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    Abstract: BACKGROUND: Outcome of low-grade glioma (WHO grade II) is highly variable, reflecting molecular heterogeneity of the disease. We compared two different, single-modality treatment strategies of standard radiotherapy versus primary temozolomide chemotherapy in patients with low-grade glioma, and assessed progression-free survival outcomes and identified predictive molecular factors. METHODS: For this randomised, open-label, phase 3 intergroup study (EORTC 22033-26033), undertaken in 78 clinical centres in 19 countries, we included patients aged 18 years or older who had a low-grade (WHO grade II) glioma (astrocytoma, oligoastrocytoma, or oligodendroglioma) with at least one high-risk feature (aged 〉40 years, progressive disease, tumour size 〉5 cm, tumour crossing the midline, or neurological symptoms), and without known HIV infection, chronic hepatitis B or C virus infection, or any condition that could interfere with oral drug administration. Eligible patients were randomly assigned (1:1) to receive either conformal radiotherapy (up to 50.4 Gy; 28 doses of 1.8 Gy once daily, 5 days per week for up to 6.5 weeks) or dose-dense oral temozolomide (75 mg/m2 once daily for 21 days, repeated every 28 days [one cycle], for a maximum of 12 cycles). Random treatment allocation was done online by a minimisation technique with prospective stratification by institution, 1p deletion (absent vs present vs undetermined), contrast enhancement (yes vs no), age (〈40 vs 〉/=40 years), and WHO performance status (0 vs 〉/=1). Patients, treating physicians, and researchers were aware of the assigned intervention. A planned analysis was done after 216 progression events occurred. Our primary clinical endpoint was progression-free survival, analysed by intention-to-treat; secondary outcomes were overall survival, adverse events, neurocognitive function (will be reported separately), health-related quality of life and neurological function (reported separately), and correlative analyses of progression-free survival by molecular markers (1p/19q co-deletion, MGMT promoter methylation status, and IDH1/IDH2 mutations). This trial is closed to accrual but continuing for follow-up, and is registered at the European Trials Registry, EudraCT 2004-002714-11, and at ClinicalTrials.gov, NCT00182819. FINDINGS: Between Sept 23, 2005, and March 26, 2010, 707 patients were registered for the study. Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 patients to receive either radiotherapy (n=240) or temozolomide chemotherapy (n=237). At a median follow-up of 48 months (IQR 31-56), median progression-free survival was 39 months (95% CI 35-44) in the temozolomide group and 46 months (40-56) in the radiotherapy group (unadjusted hazard ratio [HR] 1.16, 95% CI 0.9-1.5, p=0.22). Median overall survival has not been reached. Exploratory analyses in 318 molecularly-defined patients confirmed the significantly different prognosis for progression-free survival in the three recently defined molecular low-grade glioma subgroups (IDHmt, with or without 1p/19q co-deletion [IDHmt/codel], or IDH wild type [IDHwt]; p=0.013). Patients with IDHmt/non-codel tumours treated with radiotherapy had a longer progression-free survival than those treated with temozolomide (HR 1.86 [95% CI 1.21-2.87], log-rank p=0.0043), whereas there were no significant treatment-dependent differences in progression-free survival for patients with IDHmt/codel and IDHwt tumours. Grade 3-4 haematological adverse events occurred in 32 (14%) of 236 patients treated with temozolomide and in one (〈1%) of 228 patients treated with radiotherapy, and grade 3-4 infections occurred in eight (3%) of 236 patients treated with temozolomide and in two (1%) of 228 patients treated with radiotherapy. Moderate to severe fatigue was recorded in eight (3%) patients in the radiotherapy group (grade 2) and 16 (7%) in the temozolomide group. 119 (25%) of all 477 patients had died at database lock. Four p
