A. Laprie

αvβ3 Integrin and Fibroblast growth factor receptor 1 (FGFR1): Prognostic factors in a phase I–II clinical trial associating continuous administration of Tipifarnib with radiotherapy for patients with newly diagnosed glioblastoma

BACKGROUNDnBased on our previous results showing the involvement of the farnesylated form of RhoB in glioblastoma radioresistance, we designed a phase II trial associating the farnesyltransferase inhibitor Tipifarnib with radiotherapy in patients with glioblastoma and studied the prognostic values of the proteins which we have previously shown control this pathway.nnnPATIENTS AND METHODSnPatients were treated with 200mg Tipifarnib (recommended dose (RD)) given continuously during radiotherapy. Twenty-seven patients were included in the phase II whose primary end-point was time to progression (TTP). Overall survival (OS) and biomarker analysis were secondary end-points. Expressions of αvβ3, αvβ5 integrins, FAK, ILK, fibroblast growth factor 2 (FGF2) and fibroblast growth factor receptor 1 (FGFR1) were studied by immuno-histochemistry in the tumour of the nine patients treated at the RD during the previously performed phase I and on those of the phase II patients. We evaluated the correlation of the expressions of these proteins with the clinical outcome.nnnRESULTSnFor the phase II patients median TTP was 23.1 weeks (95%CI = [15.4; 28.2]) while the median OS was 80.3 weeks (95%CI = [57.8; 102.7]). In the pooled phase I and II population, median OS was 60.4 w (95%CI = [47.3; 97.6]) while median TTP was 18.1 w (95%CI = [16.9; 25.6]). FGFR1 over-expression (HR = 4.65; 95%CI = [1.02; 21.21], p = 0.047) was correlated with shorter TTP while FGFR1 (HR = 4.1 (95% CI = [1.09-15.4]; p = 0.036)) and αvβ3 (HR = 10.38 (95%CI = [2.70; 39.87], p = 0.001)) over-expressions were associated with reduced OS.nnnCONCLUSIONnAssociation of 200mg Tipifarnib with radiotherapy shows promising OS but no increase in TTP compared to historical data. FGFR1 and αvβ3 integrin are independent bad prognostic factors of OS and TTP.

OC-0308: Identification of significant biological subvolumes from MRI in pediatric ependymoma related to treatment outcome

Despite late complications related to radiation therapy, RT remains a standard component of treatment among pediatric patients. The current aim of many pediatric clinical trials is to reduce dose and volume of irradiation to decrease side effects without affecting the rate of local control using multimodality treatment. Recent advances in radiotherapy technology contribute also to improve therapeutic ratio thanks to better conformal dose distribution and avoidance of surrounding critical structures. Integration of multimodal imaging in target delineation, use of CT for treatment planning (3D conformal radiation therapy) and immobilization devices have significantly decreased clinical and planning target volume margins. Intensity modulated radiation therapy could be particularly useful in cases of complex and large volume closed to critical structures. While high dose to neighboring structures can be selectively decreased by the means of IMRT, low dose is raised in the rest of the body with theoretical increased risk of secondary malignancies or unexpected toxicities related to irradiation of very sensitive organs at risk located at distance of target volume. Number of prospective studies comparing IMRT to 3D CRT is low. However available data suggest that IMRT provided local control equivalent to 3D CRT with favorable short term toxicity profile and reduction of some sequelae. No excess of second tumor is described but followup is still limited. Concerning strategies for management of internal target movement due to respiratory motion, the more widespread modality in pediatric radiotherapy is 4-dimensional CT for radiation. Other techniques such as active breathing control or respiratory gating is not widely widespread because their use is conditioned by collaboration ability and patient age. Up to now stereotactic radiation therapy has been mainly used in childhood for intracranial benign disease by neurosurgeon. However development of non-invasive repositioning system and LINAC dedicated to stereotactic irradiation gives the opportunity of hypofractionated treatment of metastasis or recurrence in previously irradiated field with minimal impact of quality of live in palliative setting. With high precision techniques, reproducibility in daily set-up becomes more critical to prevent geographic misses and image-guided RT (IGRT) has become a common practice of care for children as for the adults. One of the most applied IGRT technique is cone-beam computed tomography (CBCT). A limitation in use of CBCT among pediatric population is the extra dose deposit to critical structures witch is higher in children than in adults. Because of potential of yielding a secondary cancer at long term, it is essential to adapt scanning protocol when CBCT is applied to pediatric cancer patients routinely.

Carcinomes des adolescents et jeunes adultes : quelles spécificités ?

