[Radiation dose intensification for glioblastoma]. / Majoration de dose d'irradiation pour les glioblastomes.

Glioblastoma is the most common brain tumor in adults; its treatment includes surgical excision or biopsy followed by radio-chemotherapy. Even if radiotherapy increases the survival of all patients regardless of their age or their general condition, there are always sources of radioresistance, where relapses occur and therefore treatment fails. Indeed, these foci result in a local relapse, which is observed in 95% of cases in the irradiation fields. We will describe here the current approaches to overcome this radioresistance by dose escalation, without or with guidance by metabolic and functional imaging (dose-painting). We will detail several prospective trials including the French phase III trial, SPECTRO-GLIO, randomizing the use of an integrated boost guided by spectrometric magnetic resonance imaging and similar trials developed across the Atlantic. We will also discuss approaches using different PET markers as well as diffusion or perfusion magnetic resonance imaging.

DNA repair inhibitors and radiotherapy.

Radiotherapy (RT) is one of the main cancer treatments and grows in importance due to improved techniques. DNA damage caused by ionizing radiation creates DNA strand breaks that trigger an intervention of DNA repair pathways involving numerous proteins and enzymes. In recent years, we have identified DNA repair inhibitors as targets for inhibiting cellular repair systems and thus causing cell death. Combining RT with these DNA repair inhibitors appears to be a new approach for cancer treatment, but safety and real efficiency of this combination in practice is unclear. Numerous trials are underway in various diseases and initial results are promising overall, yet remain controversial.

Specificities of clinical research in radiotherapy.

The aim of this review is to present the specificities of clinical research in radiation oncology. Objectives are similar to all research in oncology: to improve the efficacy and to decrease toxic effects. Phase III trials remain the main methodology to demonstrate an improvement in efficiency, but phase I-II and registers are also important tools to validate an improvement in the therapeutic index with new technologies. In this article we discuss the special features of end-points, selection of population, and design for radiation oncology clinical trials. Quality control of delivered treatments is an important component of these protocols. Financial issues are also discussed, in the particular context of France.

RadioTransNet: Preclinical research network coordinated at the SFRO and SFPM.

The RadioTransNet programme launched under the auspices of French societies for radiation oncology (SFRO) and medical physics (SFPM) was approved by the French national cancer institute (INCa) in December 2018 and is dedicated to proposing a relevant national and transversal structure for preclinical research including translational research in radiation oncology with well-defined priority areas of research. Its activities, coordinated by a scientific committee that includes radiation oncologists, medical physicists, academic biologists, are structured around several main areas, i.e.: target volume definition, interaction of radiation with normal tissues, combined treatments and modern dose calculation approaches. Four work packages have been created in these areas and are associated with other objectives pertaining to fundamental radiobiology, early implementation of new drugs in a preclinical setting, contribution of imaging in this task, research in medical physics including transversal components such as medical oncology, radiology, nuclear medicine and also cost/efficiency evaluation. All these tasks will be included in a national network that uses the complementary expertise provided by partners involved in the scheme. Calls for proposals will be selected by the scientific council to be submitted to INCa and the various academic associations to obtain funding for the human and technical resources required to conduct under optimal conditions projects in preclinical and translational research in radiation-oncology.

Evaluation of two modalities of perioperative treatment in the management of extremity and truncal soft tissue sarcomas: neoadjuvant concurrent chemoradiotherapy and sequential treatment.