    Type of Publication: Journal article published
    PubMed ID: 27686946
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  • 3
    Abstract: BACKGROUND: Temozolomide chemotherapy versus radiotherapy in patients with a high-risk low-grade glioma has been shown to have no significant effect on progression-free survival. If these treatments have a different effect on health-related quality of life (HRQOL), it might affect the choice of therapy. We postulated that temozolomide compromises HRQOL and global cognitive functioning to a lesser extent than does radiotherapy. METHODS: We did a prospective, phase 3, randomised controlled trial at 78 medical centres and large hospitals in 19 countries. We enrolled adult patients (aged 〉/=18 years) with histologically confirmed diffuse (WHO grade II) astrocytoma, oligodendroglioma, or mixed oligoastrocytoma, with a WHO performance status of 2 or lower, without previous chemotherapy or radiotherapy, who needed active treatment other than surgery. We randomly assigned eligible patients (1:1) using a minimisation technique, stratified by WHO performance status (0-1 vs 2), age (〈40 years vs 〉/=40 years), presence of contrast enhancement on MRI, chromosome 1p status (deleted vs non-deleted vs indeterminate), and the treating medical centre, to receive either radiotherapy (50.4 Gy in 28 fractions of 1.8 Gy for 5 days per week up to 6.5 weeks) or temozolomide chemotherapy (75 mg/m2 daily, for 21 of 28 days [one cycle] for 12 cycles). The primary endpoint was progression-free survival (results published separately); here, we report the results for two key secondary endpoints: HRQOL (assessed using the European Organisation for Research and Treatment of Cancer's [EORTC] QLQ-C30 [version 3] and the EORTC Brain Cancer Module [QLQ-BN20]) and global cognitive functioning (assessed using the Mini-Mental State Examination [MMSE]). We did analyses on the intention-to-treat population. This study is closed and is registered at EudraCT, number 2004-002714-11, and at ClinicalTrials.gov, number NCT00182819. FINDINGS: Between Dec 6, 2005, and Dec 21, 2012, we randomly assigned 477 eligible patients to either radiotherapy (n=240) or temozolomide chemotherapy (n=237). The difference in HRQOL between the two treatment groups was not significant during the 36 months' follow-up (mean between group difference [averaged over all timepoints] 0.06, 95% CI -4.64 to 4.75, p=0.98). At baseline, 32 (13%) of 239 patients who received radiotherapy and 32 (14%) of 236 patients who received temozolomide chemotherapy had impaired cognitive function, according to the MMSE scores. After randomisation, five (8%) of 63 patients who received radiotherapy and three (6%) of 54 patients who received temozolomide chemotherapy and who could be followed up for 36 months had impaired cognitive function, according to the MMSE scores. No significant difference was recorded between the groups for the change in MMSE scores during the 36 months of follow-up. INTERPRETATION: The effect of temozolomide chemotherapy or radiotherapy on HRQOL or global cognitive functioning did not differ in patients with low-grade glioma. These results do not support the choice of temozolomide alone over radiotherapy alone in patients with high-risk low-grade glioma. FUNDING: Merck Sharp & Dohme-Merck & Co, National Cancer Institute, Swiss Cancer League, National Institute for Health Research, Cancer Research UK, Canadian Cancer Society Research Institute, National Health and Medical Research Council, European Organisation for Research and Treatment of Cancer Cancer Research Fund.
