Dose-painting multicenter phase III trial in newly diagnosed glioblastoma: the SPECTRO-GLIO trial comparing arm A standard radiochemotherapy to arm B radiochemotherapy with simultaneous integrated boost guided by MR spectroscopic imaging.

BACKGROUND: Glioblastoma, a high-grade glial infiltrating tumor, is the most frequent malignant brain tumor in adults and carries a dismal prognosis. External beam radiotherapy (EBRT) increases overall survival but this is still low due to local relapses, mostly occurring in the irradiation field. As the ratio of spectra of choline/N acetyl aspartate> 2 (CNR2) on MR spectroscopic imaging has been described as predictive for the site of local relapse, we hypothesized that dose escalation on these regions would increase local control and hence global survival. METHODS/DESIGN: In this multicenter prospective phase III trial for newly diagnosed glioblastoma, 220 patients having undergone biopsy or surgery are planned for randomization to two arms. Arm A is the Stupp protocol (EBRT 60 Gy on contrast enhancement + 2 cm margin with concomitant temozolomide (TMZ) and 6 months of TMZ maintenance); Arm B is the same treatment with an additional simultaneous integrated boost of intensity-modulated radiotherapy (IMRT) of 72Gy/2.4Gy delivered on the MR spectroscopic imaging metabolic volumes of CHO/NAA > 2 and contrast-enhancing lesions or resection cavity. Stratification is performed on surgical and MGMT status. DISCUSSION: This is a dose-painting trial, i.e. delivery of heterogeneous dose guided by metabolic imaging. The principal endpoint is overall survival. An online prospective quality control of volumes and dose is performed in the experimental arm. The study will yield a large amount of longitudinal multimodal MR imaging data including planning CT, radiotherapy dosimetry, MR spectroscopic, diffusion and perfusion imaging. TRIAL REGISTRATION: NCT01507506 , registration date December 20, 2011.

Molecular PET imaging in adaptive radiotherapy: brain.

INTRODUCTION: Owing to their heterogeneity and radioresistance, the prognosis of primitive brain tumors, which are mainly glial tumors, remains poor. Dose escalation in radioresistant areas is a potential issue for improving local control and overall survival. This review focuses on advances in biological and metabolic imaging of brain tumors that are proving to be essential for defining tumor target volumes in radiation therapy (RT) and for increasing the use of DPRT (dose painting RT) and ART (adaptative RT), to optimize dose in radio-resistant areas. EVIDENCE ACQUISITION: Various biological imaging modalities such as PET (hypoxia, glucidic metabolism, protidic metabolism, cellular proliferation, inflammation, cellular membrane synthesis) and MRI (spectroscopy) may be used to identify these areas of radioresistance. The integration of these biological imaging modalities improves the diagnosis, prognosis and treatment of brain tumors. EVIDENCE SYNTHESIS: Technological improvements (PET and MRI), the development of research, and intensive cooperation between different departments are necessary before using daily metabolic imaging (PET and MRI) to treat patients with brain tumors. CONCLUSIONS: The adaptation of treatment volumes during RT (ART) seems promising, but its development requires improvements in several areas and an interdisciplinary approach involving radiology, nuclear medicine and radiotherapy. We review the literature on biological imaging to outline the perspectives for using DPRT and ART in brain tumors.

Digestive toxicities after palliative three-dimensional conformal radiation therapy (3D-CRT) for cervico-thoracic spinal metastases.

OBJECTIVE: The palliative treatment for cervico-thoracic spinal metastases is based on a three-dimensional conformal radiation therapy (3D-CRT). Digestive toxicities are common and cause a clinical impact frequently underestimated in patients. We performed a retrospective study of digestive side effects occurring after palliative 3D-CRT for cervico-thoracic spinal metastases. PATIENTS AND METHODS: All patients receiving palliative 3D-CRT at Jean Bernard Center from January 2013 to December 2014 for spinal metastases between the 5th cervical vertebra (C5) and the 12th thoracic vertebra (T12) were eligible. Three-dimensional conformal RT was delivered by a linear accelerator (CLINAC, Varian). Premedication to prevent digestive toxicities was not used. Adverse events ("esophagitis" and "nausea and/or vomiting") were evaluated according to the NCI-CTCae (version 4). RESULTS: From January 2013 to December 2014, 128 patients met the study criteria. The median age was 68.6 years [31.8; 88.6]. Most patients (84.4%) received 30 Gy in 10 fractions. The median overall time of treatment was 13 days [3-33]. Forty patients (31.3%) suffered from grade ≥ 2 of "esophagitis" (35 grade 2 (27.4%) and 5 grade 3 (3.9%)). Eight patients (6.3%) suffered from grade ≥ 2 of "nausea and/or vomiting" (6 grade 2 (4.7%), 1 grade 3 (0.8%), and 1 grade 4 (0.8%)). CONCLUSION: The high incidence of moderate to severe digestive toxicities after palliative 3D-CRT for cervico-thoracic spinal metastases led to consider static or dynamic intensity-modulated radiation therapy (IMRT) to reduce the dose to organ at risk (the esophagus and stomach). Dosimetric studies and implementation in the clinic should be the next steps.