PURPOSE: Patients with locally advanced grade 2-3 extremity/truncal soft tissue sarcomas (STS) are at high risk of recurrence. The objective of this study was to assess the efficacy and feasibility of neoadjuvant concurrent chemoradiotherapy (cCRT) in selected grade 2-3 patients with limb or trunk wall STS, and to compare this schedule to a sequential approach combining neoadjuvant chemotherapy and adjuvant radiotherapy. METHODS: We retrospectively included patients who underwent neoadjuvant cCRT at two comprehensive cancer centers from 1992-2016. We then compared these results to those of patients treated with preoperative chemotherapy and postoperative radiotherapy from a third comprehensive cancer center with a propensity score matched analysis. RESULTS: A total of 53 patients were treated by neoadjuvant cCRT; 58 patients could be matched with 29 patients in each treatment group after propensity score matching. Disease-free survival and overall survival at 5 years were 54.9 and 63.5%, respectively with neoadjuvant cCRT, with no significant difference when compared to the sequential treatment group. R0 resection rate was higher (90.9 vs 44.8%, p < 0.01) in the cCRT group than in the sequential treatment group during a shorter therapeutic sequence (118 vs 210.5 days, p < 0.01), with no impact on the surgical procedure or postoperative complications. CONCLUSION: cCRT is feasible with acceptable immediate and late toxicities. It could facilitate surgery by increasing the R0 resection rate and improve patient compliance by shortening the therapeutic sequence.

[Radiotherapy and spinal toxicity: News and perspectives]. / Radiothérapie et toxicité médullaire : actualités et perspectives.

Radiation-induced myelopathy is a devastating late effect of radiotherapy. Fortunately, this late effect is exceptional. The clinical presentation of radiation myelopathy is aspecific, typically occurring between 6 to 24 months after radiotherapy, and radiation-induced myelopathy remains a diagnosis of exclusion. Magnetic resonance imaging is the most commonly used imaging tool. Radiation oncologists must be extremely cautious to the spinal cord dose, particularly in stereotactic radiotherapy and reirradiation. Conventionally, a maximum dose of 50Gy is tolerated in normofractionated radiotherapy (1.8 to 2Gy per fraction). Repeat radiotherapies lead to consider cumulative doses above this recommendation to offer individualized reirradiation. Several factors increase the risk of radiation-induced myelopathy, such as concomitant or neurotoxic chemotherapy. The development of predictive algorithms to prevent the risk of radiation-induced myelopathy is promising. However, radiotherapy prescription should be cautious, regarding to ALARA principle (as low as reasonably achievable). As the advent of immunotherapy has improved patient survival data and the concept of oligometastatic cancer is increasing in daily practice, stereotactic treatments and reirradiations will be increasingly frequent indications. Predict the risk of radiation-induced myelopathy is therefore a major issue in the following years, and remains a daily challenge for radiation oncologists.

Radioresistant tumours: From identification to targeting.

From surviving fraction to tumour curability, definitions of tumour radioresistance may vary depending on the view angle. Yet, mechanisms of radioresistance have been identified and involve tumour-specific oncogenic signalling pathways, tumour metabolism and proliferation, tumour microenvironment/hypoxia, genomics. Correlations between tumour biology (histology) and imaging allow theragnostic approaches that use non-invasive biological imaging using tracer functionalization of tumour pathway biomarkers, imaging of hypoxia, etc. Modelling dose prescription function based on their tumour radio-resistant factor enhancement ratio, related to metabolism, proliferation, hypoxia is an area of investigation. Yet, the delivery of dose painting by numbers/voxel-based radiotherapy with low lineal energy transfer particles may be limited by the degree of modulation complexity needed to achieve the doses needed to counteract radioresistance. Higher lineal energy transfer particles or combinations of different particles, or combinations with drugs and devices such as done with radioenhancing nanoparticles may be promising.

Tolerance and efficacy of dose escalation using IMRT combined with chemotherapy for unresectable esophageal carcinoma: Long-term results of 51 patients.