Carcinomas are rare tumors of the adolescent-young adult (AYA) with a different spectrum from those of adults. The most common sites outside of the thyroid is the nasopharynx, salivary gland, colon-rectum and ovaries. If nasopharyngeal carcinoma or salivary gland tumors are good prognosis, others are more reserved prognosis, such as digestive carcinomas, gynecological or midline. The revelation modes are non-specific and depend on the location: mass, tumor syndrome, pain, impaired general condition. The unusual of pediatric carcinomas led to propose a systematic oncogenetic exploration. The medical history of the family, the symptoms and the type of the carcinoma should guide the analysis. In the absence of guidance, analysis of TP53xa0gene and, for carcinomas of the expanded spectrum of the hereditary non-polyposis colorectal cancer (HNPCC) syndrome, the search for mutation of MMR genes (mismatch repair) seems essential. Because of the rarity of these diseases and the absence of homogeneous recommendations, members of the rare tumors committee of the SFCE recommended for the management of these AJA, an histological review by a pathologist familiar with carcinomas of the adult, a double discussion between pediatric and adult oncologists, analysis of adult standards with adaptation to pediatric data, especially in terms of risk of side effects. An advice to a national opinion (by a member of FRACTURE group) or European (group EXPERT) is sometimes necessary in the most complex situations.

SP-0363: Predictive value of MR spectroscopic imaging for relapse site in GBM and integration in a dose-painting trial

Purpose: To review the current status of hypoxia PET imaging for delineating hypoxic volumes (HVs) inside the gross target volume (GTV) and for radiotherapy (RT) outcome prediction. Methods: Hypoxia PET tracers currently used in clinical trials are mainly [F]-FMISO, [F]-FAZA and [F]-HX4. Different image acquisition protocols and methods for delineating HVs will be presented in this talk. Furthermore, results of recent clinical trials will be reviewed where the prognostic value of hypoxia PET imaging before and during RT with respect to outcome as investigated. In our institution, a clinical phase II trial is currently carried out where to date n=33 head and neck cancer patients were included. Patients were examined using dynamic FMISO PET imaging plus conventional FDG PET imaging in addition to planning CT and eventually MRI before the start of RT. HVs were segmented based on parameters derived from the pharmaco-kinetic analysis of the dynamic FMISO PET data. Patients were randomized into two treatment arms. Patients in the experimental arm were treated with a 10% dose escalation to the HV whereas patients in the control arm received standard IMRT treatment with 70 Gy in 35 fractions. Results: Different manual and (semi-)automatic methods for HV delineation based on hypoxia PET data have been used in clinical studies, such as thresholding, tumour-to-background ratio (TBR) based methods, advanced automatic methods or delineations based on dynamic PET imaging. Different contouring techniques for HV definition may result in strongly varying volumes. Recently published clinical trials confirm the prognostic character of hypoxia PET imaging. However, no consensus was found yet with regard to the timing of the hypoxia PET examination. Some studies found that pretreatment hypoxia PET information was correlated to outcome whereas others stated that hypoxia PET data acquired two weeks into RT had prognostic value. For our hypoxia dose painting trial, a planned interim analysis was carried out after recruiting n=20 patients. Median followup time for this group was 36 (11 52) months. 5 patients did not show any tumour hypoxia (HV = 0 mL). The mean HV of the hypoxic tumours was 8.6 mL (0.3 – 49.2 mL). Furthermore, data acquired in this study could confirm a prognostic model relating TCP to a measure derived from dynamic FMISO PET imaging acquired before the start of RT. Conclusion: Hypoxia PET imaging is a very promising tool for the stratification of patients into different risk groups and thus a potentially very interesting molecular marker in the advent of biologically adapted, personalized RT. However, a comparison of results from different clinical trials is difficult due to large discrepancies in terms of imaging protocols and data analysis strategies.

OC-0615: Voxel-based perfusion normalisation in GBM patients included in a phase I-II trial of RT/Tipifarnib combination

2.7%, p= 0.041). In the Capox-RT group, 85.7% (191/223) patients received radiotherapy on schedule and 74.9% (166/223) with concurrent chemotherapy on schedule, as did 94.1% (238/253) and 92.1% (233/353) in the Cap-RT group, respectively. Grade 3-4 acute toxicity was observed in 38.1% of patients in the Capox-RT group and in 29.2% in the Cap-RT group (p = 0.041). Grade 3–4 tenesmus was more common in the Capox-RT group than in the Cap-RT group (5.4% vs. 2.0%), as were grade 3–4 nausea (2.2% vs. 0%), grade 3–4 vomiting (1.8% vs. 0%), and grade 3–4 fatigue (3.1% vs. 0.4%). Conclusions: The interim analysis revealed that inclusion of oxaliplatin into capecitabine based postoperative chemoradiotherapy was feasible and could decrease cumulative locoregional recurrence rate for patients with locally advanced rectal cancer.