Prognostic value of circulating short-length DNA fragments in unresected glioblastoma patients.

BACKGROUND: Liquid biopsy application is still challenging in glioblastoma patients and the usefulness of short-length DNA (slDNA) fragments is not established. The aim was to investigate slDNA concentration as a prognostic marker in unresected glioblastoma patients. METHODS: Patients with unresected glioblastoma and treated by radiochemotherapy (RT/TMZ) were included. Plasmas were prospectively collected at three times: before (pre-) RT, after (post-) RT and at the time of progression. Primary objective was to investigate the impact on survival of slDNA concentration [slDNA] variation during RT/TMZ. Secondary objectives were to explore the association between tumor volume, corticosteroid exposition and [slDNA]; and the impact of slDNA detection at pre-RT on survival. RESULTS: Thirty-six patients were analyzed: 11 patients (30.6 %) experienced [slDNA] decrease during RT/TMZ, 22 patients (61.1 %) experienced increase and 3 patients (8.3 %) had stability. Decrease of [slDNA] during RT/TMZ was associated with better outcome compared to increase or stability: median OS, since end of RT, of 13.2 months [11.4 - NA] vs 10.1 months [7.8 - 12.6] and 6.8 months [4.5 - NA], p = 0.015, respectively. slDNA detection at pre-RT time was associated with improved OS: 11.7 months in the slDNA(+) group versus 8.8 months in the slDNA(-) group, p = 0.004. [slDNA] was not associated with corticosteroids exposition or tumor volume. No influence on survival was observed for both whole cfDNA concentration or slDNA peak size. CONCLUSION: [slDNA] decrease during radiochemotherapy phase is a favorable prognostic marker on OS for unresected glioblastoma patients. Larger and independent cohorts are now required. TRIAL REGISTRATION: ClinicalTrial, NCT02617745. Registered 1 December 2015, https://clinicaltrials.gov/ct2/show/NCT02617745?term=glioplak&draw=2&rank=1.

Target volume delineation for radiotherapy of meningiomas: an ANOCEF consensus guideline.

PURPOSE: Radiotherapy is, with surgery, one of the main therapeutic treatment strategies for meningiomas. No prospective study has defined a consensus for the delineation of target volumes for meningioma radiotherapy. Therefore, target volume definition is mainly based on information from retrospective studies that include heterogeneous patient populations. The aim is to describe delineation guidelines for meningioma radiotherapy as an adjuvant or definitive treatment with intensity-modulated radiation therapy and stereotactic radiation therapy techniques. This guideline is based on a consensus endorsed by a multidisciplinary group of brain tumor experts, members of the Association of French-speaking Neuro-oncologists (ANOCEF). MATERIALS AND METHODS: A 3-step procedure was used. First, the steering group carried out a comprehensive review to identify divergent issues on meningiomas target volume delineation. Second, an 84-item web-questionnaire has been developed to precisely define meningioma target volume delineation in the most common clinical situations. Third, experts members of the ANOCEF were requested to answer. The first two rounds were completed online. A third round was carried out by videoconference to allow experts to debate and discuss the remaining uncertain questions. All questions remained in a consensus. RESULTS: Limits of the target volume were defined using visible landmarks on computed tomography and magnetic resonance imaging, considering the pathways of tumor extension. The purpose was to develop clear and precise recommendations on meningiomas target volumes. CONCLUSION: New recommendations for meningiomas delineation based on simple anatomic boundaries are proposed by the ANOCEF. Improvement in uniformity in target volume definition is expected.

Characterization of positioning uncertainties in PET-CT-MR trimodality solutions for radiotherapy.

The purpose of this study was to evaluate the positioning uncertainties of two PET/CT-MR imaging setups, C1 and C2. Because the PET/CT data were acquired on the same hybrid device with automatic image registration, experiments were conducted using CT-MRI data. In C1, a transfer table was used, which allowed the patient to move from one imager to another while maintaining the same position. In C2, the patient stood up and was positioned in the same radiotherapy treatment position on each imager. The two setups provided a set of PET/CT and MR images. The accuracy of the registration software was evaluated on the CT-MRI data of one patient using known translations and rotations of MRI data. The uncertainties on the two setups were estimated using a phantom and a cohort of 30 patients. The accuracy of the positioning uncertainties was evaluated using descriptive statistics and a t-test to determine whether the mean shift significantly deviated from zero (p < 0.05) for each setup. The maximum registration errors were less than 0.97 mm and 0.6° for CT-MRI registration. On the phantom, the mean total uncertainties were less than 2.74 mm and 1.68° for C1 and 1.53 mm and 0.33° for C2. For C1, the t-test showed that the displacements along the z-axis did not significantly deviate from zero (p = 0.093). For C2, significant deviations from zero were present for anterior-posterior and superior-inferior displacements. The mean total uncertainties were less than 4 mm and 0.42° for C1 and less than 1.39 mm and 0.27° for C2 in the patients. Furthermore, the t-test showed significant deviations from zero for C1 on the anterior-posterior and roll sides. For C2, there was a significant deviation from zero for the left-right displacements.This study shows that transfer tables require careful evaluation before use in radiotherapy.