PURPOSE: The optimal dose in esophageal cancer patients treated with definitive chemoradiation (CRT) remains debated. We herein report on the dosimetric results, treatment-related toxicities and long-term outcomes of escalated dose up to 60Gy delivered with intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: All consecutive patients that received a definitive CRT>50Gy for an unresectable esophageal carcinoma between 2010 and 2015 were retrospectively evaluated for this study. Methodology included data base search, delayed toxicity grading, statistical testing including frequency analysis and survival analysis. RESULTS: A total of 51 patients were irradiated for a squamous cell carcinoma (86.3%) or an adenocarcinoma (13.7%). The median age at diagnosis was 62 years. Seven patients were simultaneously irradiated for another synchronous primary tumor. Forty-six patients (90.2%) received concurrent platin-based chemotherapy. The median prescribed doses were 60Gy (54-66) and 48Gy (44.8-56) delivered in 30 (27-35) fractions to the high and the low risks PTV respectively. The mean dose delivered to the lungs was 11.4Gy (IC 95%: 4.8-19.8), the median volumes receiving up to 20Gy (V20) and 30Gy (V30) were 13.5% (3.0-46.0) and 4.6% (0.7-19.8) respectively. The mean dose delivered to the heart was 13.9Gy (IC 95%:0.3-31.3) with a median V40 of 3.3% (0.0-25.0). One treatment-related death occurred within days after RT completion (neutropenic aplasia). After a median follow-up of 2.7 years (95% CI: 1.9-4.3), the 2-year overall survival, disease free survival and loco-regional control rates were 53.6%, 42.0% and 72.8% respectively. Delayed treatment related-toxicities ≤grade 3 occurred among 25 patients (62.5%) mostly esophageal stricture (79.2%). CONCLUSION: We demonstrated in this study that dose escalation using IMRT in combination with platin-based chemotherapy as a definitive treatment for esophageal carcinoma is safe and results in higher loco-regional and control survival when compared to previously reported data.

[RadioTransNet, the French network for preclinical research in oncological radiotherapy]. / RadioTransNet, le réseau national de radiothérapie oncologique préclinique.

The ambition of the RADIOTRANSNET network, launched by the INCa at the end of 2018, is to create a French research consortium dedicated to preclinical radiotherapy to foster scientific and clinical interactions at the interface of radiotherapy and radiobiology, and to identify research priorities dedicated to innovation in radiotherapy. The activities of the network are organized around four major axes that are target definition, normal tissue, combined treatments and dose modelling. Under the supervision of the Scientific Council, headed by a coordinator designated by the SFRO and a co-coordinator designated by the SFPM, three leaders coordinate each axis: a radiation-oncologist, a medical physicist and a biologist, who are responsible for organizing a scientific meeting based on the consensus conference methodology to identify priority issues. The selected themes will be the basis for the establishment of a strategic research agenda and a roadmap to help coordinate national basic and translational research efforts in oncological radiotherapy. This work will be published and will be transmitted to the funding institutions and bodies with the aim of opening dedicated calls to finance the necessary human and technical resources. Structuration of a preclinical research network will allow coordinating the efforts of all the actors in the field and thus promoting innovation in radiotherapy.

[Treatment of patients with brain metastases from a melanoma]. / Prise en charge des patients atteints de métastases cérébrales de mélanome.

Whereas immune checkpoint inhibitors of serine/threonine protein kinase B-raf therapy dramatically changed metastatic outcomes of patients with melanoma, they remain at high risk of brain extension. Additional local treatment can be offered in this situation such as surgery and or stereotactic radiotherapy. In this review article, we describe the different options with published data and their optimal timing.

Subventricular zone involvement at recurrence is a strong predictive factor of outcome following high grade glioma reirradiation.

We aimed to assess the efficacy of stereotactic irradiation for patients with recurrent high-grade glioma (HGG) and identify predictive factors of progression-free survival (PFS) and overall survival (OS) following reirradiation. We identified 32 patients with recurrent brain HGG who had been treated with either single-dose (stereotactic radiosurgery) or fractionated stereotactic radiotherapy between April 2008 and October 2015. Median follow up was 21.4 months (range 12.9-23.2) and median PFS was and 3.3 months (95% CI [2.3-4.7]), respectively. OS was 90.40% (95% CI [73.09-96.80]) at 6 months and 79.55% (95% CI [59.9-90.29]) at 12 months. Univariate analysis showed that biological effective dose at isocenter ≤ 76 Gy was a poor prognostic factor for both OS (83.33 vs. 100% at 6 months, p = 0.032) and median PFS (2.7 vs. 4.7 months, p = 0.025), as was gross tumor volume (GTV) above 1 cm3 for OS (86.15 vs. 94.12% at 6 months, p = 0.043). Contact with the subventricular zone (SVZ) was also a poor prognostic factor for median PFS (2.3 vs. 4.7 months, p = 0.002). Multivariate analysis showed that SVZ contact remained a poor prognostic factor for PFS (hazard ratio = 3.44, 95% CI [1.21-9.82], p = 0.021). Results suggest that reirradiation is a safe and effective treatment option for recurrent HGG in patients with a good Karnosfsky Performance Scale score, a long progression-free interval since first radiation and limited GTV, and that contact to SVZ is a strong prognostic factor for PFS.

