L. Feuvret

Temozolomide chemotherapy versus radiotherapy in high-risk low-grade glioma (EORTC 22033-26033) : a randomised, open-label, phase 3 intergroup study

Background Outcome of low-grade glioma (LGG, WHO grade II) is highly variable reflecting molecular heterogeneity of the disease. We compared two different single modality treatment strategies: standard radiotherapy (RT) versus primary temozolomide (TMZ) chemotherapy with the aim of tailoring treatment and identifying predictive molecular factors. Methods 477 patients (2005 – 2012, median FU 48 months) with a low-grade glioma (astrocytoma, oligoastrocytoma, oligodendroglioma, WHO grade II) with at least one high-risk feature (age > 40 years, progressive disease, tumor > 5 cm or crossing the midline, neurological symptoms (e.g. focal or mental deficits, increased intracranial pressure or intractable seizures)) were, after stratification by chromosome 1p-status, randomized to either conformal RT (50.4 Gy/28 fractions) or dose-dense TMZ (75 mg/m2 daily × 21 days, q28 days, max. 12 cycles). Random treatment allocation was performed online using a minimization technique. A planned analysis was performed after 246 progression events. All analyses are intent to treat. Primary clinical endpoint was progression-free survival (PFS), correlative analyses included molecular markers (1p/19q co-deletion, MGMT methylation status, IDH1+2 mutations). The trial has been registered at the European Trials Registry (EudraCT 2004-002714-11) and at ClinicalTrials.gov (NCT00182819). Findings Four hundred seventy-seven patients were randomized. Severe hematological toxicity occurred in 14% of TMZ-treated patients, infections in 3% of TMZ-treated patients, and 1% of RT-treated patients. Moderate to severe fatigue was recorded in 3% of patients in the RT group and 7% in the TMZ group. At a median follow-up of 48 months (IQR:31–56), median PFS was 39 months (IQR:16–46) in the TMZ arm and 46 months (IQR:19–48) in the RT group (hazard ratio 1.16, 95% CI, 0.9–1.5; p=0.22). Median OS has not been reached. Exploratory analyses identified treatment-dependent variation in outcome of molecular LGG subgroups (n=318). Interpretation There was no significant difference in outcome of the overall patient population treated with either radiotherapy alone or TMZ chemotherapy alone. Further data maturation is needed for overall survival analyses and evaluation of the full predictive impact of the molecular subtypes for individualized treatment choices. Funding Merck & Co, Swiss-Bridge Award 2011, Swiss Cancer League.

Treatment of Malignant Gliomas in the Elderly

The benefit of standard treatment of malignant glioma in older patients is debated. In order to assess the effect of a combination of surgery, radiotherapy and chemotherapy on survival of elderly patients with high grade gliomas, 30 consecutive patients older than 70 years with malignant supratentorial gliomas were studied between 9/93 and 9/96. Median age was 73 years (70–79). The mean Karnofsky performance status (KPS) was 66 (30–100). Patients underwent maximum possible surgery, followed by a course of radiotherapy (45 Gy/25 fractions/5 weeks) with 3 or 4 orthogonal beams and a 2 cm margin around the tumor bed. The administration of chemotherapy was left at the discretion of the responsible physician and 12 patients received reduced dose nitrosourea-based chemotherapy. The overall median survival was 36 weeks. The median time to progression was 26 weeks. Three months after surgery, 26 patients were alive, 5 were in complete response, 2 in partial response and 10 were stabilized. Pre-radiotherapy KPS was the only significant prognostic factor with a median survival of 40 weeks in patients with KPS ≥70 and 25 weeks when KPS was >70 (logrank test, p=0.05). In responding and stable patients (57% of the group) the median KPS was 68 and 66 at 1 and 3 months after the completion of radiotherapy. There was no case of radiotherapy-induced dementia with this regimen. Four out of 12 patients who received chemotherapy, experienced WHO grade 3/4 hematotoxicity.This study suggest that some patients older than 70 years with KPS ≥70 may benefit from the treatment of malignant gliomas with surgery followed by reduced dose of limited field radiotherapy. Further studies are needed to define the most appropriate dose of radiotherapy and to evaluate further the risk/benefit ratio of a reduced dose chemotherapy in this population.