Prospective Evaluation of Sarcopenia in Head and Neck Cancer Patients Treated with Radiotherapy or Radiochemotherapy.

Highlights: Sarcopenia is frequent in patients treated with radiation therapy (RT) or radiochemotherapy (RTCT) for head and neck squamous cell carcinomas. Sarcopenia is associated with poor disease-free survival and overall survival outcomes. Sarcopenia is not associated with a higher rate of treatment-related toxicity. Background: Sarcopenia occurs frequently with the diagnosis of head and neck squamous cell carcinoma (HNSCC). We aimed to assess the impact of sarcopenia on survival among HNSCC patients treated with radiotherapy (RT) or radiochemotherapy (RTCT). Methods: Patients treated between 2014 and 2018 by RT or RTCT with curative intent were prospectively included (NCT02900963). Optimal nutritional support follow-up, including weekly consultation with a dietician and an oncologist and daily weight monitoring, was performed. Sarcopenia was determined by measuring the skeletal muscles at the L3 vertebra on the planning CT scan for radiotherapy. For each treatment group (RT or RTCT), we assessed the prognostic value of sarcopenia for disease-free survival (DFS) and overall survival (OS) and its impact on treatment-related toxicity. Results: Two hundred forty-three HNSCC patients were included: 116 were treated by RT and 127 were treated by RTCT. Before radiotherapy, eight (3.3%) patients were considered malnourished according to albumin, whereas 88 (36.7%) patients were sarcopenic. Overall, sarcopenia was associated with OS and DFS in a multivariate analysis (HR 1.9 [1.1-3.25] and 1.7 [1.06-2.71], respectively). It was similar for patients treated with RT (HR 2.49 [1.26-4.9] for DFS and 2.24 [1.03-4.86] for OS), whereas for patients treated with RTCT sarcopenia was significantly associated with OS and DFS in univariate analysis only. Sarcopenia was not related to higher treatment-related toxicity. Conclusions: Pretherapeutic sarcopenia remains frequent and predicts OS and DFS for non-frail patients treated with curative intent and adequate nutritional support.

Phase II study of concomitant radiotherapy with atezolizumab in oligometastatic soft tissue sarcomas: STEREOSARC trial protocol.

INTRODUCTION: Up to 50% of soft tissue sarcoma (STS) patients develop metastases in the course of their disease. Cytotoxic therapy is a standard treatment in this setting but yields average tumour response rates of 25% at first line and ≤10% at later lines. In oligometastatic stage, stereotactic body radiation therapy (SBRT) allows reaching high control rates at treated sites (≥80%) and is potentially equally effective to surgery in term of overall survival. In order to shift the balance towards antitumour immunity by multisite irradiation, radiation could be combined with inhibitors of the immunosuppressive pathways. METHODS AND ANALYSIS: STEREOSARC is a prospective, multicentric, randomised phase II, designed to evaluate the efficacy of SBRT associated with immunotherapy versus SBRT only. Randomisation is performed with a 2:1 ratio within two arms. The primary objective is to evaluate the efficacy, in term of progression-free survival (PFS) rate at 6 months, of immunomodulated stereotactic multisite irradiation in oligometastatic sarcoma patients. The secondary objectives include PFS by immune response criteria, overall survival, quality-of-life evaluation and developing mathematical models of tumour growth and dissemination predictive of oligometastatic versus polymetastatic evolution. Patients will be randomised in two groups: SBRT with atezolizumab and SBRT alone. The total number of included patients should be 103. TRIAL REGISTRATION: The trial is registered on ClinicalTrials.gov (ID: NCT03548428). ETHICS AND DISSEMINATION: This study has been approved by Comité de Protection des Personnes du sud-ouest et outre-mer 4 on 18 October 2019 (Reference CPP2019-09-076-PP) and from National Agency for Medical and Health products Safety (Reference: MEDAECNAT-2019-08-00004_2017-004239-35) on 18 September 2019.The results will be disseminated to patients upon individual request or through media release from scientific meetings. The results will be communicated through scientific meetings and publications.