[Acute toxicity of breast cancer irradiation with modulated intensity by tomotherapy®]. / Toxicité aiguë de la tomothérapie des cancers mammaires.

PURPOSE: Helical radiation intensity modulated by tomotherapy improves dose distribution to complex and large volumes. The aim of the study was to assess acute toxicity of this technique during breast cancer irradiation after conserving surgery or mastectomy. PATIENTS AND METHODS: Cutaneous toxicities, lung and oesophageal side effects, and breast lymphedema were retrospectively collected according to the Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0) in 292 patients treated for a breast cancer by tomotherapy between May 2010 and December 2014. After conservative surgery, the dose administered to breast volume and the tumour bed was respectively 52.2Gy and 63.8Gy in 29 fractions. After mastectomy, the dose was 50Gy in 25 fractions. Univariate and multivariate analyses were performed to highlight risk factors for dermatitis and breast oedema. RESULTS: The rate of dermatitis grade 2 and 3 were 22.9% and 1.7% respectively. In univariate analysis, factors associated with acute radiation dermatitis were breast volume (P=0.002), body mass index (BMI) (P<0.0001), the use of chest compression mask (net) (P=0.005) and the localization of the irradiation (P <0.0001). In multivariate analysis, BMI greater than 25kg/m2 (odds ratio [OR]: 3.61, 95% confidence interval [CI]: [1.93-6.74], P<0.0001), the use of a chest mask (OR 2.01, 95% CI [1.06-3.79] P=0.0328) and irradiation after conservative treatment increase the risk of acute radiation dermatitis (mastectomy: OR 0.64, 95% CI [0.04-0.43]; mastectomy with immediate reconstruction with prosthesis: OR 0.13 95% CI [0.10-0.38] P=0.0003). The incidence of breast oedema grade 2 or above was 19.5%, in univariate analysis, there was a correlation with BMI (P=0.003) and smoking (P=0.009). In multivariate analysis, smoking and BMI greater than 25kg/m2 increased the risk of breast oedema (OR 2.47, respectively [95% CI 1.22-5.01] P=0.012 and OR 2.37 [95% CI 1.22-4.59] P=0.01). The rate of radiation pneumonitis of grade 2 or above was 1.4%. Among the patients, 19.9% had esophagitis grade 1 or 2. CONCLUSION: The helical irradiation intensity modulation tomotherapy is a well-tolerated treatment for breast cancer that reduces the high radiation doses to organs at risk.

Subventricular zones: new key targets for glioblastoma treatment.

BACKGROUND: We aimed to identify subventricular zone (SVZ)-related prognostic factors of survival and patterns of recurrence among patients with glioblastoma. METHODS: Forty-three patients with primary diagnosed glioblastoma treated in our Cancer Center between 2006 and 2010 were identified. All patients received surgical resection, followed by temozolomide-based chemoradiation. Ipsilateral (iSVZ), contralateral (cSVZ) and bilateral (bSVZ) SVZs were retrospectively segmented and radiation dose-volume histograms were generated. Multivariate analysis using the Cox proportional hazards model was assessed to examine the relationship between prognostic factors and time to progression (TTP) or overall survival (OS). RESULTS: Median age was 59 years (range: 25-85). Median follow-up, OS and TTP were 22.7 months (range 7.5-69.7 months), 22.7 months (95% CI 14.5-26.2 months) and 6.4 months (95% CI 4.4-9.3 months), respectively. On univariate analysis, initial contact to SVZ was a poor prognostic factor for OS (18.7 vs 41.7 months, p = 0.014) and TTP (4.6 vs 12.9 months, p = 0.002). Patients whose bSVZ volume receiving at least 20 Gy (V20Gy) was greater than 84% had a significantly improved TTP (17.7 months vs 5.2 months, p = 0.017). This radiation dose coverage was compatible with an hippocampal sparing. On multivariate analysis, initial contact to SVZ and V20 Gy to bSVZ lesser than 84% remained poor prognostic factors for TTP (HR = 3.07, p = 0.012 and HR = 2.67, p = 0.047, respectively). CONCLUSION: Our results suggest that contact to SVZ, as well as insufficient bSVZ radiation dose coverage (V20Gy <84%), might be independent poor prognostic factors for TTP. Therefore, targeting SVZ could be of crucial interest for optimizing glioblastoma treatment.