Influence of Nucleoshuttling of the ATM Protein in the Healthy Tissues Response to Radiation Therapy: Toward a Molecular Classification of Human Radiosensitivity

PURPOSE Whereas post-radiation therapy overreactions (OR) represent a clinical and societal issue, there is still no consensual radiobiological endpoint to predict clinical radiosensitivity. Since 2003, skin biopsy specimens have been collected from patients treated by radiation therapy against different tumor localizations and showing a wide range of OR. Here, we aimed to establish quantitative links between radiobiological factors and OR severity grades that would be relevant to radioresistant and genetic hyperradiosensitive cases. METHODS AND MATERIALS Immunofluorescence experiments were performed on a collection of skin fibroblasts from 12 radioresistant, 5 hyperradiosensitive, and 100 OR patients irradiated at 2 Gy. The numbers of micronuclei, γH2AX, and pATM foci that reflect different steps of DNA double-strand breaks (DSB) recognition and repair were assessed from 10 minutes to 24 hours after irradiation and plotted against the severity grades established by the Common Terminology Criteria for Adverse Events and the Radiation Therapy Oncology Group. RESULTS OR patients did not necessarily show a gross DSB repair defect but a systematic delay in the nucleoshuttling of the ATM protein required for complete DSB recognition. Among the radiobiological factors, the maximal number of pATM foci provided the best discrimination among OR patients and a significant correlation with each OR severity grade, independently of tumor localization and of the early or late nature of reactions. CONCLUSIONS Our results are consistent with a general classification of human radiosensitivity based on 3 groups: radioresistance (group I); moderate radiosensitivity caused by delay of nucleoshuttling of ATM, which includes OR patients (group II); and hyperradiosensitivity caused by a gross DSB repair defect, which includes fatal cases (group III).

Dramatic response of a BRAF V600E-mutated primary CNS histiocytic sarcoma to vemurafenib

Histiocytic sarcoma (HS) is classified within the malignant histiocytic disorders.1 Involvement of isolated CNS in HS, termed primary CNS-HS (PCNS-HS), is characterized by a proliferation of cells in the monocyte/macrophage lineage within the CNS.2–6 This case report documents the clinical, biological, pathologic, and radiologic spectrums of PCNS-HS.

Proton beam therapy for iris melanomas

AimsTo describe the results in terms of local control, eye preservation and systemic evolution of iris melanomas treated by proton beam irradiation.MethodsRetrospective review of the charts of patients with iris melanoma treated by proton beam therapy between April 1998 and September 2002. Ciliary body melanomas with iris involvement or tumours with extrascleral invasion were excluded. Treatment consisted of 60 Gy of proton beam irradiation delivered in four fractions to the tumour volume.ResultsA total of 21 patients were treated, median follow-up of 33 months (8–72 months). 15 patients presented a lesion with documented growth. The median clinical diameter was 5 mm (2–8 mm), the median ultrasound diameter 4.8 mm (2–7.7 mm) The patients were 6% T1, 57.1% T2, and 14.3% T3 all N0M0. The iridocorneal angle was invaded by the tumour in 71.4% of patients. At the end of follow-up, all patients were alive with no proven metastatic disease except one patient with suspicious liver lesions. None of the patients showed tumour progression or ocular relapse. The tumour response at 2 years was a flat lesion for 6.3% of cases, partial regression in 75% and stable in 18.8%. None of the patients required secondary enucleation. The main complication was cataract (45% within 24 months of treatment). Raised intraocular pressure was observed in 15% of patients but no neovascular glaucoma.ConclusionsProton beam therapy shows potential utility for selected cases of localised iris melanomas allowing excellent local tumour control and eye preservation. Further follow-up on larger series is needed to confirm these results.

Treatment of Head and Neck Paragangliomas With External Beam Radiation Therapy

PURPOSE To retrospectively assess the outcomes of radiation therapy in patients with head and neck paragangliomas. METHODS AND MATERIALS From 1990 to 2009, 66 patients with 81 head and neck paragangliomas were treated by conventional external beam radiation therapy in 25 fractions at a median dose of 45 Gy (range, 41.4-68 Gy). One case was malignant. The median gross target volume and planning target volume were 30 cm(3) (range, 0.9-243 cm(3)) and 116 cm(3) (range, 24-731 cm(3)), respectively. Median age was 57.4 years (range, 15-84 years). Eleven patients had multicentric lesions, and 8 had family histories of paraganglioma. Paragangliomas were located in the temporal bone, the carotid body, and the glomus vagal in 51, 18, and 10 patients, respectively. Forty-six patients had exclusive radiation therapy, and 20 had salvage radiation therapy. The median follow-up was 4.1 years (range, 0.1-21.2 years). RESULTS One patient had a recurrence of temporal bone paraganglioma 8 years after treatment. The actuarial local control rates were 100% at 5 years and 98.7% at 10 years. Patients with multifocal tumors and family histories were significantly younger (42 years vs 58 years [P=.002] and 37 years vs 58 years [P=.0003], respectively). The association between family predisposition and multifocality was significant (P<.001). Two patients had cause-specific death within the 6 months after irradiation. During radiation therapy, 9 patients required hospitalization for weight loss, nausea, mucositis, or ophthalmic zoster. Two late vascular complications occurred (middle cerebral artery and carotid stenosis), and 2 late radiation-related meningiomas appeared 15 and 18 years after treatment. CONCLUSION Conventional external beam radiation therapy is an effective and safe treatment option that achieves excellent local control; it should be considered as a first-line treatment of choice for head and neck paragangliomas.