Concurrent cisplatin and dose escalation with intensity-modulated radiotherapy (IMRT) versus conventional radiotherapy for locally advanced head and neck squamous cell carcinomas (HNSCC): GORTEC 2004-01 randomized phase III trial.

BACKGROUND: Concurrent chemoradiotherapy (CRT) is the standard of care (SoC) in locally advanced (LA) head and neck squamous cell carcinomas (HNSCC). This trial was designed to test whether dose-escalated IMRT and cisplatin could improve locoregional control without increasing complications over 3D-radiotherapy. METHODS: Patients were randomized between 70 Gy/35F in 7 weeks with 3D-RT (Arm A) versus 75 Gy/35F with IMRT (Arm B). Both arms received 50 Gy in 25 fractions followed by a sequential boost of 20 Gy/10F in Arm A and 25 Gy/10F to gross tumor volume in Arm B, as well as 3 cycles of cisplatin at 100 mg/m2 during RT. The primary endpoint was locoregional progression (LRP). RESULTS: 188 patients were randomized: 85% oropharynx and 73% stage IVa. P16 status was documented for 137 oropharyngeal tumors with P16+ in 53 (39%) patients; and 90% were smokers. Median follow-up was 60.5 months. Xerostomia was markedly decreased in arm B (p < 0.0001). The 1-year grade ≥2 xerostomia (RTOG criteria) was 63% vs 23% and 3-year 45% vs 11% in arms A and B, respectively. Xerostomia LENT-SOMA scale was also reduced in arm B. Dose-escalated IMRT did not reduce LRP with an adjusted HR of 1.13 [95%CI = 0.64-1.98] (p = 0.68). Survival was not different (adjusted HR: 1.19 [95%CI = 0.78-1.81], p = 0.42). No interaction between p16 and treatment effect was found. CONCLUSION: Dose-escalated IMRT did not improve LRC in LA-HNSCC patients treated with concomitant CRT over standard 3D-RT. This trial reinforces the evidence showing IMRT reduces xerostomia in LA-HNSCC treated with radiotherapy. Clinicaltrial.gov: NCT00158678.

Trimodality PET/CT/MRI and Radiotherapy: A Mini-Review.

Computed tomography (CT) has revolutionized external radiotherapy by making it possible to visualize and segment the tumors and the organs at risk in a three-dimensional way. However, if CT is a now a standard, it presents some limitations, notably concerning tumor characterization and delineation. Its association with functional and anatomical images, that are positron emission tomography (PET) and magnetic resonance imaging (MRI), surpasses its limits. This association can be in the form of a trimodality PET/CT/MRI. The objective of this mini-review is to describe the process of performing this PET/CT/MRI trimodality for radiotherapy and its potential clinical applications. Trimodality can be performed in two ways, either a PET/MRI fused to a planning CT (possibly with a pseudo-CT generated from the MRI for the planning), or a PET/CT fused to an MRI and then registered to a planning CT (possibly the CT of PET/CT if calibrated for radiotherapy). These examinations should be performed in the treatment position, and in the second case, a patient transfer system can be used between the PET/CT and MRI to limit movement. If trimodality requires adapted equipment, notably compatible MRI equipment with high-performance dedicated coils, it allows the advantages of the three techniques to be combined with a synergistic effect while limiting their disadvantages when carried out separately. Trimodality is already possible in clinical routine and can have a high clinical impact and good inter-observer agreement, notably for head and neck cancers, brain tumor, prostate cancer, cervical cancer.

TERTp Mutation Detection in Plasma by Droplet-Digital Polymerase Chain Reaction in Spinal Myxopapillary Ependymoma with Lung Metastases.

BACKGROUND: Spinal myxopapillary ependymoma (SP-MPE) is a subgroup of ependymomas in which after initial gross tumor resection, recurrences occur in more than half of the patients. Anaplastic transformation may also occur and contributes to intraneural and extraneural metastatic dissemination. Extraneural metastases from SP-MPE are rare and worsen the prognosis. In this situation, the noninvasive detection of recurrent somatic mutations in the circulating tumor DNA (ctDNA) from plasma is challenging. Telomerase-reverse transcriptase gene promoter (TERTp) mutation has been identified in a subset of ependymomas with aggressive behavior. CASE DESCRIPTION: We report on a patient with TERTp mutated SP-MPE presenting with an extraneural anaplastic metastatic dissemination after iterative local recurrences. From the initial SP-MPE to pleural anaplastic lesion, TERTp C228T mutation was present with allele frequency varying from 33% to 39%. Interestingly, TERTp mutation was also detected by droplet digital polymerase chain reaction in the plasma with a frequency of 2.1% at the time of pleural metastases, highlighting that ctDNA is released in plasma of patients suffering from SP-MPE with extraneural metastatic dissemination. CONCLUSIONS: Despite the rarity of this evolution, plasmatic liquid biopsy appears to be a useful diagnostic and follow-up tool in a subset of primary brain tumors.