Exclusive concurrent radiochemotherapy for advanced head and neck cancers with 'fractionated' 5-fluorouracil and cisplatin.

Concurrent radiochemotherapy (CRC) is a standard treatment in patients with inoperable locoregionally advanced ear-nose-throat (ENT) cancer. We report the safety and efficacy of CRC with daily fractionated 5-fluorouracil and cisplatin ('F' 5FU-CDDP) in a monocentric retrospective cohort. From January 2006 to August 2012, all patients with unresectable (or inoperable) nonmetastatic locoregionally advanced ENT cancer treated curatively by means of radiotherapy (normal fractionated 70 Gy to the macroscopic tumor and prophylactic 50 Gy) with three courses (week 1-week 4-week 7) of 'F' 5FU-CDDP regimen (800 mg/m/day of 5-fluorouracil and 20 mg/m/day of CDDP from day 1 to day 4) were included. Seventy patients underwent CRC (86% men, median age 58 years old, 100% squamous cell carcinoma, 97% stage III/IV). Fifty-six patients received the three complete courses of chemotherapy with cumulative doses of CDDP of 217 mg/m/patient (dose intensity ratio of 90.5%). After a median follow-up period of 30.7 months, median overall and disease-free survivals were 34.1 [95% confidence interval (CI) (21.6-56.8)] and 50.2 months [95% CI (17.4-NA)] with 71% [95% CI (57.5-81)] and 67% [95% CI (51.8-78.5)] for locoregional control at 2 and 5 years, respectively. In all, 58.5% of grade 3 or higher mucositis and 24% of radioepithelitis were observed, but only 11.5, 3, and 1.5% of grade 3 or higher neutropenia, nephrotoxicity, and neurotoxicity were observed, respectively. No deaths from toxicity occurred. CRC with three courses of 'F' 5FU-CDDP appears effective and could be an alternative to standard CRC treatment. Randomized studies are required to be able to use this treatment regimen routinely.

Treatment of cutaneous and/or soft tissue manifestations of corticosteroids refractory chronic graft versus host disease (cGVHD) by a total nodal irradiation (TNI).

The management of corticosteroids refractory chronic graft versus host disease (cGVHD) remains controversial. Retrospective analysis of patients treated at the Integrated Center of Oncology by total nodal irradiation (TNI) was performed to evaluate its therapy potency. TNI delivers a dose of 1 Gy in a single session. The delimitation of the fields is clinical (upper limit: external auditory meatus; lower limit: mid-femur). No pre-therapeutic dosimetry scanner was necessary. Evaluation of the efficacy was by clinical measures at 6 months after the treatment. Twelve patients were treated by TNI between January 2010 and December 2013. TNI was used in second-line treatment or beyond. The median time between allograft and TNI was 31.2 months, and the median time between the first manifestations of cGVHD and TNI was about 24.2 months. Of the 12 patients, nine had a clinical response at 6 months (75%), including five complete clinical responses (41.6%). Five patients could benefit from a reduction of corticosteroid doses. Three patients had hematologic toxicity. TNI could be considered as an option for the treatment of a cutaneous and/or soft tissues corticosteroids refractory cGVHD. However, prospective randomized and double-blind trials remain essential to answer the questions about TNI safety and effectiveness.

Feasibility and safety of dose-dense modified docetaxel-cisplatin or carboplatin and 5-fluorouracil regimen (mTPF) in locally advanced or metastatic head and neck cancers: a retrospective monocentric study.

BACKGROUND: Docetaxel-cisplatin and 5-fluorouracil (TPF) chemotherapy (days 1-21) represents a standard but toxic regimen for advanced head and neck cancer (HNC). We report a retrospective monocentric study evaluating the safety and the efficacy of a dose-dense modified TPF (mTPF) regimen (days 1-14) in patients with stage III-IV HNC. METHODS: Thirty-seven patients retrospectively included from May 2011 to May 2014 were treated with a bimonthly dose-dense mTPF regimen (40 mg/m(2) docetaxel, 40 mg/m(2) cisplatin or AUC2 carboplatin, folinic acid 400 mg/m(2) for 2 h, bolus 5-FU 400 mg/m(2) for 10 min and 5-FU 1,000 mg/m(2)/day) by continuous infusion over 46 h). RESULTS: Chemotherapy was used as induction or palliative treatment in 12 and 25 patients, respectively, with a median age of 60 years (range 46-83). Median follow-up time was 7.4 months (2.53-16.7 months). There was no intestinal toxicity in 25 patients (68 %). Grade 3-4 hematological toxicity was noticed for 5 (13.5 %) patients. Granulocyte-colony stimulating factor was used as primary prophylaxis in 30 patients (81 %). After at least 4 delivered cycles, complete responses, partial responses and stable diseases were reported in 5 (15 %), 13 (39 %) and 5 (15 %) of the 33 evaluable patients, respectively, yielding an objective response rate of 54.5 % (39 % for palliative chemotherapy and 90 % for induction chemotherapy). CONCLUSION: Dose-dense mTPF (days 1-14) is safe and seems to be as effective as TPF (days 1-21). Future prospective trials are required to confirm our results.