    Type of Publication: Journal article published
    PubMed ID: 27686943
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  • 4
    Keywords: SONIC HEDGEHOG ; pancreatic cancer ; SPARC ; GEMCITABINE ; extracellular matrix ; stem cells ; stellate cells ; stroma ; Nab-paclitaxel
    Abstract: Most patients with pancreatic cancer present with advanced/metastatic disease and have a dismal prognosis. Despite the proven albeit modest benefits of gemcitabine demonstrated over a decade ago, subsequent advances have been slow, suggesting it may be time to take a different approach. It is thought that some key characteristics of pancreatic cancer, such as the desmoplasia, restricted vasculature and hypoxic environment, may prevent the delivery of chemotherapy to the tumour thereby explaining the limited benefits observed to-date. Moreover, there is evidence to suggest that the stroma is not only a mechanical barrier but also constitutes a dynamic compartment of pancreatic tumours that is critically involved in tumour formation, progression and metastasis. Thus, targeting the stroma and the tumour represents a promising therapeutic strategy. Currently, several stroma-targeting agents are entering clinical development. Among these, nab-paclitaxel appears promising since it combines cytotoxic therapy with targeted delivery via its proposed ability to bind SPARC on tumour and stromal cells. Preclinical data indicate that co-treatment with nab-paclitaxel and gemcitabine results in stromal depletion, increased tumour vascularization and intratumoural gemcitabine concentration, and increased tumour regression compared with either agent alone. Phase I/II study data also suggest that a high level of antitumor activity can be achieved with this combination in pancreatic cancer. This was recently confirmed in a Phase III study which showed that nab-paclitaxel plus gemcitabine significantly improved overall survival (HR 0.72) and progression-free survival (HR 0.69) versus gemcitabine alone for the first-line treatment of patients with metastatic pancreatic cancer.
    Type of Publication: Journal article published
    PubMed ID: 23849556
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  • 5
    Abstract: Rare diseases are an important public health issue with high unmet need. The introduction of the EU Regulation on orphan medicinal products (OMP) has been successful in stimulating investment in the research and development of OMPs. Despite this advancement, patients do not have universal access to these new medicines. There are many factors that affect OMP uptake, but one of the most important is the difficulty of making pricing and reimbursement (P&R) decisions in rare diseases. Until now, there has been little consensus on the most appropriate assessment criteria, perspective or appraisal process. This paper proposes nine principles to help improve the consistency of OMP P&R assessment in Europe and ensure that value assessment, pricing and funding processes reflect the specificities of rare diseases and contribute to both the sustainability of healthcare systems and the sustainability of innovation in this field. These recommendations are the output of the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL), a collaboration between rare disease experts, patient representatives, academics, health technology assessment (HTA) practitioners, politicians and industry representatives. ORPH-VAL reached its recommendations through careful consideration of existing OMP P&R literature and through a wide consultation with expert stakeholders, including payers, regulators and patients. The principles cover four areas: OMP decision criteria, OMP decision process, OMP sustainable funding systems and European co-ordination. This paper also presents a guide to the core elements of value relevant to OMPs that should be consistently considered in all OMP appraisals. The principles outlined in this paper may be helpful in drawing together an emerging consensus on this topic and identifying areas where consistency in payer approach could be achievable and beneficial. All stakeholders have an obligation to work together to ensure that the promise of OMP's is realised.
    Type of Publication: Journal article published
    PubMed ID: 28283046
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  • 6
    Abstract: Variations in the reporting of potentially confounding variables in studies investigating systemic treatments for unresectable pancreatic cancer pose challenges in drawing accurate comparisons between findings. In this Review, we establish the first international consensus on mandatory baseline and prognostic characteristics in future trials for the treatment of unresectable pancreatic cancer. We did a systematic literature search to find phase 3 trials investigating first-line systemic treatment for locally advanced or metastatic pancreatic cancer to identify baseline characteristics and prognostic variables. We created a structured overview showing the reporting frequencies of baseline characteristics and the prognostic relevance of identified variables. We used a modified Delphi panel of two rounds involving an international panel of 23 leading medical oncologists in the field of pancreatic cancer to develop a consensus on the various variables identified. In total, 39 randomised controlled trials that had data on 15 863 patients were included, of which 32 baseline characteristics and 26 prognostic characteristics were identified. After two consensus rounds, 23 baseline characteristics and 12 prognostic characteristics were designated as mandatory for future pancreatic cancer trials. The COnsensus statement on Mandatory Measurements in unresectable PAncreatic Cancer Trials (COMM-PACT) identifies a mandatory set of baseline and prognostic characteristics to allow adequate comparison of outcomes between pancreatic cancer studies.