Identification of a candidate biomarker from perfusion MRI to anticipate glioblastoma progression after chemoradiation.

OBJECTIVE: To identify relevant relative cerebral blood volume biomarkers from T2* dynamic-susceptibility contrast magnetic resonance imaging to anticipate glioblastoma progression after chemoradiation. METHODS: Twenty-five patients from a prospective study with glioblastoma, primarily treated by chemoradiation, were included. According to the last follow-up MRI confirmed status, patients were divided into: relapse group (n = 13) and control group (n = 12). The time of last MR acquisition was tend; MR acquisitions performed at tend-2M, tend-4M and tend-6M (respectively 2, 4 and 6 months before tend) were analyzed to extract relevant variations among eleven perfusion biomarkers (B). These variations were assessed through R(B), as the absolute value of the ratio between ∆B from tend-4M to tend-2M and ∆B from tend-6M to tend-4M. The optimal cut-off for R(B) was determined using receiver-operating-characteristic curve analysis. RESULTS: The fraction of hypoperfused tumor volume (F_hPg) was a relevant biomarker. A ratio R(F_hPg) ≥ 0.61 would have been able to anticipate relapse at the next follow-up with a sensitivity/specificity/accuracy of 92.3 %/63.6 %/79.2 %. High R(F_hPg) (≥0.61) was associated with more relapse at tend compared to low R(F_hPg) (75 % vs 12.5 %, p = 0.008). CONCLUSION: Iterative analysis of F_hPg from consecutive examinations could provide surrogate markers to predict progression at the next follow-up. KEY POINTS: • Related rCBV biomarkers from DSC were assessed to anticipate GBM progression. • Biomarkers were assessed through their patterns of variation during the follow-up. • The fraction of hypoperfused tumour volume (F_hP g ) seemed to be a relevant biomarker. • An innovative ratio R(F_hP g ) could be an early surrogate marker of relapse. • A significant time gain could be achieved in the management of GBM patients.

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.

Progastrin a new pro-angiogenic factor in colorectal cancer.

Angiogenesis is essential in tumor progression and metastatic process, and increased angiogenesis has been associated with poor prognosis and relapse of colorectal cancer (CRC). VEGF has become the main target of anti-angiogenic therapy. However, most patients relapse after an initial response or present a resistance to the treatment. Identification of new pro-angiogenic factors may help to improve anti-angiogenic therapy. In this study, we demonstrated that the pro-hormone progastrin (PG), over-expressed in CRC, recognized as a growth factor, is a potent pro-angiogenic factor. In transgenic mice and human colorectal HPs producing high levels of PG, we correlated PG overexpression with an increased vascularization. In vitro, exogenous PG and conditioned media (CM) from CRC cells producing PG increased endothelial cell proliferation and migration. We also showed that treatment with exogenous PG can increase the ability of endothelial cells to form capillary-like structures. Moreover, we demonstrated that PG enhanced endothelial permeability. The finding that PG stimulated the phosphorylation of vascular endothelial (VE)-cadherin, p125-FAK, paxillin and induced actin remodelling was consistent with a role of these components in PG-stimulated endothelial cell migration and permeability. The pro-angiogenic effects observed with CM were significantly inhibited when CRC cells expressed a PG shRNA. In vivo, we found an important decrease in tumor growth and neovascularization when the CRC cells expressing the PG shRNA were xenografted in mice or in the chick chorioallantoic membrane model. We also observed an increase in the coverage of blood vessels by pericytes and a decrease in endothelial permeability when PG expression was blocked. Our results demonstrate that PG is a new pro-angiogenic factor in CRC and an attractive therapeutic target.