Early platelet variation during concomitant chemo-radiotherapy predicts adjuvant temozolomide-induced thrombocytopenia in newly diagnosed glioblastoma patients.

PURPOSE: Temozolomide (TMZ) is known to induce thrombocytopenia but no early predictive test has yet been clearly established. The aim of the study was to retrospectively identify and validate a threshold of early platelet variation predicting TMZ-induced thrombocytopenia during the TMZ phase in patients treated according to the Stupp protocol for glioblastoma. METHODS: A training set was used to analyze variations in platelet count occurring from the first week (W1) to week 6 (W6) during radiotherapy. Our aim was to identify the most relevant platelet decrease associated with TMZ-induced thrombocytopenia ≤ 100 G/L at day 28 during the TMZ phase. The performance of the threshold was confirmed in an independent validation set. RESULTS: Overall, 147 patients were included, 85 and 62 in the training and validation sets, respectively. Twenty-seven patients (18%) experienced at least one TMZ-induced thrombocytopenia in the TMZ phase. A platelet decrease at W6 ≥ 35% (∆W6 ≥ 35%) was identified as the best predictive variation with an AUC of 0.83, a sensitivity of 65%, and a specificity of 96%. In the validation set, ∆W6 ≥ 35% platelet variation was identified as an independent marker of TMZ-induced thrombocytopenia during the TMZ phase (OR 15.23 (95% CI 3.5-107.5)) corresponding to sensitivity of 77% (66-87%), specificity of 73% (62-84%), a positive predictive value of 42% (29-54%), and a negative predictive value of 92% (86-99%). CONCLUSION: Platelet decrease at W6 ≥ 35% during the RT-TMZ phase is an early and simple predictive marker of clinically relevant TMZ-induced thrombocytopenia during TMZ maintenance.

Adaptive radiation therapy in head and neck cancer for clinical practice: state of the art and practical challenges.

Modern radiation therapy techniques are characterized by high conformality to tumor volumes and steep dose gradients to spare normal organs. These techniques require accurate clinical target volume definitions and rigorous assessment of set up uncertainties using image guidance, a concept called image-guided radiation therapy. Due to alteration of patient anatomy, changes in tissue density/volumes and tumor shrinkage over the course of treatment, treatment accuracy may be challenged. This may result in excessive irradiation of organs at risk/healthy tissues and undercoverage of target volumes with a significant risk of locoregional failure. Adaptive radiation therapy (ART) is a concept allowing the clinician to reconsider the planned dose based on potential changes to accurately delivering the remaining radiation dose to the tumor while optimally minimizing irradiation of healthy tissues. There is little consensus on how to apply this concept in clinical practice. The current review investigates the current ART issues, including patient selection, clinical/dosimetric criteria and timing for re-planning, and practical technical issues. A practical algorithm is proposed for patient management in cases where ART is required.

Definitive radiotherapy for squamous cell carcinoma of the pyriform sinus.

BACKGROUND AND PURPOSE: To report the long-term results after definitive radiotherapy (RT) for pyriform sinus squamous cell carcinoma (SCC). MATERIAL AND METHODS: The data concerning all patients treated for pyriform sinus SCC with RT with a curative intent between 1990 and 2006 were reviewed. RESULTS: A total of 249 patients were included. The median follow-up is 6.5 years. Overall 123 patients had relapsed. For the entire population, the 5-year local control, regional control, freedom-from-distant metastasis, and overall survival rate were 68%, 69%, 78% and 38%, respectively. The 5-year local control rate for the 107 T1-T2 tumors was 85% (95% confidence interval (CI): 75-91). N stage was the main risk factor for the development of distant metastases, with a hazard ratio of 8.9 (95% CI: 2.1-39) and 15.6 (95% CI: 3.6-67.8) for N2 and N3 patients respectively. For patients with N2-N3 disease, pre-RT neck dissection improved regional control but not overall survival. Moderate to severe late complications occurred in 50 patients (28% of the patients without local relapse). CONCLUSION: A high local control rate can be achieved when treating T1-T2 hypopharynx cancers with definitive radiotherapy. The high rate of nodal and distant relapses among patients with N2-N3 disease warrants intensification of therapy.