, to 13.5% and 8.5% of baseline values for doses <or=2 Gy and to 8.2% and 4.6% for doses ranging between 2.1 and 5 Gy. No dose effect was observed for residual MNCs. LTC-ICs were not detectable after 0.8 Gy. The expansion was not successful after 1.2 Gy. CONCLUSION This study confirms the significant decrease of human mature and immature progenitors in BM and PB immediately after low-dose TBI. In addition, the lack of expansion suggests that autografting using BM or PB residual stem cells collected and expanded in vitro in case of accidental whole body exposure may be impractical.

Inflammatory Myofibroblastic Tumour of the Skull Base

Inflammatory myofibroblastic tumors (IMTs) are rare benign clinical and pathological entities. IMTs have been described in the lungs, abdomen, retroperitoneum, and extremities but rarely in the head and neck region. A 38-year-old man presented with headache, right exophthalmia, and right 6th nerve palsy. A CT scan revealed enlargement of the right cavernous sinus and osteolytic lesions of the right sphenoid and clivus. MR imaging showed a large tumor of the skull base which was invading the sella turcica, right cavernous sinus, and sphenoidal sinus. A biopsy was performed and revealed an IMT. Corticosteroids were given for 3 months but were inefficient. In the framework of our pluridisciplinary consultation, fractionated conformal radiotherapy (FRT) was indicated at a low dose; 20 Gy in 10 fractions of 2 Gy over 12 days were delivered. Clinical response was complete 3 months after FRT. Radiological response was subtotal 6 months after FRT. Two years later, the patient is well.

Patterns of failure after radiotherapy for pediatric patients with intracranial ependymoma

PURPOSE To investigate the patterns of failure after radiotherapy for pediatric intracranial ependymoma and their correlation with dose parameters. METHODS Between 2000 and 2013, 206 patients were treated in France. MRI scans at relapse were registered to the original planning CTs for topographic analysis of failure patterns. To compare relapse patients (RP) with non relapse patients (NRP), several dose parameters were derived from dose volume histograms. RESULTS Over a median follow-up of 53.8months, 84 patients presented with relapse. Topographic analysis showed 50 patients with local relapse in the radiation field, 6 in the edge of field, 6 locoregional outside the field, 10 in the spine, 5 supratentorial and 7 local and distant. The median coverage, target coverage and homogeneity indices did not differ significantly between RP and NRP. The median volume of in-field relapse was 1.25cc [0.11, 27], with a median dose of 57.83Gy [50.04, 61.69]. CONCLUSIONS Local relapse in the tumor bed and the higher dose regions was the predominant pattern of failure. Improving coverage of the target volume and increasing the dose to the high radioresistant regions, taking into consideration other clinical and biological pronostic factors, may be an effective way of reducing local failures.

Dose de tolérance à l’irradiation des tissus sains : l’os chez l’adulte

Radiation tolerance for bone tissue has been mostly evaluated with regard to bone fracture. Main circumstances are mandibula osteoradionecrosis, hip and costal fracture, and patent or radiologic fractures in the treated volume. After radiation therapy of bone metastasis, the analysis of related radiation fracture is difficult to individualize from a pathologic fracture. Frequency of clinical fracture is less than 5% in the large series or cohorts and is probably underevaluated for the asymptomatic lesions. Women older than 50 years and with osteoporosis are probably the main population at risk. Dose-effect relations are difficult to qualify in older series. Recent models evaluating radiations toxicity on diaphysa suggest an important risk after 60 Gy, for high dose-fraction and for a large volume.