Ionizing radiations sustain glioblastoma cell dedifferentiation to a stem-like phenotype through survivin: possible involvement in radioresistance.

Glioblastomas (GBM) are some bad prognosis brain tumors despite a conventional treatment associating surgical resection and subsequent radio-chemotherapy. Among these heterogeneous tumors, a subpopulation of chemo- and radioresistant GBM stem-like cells appears to be involved in the systematic GBM recurrence. Moreover, recent studies showed that differentiated tumor cells may have the ability to dedifferentiate and acquire a stem-like phenotype, a phenomenon also called plasticity, in response to microenvironment stresses such as hypoxia. We hypothesized that GBM cells could be subjected to a similar dedifferentiation process after ionizing radiations (IRs), then supporting the GBM rapid recurrence after radiotherapy. In the present study we demonstrated that subtoxic IR exposure of differentiated GBM cells isolated from patient resections potentiated the long-term reacquisition of stem-associated properties such as the ability to generate primary and secondary neurospheres, the expression of stemness markers and an increased tumorigenicity. We also identified during this process an upregulation of the anti-apoptotic protein survivin and we showed that its specific downregulation led to the blockade of the IR-induced plasticity. Altogether, these results demonstrated that irradiation could regulate GBM cell dedifferentiation via a survivin-dependent pathway. Targeting the mechanisms associated with IR-induced plasticity will likely contribute to the development of some innovating pharmacological strategies for an improved radiosensitization of these aggressive brain cancers.

[Radiotherapy for brain tumors: which margins should we apply?]. / Radiothérapie des tumeurs cérébrales : quelles marges ?

Radiotherapy is a major modality in the treatment of brain tumours. The target volumes definition has to be precise for the radiation planification. The gross target volume (GTV) is most of the time delineated within the fusion of the planning CT scan with the appropriated MRI sequences. The clinical target volume (CTV) definition is more complex: it varies in time following the evolution of scientific knowledge and also depending of the school of thought. This article offers a review of the literature about the margins applied in brain tumours radiotherapy for gliomas (high grade, anaplastic, low grade and brain stem gliomas), embryologic tumours (medulloblastomas and primitive neuroectodermal tumours [PNET]), ependymomas, atypical teratoid rahbdoid tumours (ATRT), craniopharyngiomas, pineal gland tumours, primary central nervous cell lymphomas, meningiomas and schwannomas. New imaging modalities such as diffusion-weighted imaging, dynamic contrast enhanced, spectroscopic MRI and PET scan will allow us to delineate more precisely the target volumes and to realise dose-painting by adapting the dose to the tumour metabolism.

[From bench to bedside: experience of the glioblastoma model for the optimization of radiosensitization]. / Du laboratoire vers la clinique : expérience du glioblastome pour moduler la radiosensibilité tumorale.

Despite significant progress in the treatment of glioblastoma, the prognosis of these radioresistant, invasive and hypoxic tumours remain dark. The constant relapse after treatment of this tumour is in part due to its intra-cellular but also micro-environmental radioresistance, largely controlled by growth factors and their receptors. The complexity of the biology of these tumours and the presence of numerous cross-talks between the pathways of these different growth factors can be in part responsible for the negative results obtained in clinical trials associating radiotherapy and targeted drugs designed without previous in vitro and in vivo studies validating the proof of concept of a specific target as key factor of radioresistance. In the aim to optimize the treatment of glioblastoma and to reduce the risks of failure of new trials, several laboratories and clinical departments are developing translational research in radiotherapy and radiobiology, validating in vitro and then in orthotopic xenografts interesting targets, then studying the radiosensitizing effect of targeted drugs directed against these proteins, studying the mechanisms of action and resistance of these drugs, validating these proteins as predictive factors of response to radiotherapy in the patients, and then designing clinical trials, integrating metabolic or functional imaging and surrogate markers to better understand the mechanism of action of these associations. We describe in this article the main translational research axis developed for radiosensitizing glioblastoma, which our lab and department have pursued for several years.