Short course of radiation therapy in elderly patients with glioblastoma multiforme

PURPOSE The optimal schedule of irradiation in elderly patients suffering from glioblastoma multiforme (GBM) is unsettled. MATERIALS AND METHODS This study reviewed the charts of 28 consecutive GBM patients aged 70 years or more with a Karnofsky Performance Status (KPS) greater than or equal to 70 who received a short course of radiotherapy (40 grays in 15 fractions over three weeks). RESULTS The median age at surgery was 74.6 years (range, 70.1-85.7). No patient received prior or concomitant chemotherapy. The median progression-free survival and overall survival were 21.6 weeks (95% CI, 17.0-39.9) and 50.6 weeks (95% CI, 26.3-62.0), respectively. Even within a narrow range (<90 or >or=90), KPS remained a prognostic factor (p=0.03). Tolerance appeared acceptable in terms of KPS changes and corticosteroid use during radiation therapy. CONCLUSION These results support the efficacy of short schedule radiotherapy for GBM in elderly patients with a good KPS.

Chondrosarcomas of the base of the skull in Ollier's disease or Maffucci's syndrome Three Case Reports and Review of the Literature

Olliers disease is a rare disease characterized by constitutional bone dysplasia with multiple enchondromas. The combination of haemangioma and chondromatoses is known as Maffuccis syndrome. Malignant degeneration of bone dysplasia into chondrosarcoma is a well-known complication, but a lesion of the base of the skull is exceptional. It is a slowly growing low-grade malignant tumour. Three new cases of chondrosarcoma of the base of the skull occurring in one patient with Marfuccis syndrome and two patients with Olliers disease are reported and these cases are discussed in the light of the literature. A multidisciplinary approach, comprising surgery and radiotherapy, achieved good results.

Reappraisal of clinical outcome in adult medulloblastomas with emphasis on patterns of relapse

Background. Clinical outcome and prognostic factors were assessed in adult medulloblastoma patients, with emphasis on patterns of relapse. Patients and methods. Records of 36 consecutive adult patients with medulloblastoma were reviewed. Patients were classified into 2 prognostic groups according to the extent of disease and quality of surgical excision based on the early postoperative magnetic resonance imaging (MRI) findings. Standard-risk (SR) patients (n = 11) received postoperative craniospinal radiation therapy (RT) only, 36 Gy, 1.8 Gy per daily fraction, with a 18 Gy boost to the posterior cerebral fossa (PCF). High-risk (HR) patients (n = 25) received additional adjuvant chemotherapy. Results. With a median follow-up of 46 months (range 5–155), 19 patients experienced tumour relapse. Sites of relapse(s) included tumour bed in 6 patients, resulting in a PCF control of 83.4%. Three-year overall survival (OS) and progression-free survival (PFS) were 67.3% and 57.4%, respectively. The comparison of the HR and SR populations demonstrated significant differences in OS (p = 0.005) and PFS (p = 0.001). Quality of surgical excision and extent of disease beyond the PCF were predictive factors for OS (p = 0.04, p = 0.001, respectively) and PFS (p = 0.004, and p = 0.02, respectively). Conclusion. The quality of resection was a significant prognostic factor, suggesting that surgery should be as extensive as possible. Systematic postoperative MRI allowed accurate selection of SR patients for whom RT alone was enough to obtain high local control. Every effort should be made to avoid RT disruption. Increased delay led to worse outcome.

Radiothérapie des glioblastomes

Glioblastoma cells appear to be inherently radioresistant and to present a significant fraction of hypoxic cells. The most significant prognostic factors to compare results achieved in several series of patients are the age, performance status and quality of surgical resection. Several randomized trials have provided evidence supporting the efficacy of radiation therapy in the treatment of glioblastoma. Prescription of a 60-Gy dose delivered according to a conventional dose-fractionation scheme (single daily fractions of 1.7 to 2 Gy five times per week) in a target volume with a 2-3 cm margin of tissue surrounding the perimeter of the contrast enhancing lesion on computerized tomography and magnetic resonance imaging is derived from observations made in several retrospective and prospective studies. Evidence of improvement in survival was observed neither in patients receiving hyperfractioned and accelerated radiotherapy, nor in patients for whom radiation sensitizers such as nitroimidazole compounds or halogenated pyrimidine analogs were associated to radiation therapy. The addition of nitrosourea to radiotherapy increases the 2-year survival rate by about 10%. Combination of full-dose external beam radiotherapy and brachytherapy or radiosurgery boost in selected patients with glioblastoma leads to an increase in the median survival, while external beam radiation alone in patients with similar prognosis does not.