    Type of Publication: Journal article published
    PubMed ID: 29508762
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  • 7
    ISSN: 1569-8041
    Keywords: brain lymphomas ; chemotherapy ; intrathecal chemotherapy ; methotrexate ; primary central nervous system lymphoma ; radiotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Primary central nervous system lymphomas (PCNSL) are aggressivemalignancies, exhibiting one of the worst prognoses among lymphomas. The besttreatment modality for PCNSL has not yet been identified. Several therapeuticquestions still remain unanswered, and some methodological pitfalls inclinical trials prevent definitive conclusions from being drawn. In thisreview, certain aspects of trial design as well as emerging therapeuticguidelines are analyzed, and future perspectives are discussed. In the vast majority of prospective trials, general criteria for treatmentof aggressive lymphomas were adopted, choosing primary chemotherapy (CHT)followed by radiotherapy (RT) as therapeutic modality. This strategy produceda five-year survival of 22%–40% in comparison to the3%–26% reported with RT alone. Systemic high-dosemethotrexate (HD-MTX) seems to be the most effective drug, producing aresponse rate of 80%–90% and a two-year survival of60%–65%. To date, the addition of other drugs atconventional doses have not consistently improved outcome. With a fewexceptions, any regimen without HD-MTX comprehensively performed no betterthan RT alone. In combined treatment, RT doses should be decided on the bases of responseto primary CHT and the number of lesions, and, until definitive conclusionsfrom well-designed trials are available, RT parameters should follow thewidely accepted principles used for other aggressive lymphomas. CHT asexclusive treatment, keeping RT for relapses or persistent disease, appearsto be an attractive strategy. However, the worldwide experience with thismodality is still limited, and corroborating data are needed. Intrathecal CHTstill has not found a defined role in PCNSL management. Preliminary data seemto indicate that adequate meningeal treatment with HD-MTX, but withoutintrathecal CHT, could also be suitable in positive-cerebrospinal fluidpatients. Future efforts should be addressed to identify new active drugs and moreefficient CHT combinations, to evaluate the efficacy of high-dose CHTsupported by autologous peripheral blood stem cells transplantation, and toclarify the impact of RT delay in complete responders, the usefulness ofintrathecal CHT, and the best management for elderly patients. The assessmentof impact of treatment on neuropsychological functions and quality of life isa mandatory endpoint in clinical trials.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1569-8041
    Keywords: brain neoplasms ; chemotherapy ; combined treatment ; extranodal lymphomas ; primary central nervous system lymphoma ; radiotherapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: The optimal treatment for primary central nervous systemlymphomas (PCNSL) has not yet been defined. Patients and methods: Therapeutic results of 1180 immunocompetentpatients (pts) with PCNSL reported in 50 series published in English between1980 and 1995 were analysed. The impact on survival of age, treatmentstrategy, radiation field and doses, systemic and intrathecal chemotherapy(CHT) and treatment sequence was evaluated. Results: Univariate analyses showed a longer survival in pts of≤60 years (P 〈 0.00001); pts treated with 〉40 Gy to whole brain(WB) (P = 0.02); pts receiving 〉50 Gy to the tumor bed after a WBdose 〉40 Gy (P = 0.02); pts submitted to a combined treatment asopposed to CHT alone (P = 0.007) or radiotherapy alone (P 〈0.00001); pts receiving CHT followed by radiotherapy rather than in thereverse sequence (P = 0.05); pts treated with high-dose methotrexate(HD-MTX) (P = 0.04) and pts receiving intrathecal CHT (P = 0.03).Multivariate analysis confirmed the independent prognostic value of age, WBdose, HD-MTX and intrathecal CHT. Conclusions: Current data confirm the prognostic value of age andappear to support the use of systemic CHT consisting of HD-MTX and intrathecaldrug administration followed by 41–50 Gy to WB and 〉50 Gy to thetumor bed in the treatment of PCNSL in immunocompetent pts.
    Type of Medium: Electronic Resource
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