A Multigene Signature Associated with Progression-Free Survival after Treatment for IDH Mutant and 1p/19q Codeleted Oligodendrogliomas.

BACKGROUND: IDH mutant and 1p/19q codeleted oligodendrogliomas are the gliomas associated with the best prognosis. However, despite their sensitivity to treatment, patient survival remains heterogeneous. We aimed to identify gene expressions associated with response to treatment from a national cohort of patients with oligodendrogliomas, all treated with radiotherapy +/- chemotherapy. METHODS: We extracted total RNA from frozen tumor samples and investigated enriched pathways using KEGG and Reactome databases. We applied a stability selection approach based on subsampling combined with the lasso-pcvl algorithm to identify genes associated with progression-free survival and calculate a risk score. RESULTS: We included 68 patients with oligodendrogliomas treated with radiotherapy +/- chemotherapy. After filtering, 1697 genes were obtained, including 134 associated with progression-free survival: 35 with a better prognosis and 99 with a poorer one. Eight genes (ST3GAL6, QPCT, NQO1, EPHX1, CST3, S100A8, CHI3L1, and OSBPL3) whose risk score remained statistically significant after adjustment for prognostic factors in multivariate analysis were selected in more than 60% of cases were associated with shorter progression-free survival. CONCLUSIONS: We found an eight-gene signature associated with a higher risk of rapid relapse after treatment in patients with oligodendrogliomas. This finding could help clinicians identify patients who need more intensive treatment.

Cranial organs at risk delineation: heterogenous practices in radiotherapy planning.

BACKGROUND: Segmentation is a crucial step in treatment planning that directly impacts dose distribution and optimization. The aim of this study was to evaluate the inter-individual variability of common cranial organs at risk (OAR) delineation in neurooncology practice. METHODS: Anonymized simulation contrast-enhanced CT and MR scans of one patient with a solitary brain metastasis was used for delineation and analysis. Expert professionals from 16 radiotherapy centers involved in brain structures delineation were asked to segment 9 OAR on their own treatment planning system. As reference, two experts in neurooncology, produced a unique consensual contour set according to guidelines. Overlap ratio, Kappa index (KI), volumetric ratio, Commonly Contoured Volume, Supplementary Contoured Volume were evaluated using Artiview™ v 2.8.2-according to occupation, seniority and level of expertise of all participants. RESULTS: For the most frequently delineated and largest OAR, the mean KI are often good (0.8 for the parotid and the brainstem); however, for the smaller OAR, KI degrade (0.3 for the optic chiasm, 0.5% for the cochlea), with a significant discrimination (p < 0.01). The radiation oncologists, members of Association des Neuro-Oncologue d'Expression Française society performed better in all indicators compared to non-members (p < 0.01). Our exercise was effective in separating the different participating centers with 3 of the reported indicators (p < 0.01). CONCLUSION: Our study illustrates the heterogeneity in normal structures contouring between professionals. We emphasize the need for cerebral OAR delineation harmonization-that is a major determinant of therapeutic ratio and clinical trials evaluation.

Cost-Effectiveness of Web-Based Patient-Reported Outcome Surveillance in Patients With Lung Cancer.

INTRODUCTION: A multicenter randomized clinical trial in France found an overall survival benefit of web-based patient-reported outcome (PRO)-based surveillance after initial treatment for lung cancer compared with conventional surveillance. The aim of this study was to assess the cost-effectiveness of this PRO-based surveillance in lung cancer patients. METHODS: This medico-economic analysis used data from the clinical trial, augmented by abstracted chart data and costs of consultations, imaging, transportations, information technology, and treatments. Costs were calculated based on actual reimbursement rates in France, and health utilities were estimated based on scientific literature review. Willingness-to-pay thresholds of €30,000 per quality-adjusted life year (QALY) and €90,000 per QALY were used to define a very cost-effective and cost-effective strategy, respectively. Average annual costs of experimental and control surveillance approaches were calculated. The incremental cost-effectiveness ratio was expressed as cost per life-year gained and QALY gained, from the health insurance payer perspective. One-way and multivariate probabilistic sensitivity analyses were performed. RESULTS: Average annual cost of surveillance follow-up was €362 lower per patient in the PRO arm (€941/year/patient) compared to control (€1,304/year/patient). The PRO approach presented an incremental cost-effectiveness ratio of €12,127 per life-year gained and €20,912 per QALY gained. The probabilities that the experimental strategy is very cost-effective and cost-effective were 97% and 100%, respectively. CONCLUSIONS: Surveillance of lung cancer patients using web-based PRO reduced the follow-up costs. Compared to conventional monitoring, this surveillance modality represents a cost-effective strategy and should be considered in cancer care delivery.