Current Issue : April - June Volume : 2017 Issue Number : 2 Articles : 5 Articles
Background: The higher specificity of amino-acid positron emission tomography (AA-PET) in the diagnosis of\ngliomas, as well as in the differentiation between recurrence and treatment-related alterations, in comparison to\ncontrast enhancement in T1-weighted MRI was demonstrated in many studies and is the rationale for their\nimplementation into radiation oncology treatment planning. Several clinical trials have demonstrated the\nsignificant differences between AA-PET and standard MRI concerning the definition of the gross tumor volume\n(GTV). A small single-center non-randomized prospective study in patients with recurrent high grade gliomas\ntreated with stereotactic fractionated radiotherapy (SFRT) showed a significant improvement in survival when\nAA-PET was integrated in target volume delineation, in comparison to patients treated based on CT/MRI alone.\nMethods: This protocol describes a prospective, open label, randomized, multi-center phase II trial designed to\ntest if radiotherapy target volume delineation based on FET-PET leads to improvement in progression free survival (PFS)\nin patients with recurrent glioblastoma (GBM) treated with re-irradiation, compared to target volume delineation based\non T1Gd-MRI. The target sample size is 200 randomized patients with a 1:1 allocation ratio to both arms. The primary\nendpoint (PFS) is determined by serial MRI scans, supplemented by AA-PET-scans and/or biopsy/surgery if suspicious\nof progression. Secondary endpoints include overall survival (OS), locally controlled survival (time to local progression\nor death), volumetric assessment of GTV delineated by either method, topography of progression in relation to MRIor\nPET-derived target volumes, rate of long term survivors (>1 year), localization of necrosis after re-irradiation, quality\nof life (QoL) assessed by the EORTC QLQ-C15 PAL questionnaire, evaluation of safety of FET-application in AA-PET\nimaging and toxicity of re-irradiation.\nDiscussion: This is a protocol of a randomized phase II trial designed to test a new strategy of radiotherapy target\nvolume delineation for improving the outcome of patients with recurrent GBM. Moreover, the trial will help to develop a\nstandardized methodology for the integration of AA-PET and other imaging biomarkers in radiation treatment planning....
Background: Randomization procedure in randomized controlled trials (RCTs) permits an unbiased estimation of\ncausal effects. However, in clinical practice, differential compliance between arms may cause a strong violation of\nrandomization balance and biased treatment effect among those who comply. We evaluated the effect of the\nconsolidation phase on disease-free survival of patients with multiple myeloma in an RCT designed for another\npurpose, adjusting for potential selection bias due to different compliance to previous treatment phases.\nMethods: We computed two propensity scores (PS) to model two different selection processes: the first to\nundergo autologous stem cell transplantation, the second to begin consolidation therapy. Combined stabilized\ninverse probability treatment weights were then introduced in the Cox model to estimate the causal effect of\nconsolidation therapy miming an ad hoc RCT protocol.\nResults: We found that the effect of consolidation therapy was restricted to the first 18 months of the phase (HR: 0.40,\nrobust 95 % CI: 0.17-0.96), after which it disappeared.\nConclusions: PS-based methods could be a complementary approach within an RCT context to evaluate the\neffect of the last phase of a complex therapeutic strategy, adjusting for potential selection bias caused by\ndifferent compliance to the previous phases of the therapeutic scheme, in order to simulate an ad hoc\nrandomization procedure....
Background: After definitive chemoradiotherapy for non-metastatic nasopharyngeal carcinoma (NPC), more than\n10% of patients will experience a local recurrence. Salvage treatments present significant challenges for locally recurrent\nNPC. Surgery, stereotactic ablative body radiotherapy, and brachytherapy have been used to treat locally recurrent\nNPC. However, only patients with small-volume tumors can benefit from these treatments. Re-irradiation with\nX-rayââ?¬â?based intensity-modulated radiotherapy (IMXT) has been more widely used for salvage treatment of locally\nrecurrent NPC with a large tumor burden, but over-irradiation to the surrounding normal tissues has been shown to\ncause frequent and severe toxicities. Furthermore, locally recurrent NPC represents a clinical entity that is more radioresistant\nthan its primary counterpart. Due to the inherent physical advantages of heavy-particle therapy, precise dose\ndelivery to the target volume(s), without exposing the surrounding organs at risk to extra doses, is highly feasible\nwith carbon-ion radiotherapy (CIRT). In addition, CIRT is a high linear energy transfer (LET) radiation and provides an\nincreased relative biological effectiveness compared with photon and proton radiotherapy. Our prior work showed\nthat CIRT alone to 57.5 GyE (gray equivalent), at 2.5 GyE per daily fraction, was well tolerated in patients who were previously\ntreated for NPC with a definitive dose of IMXT. The short-term response rates at 3ââ?¬â??6 months were also acceptable.\nHowever, no patients were treated with concurrent chemotherapy. Whether the addition of concurrent chemotherapy\nto CIRT can benefit locally recurrent NPC patients over CIRT alone has never been addressed. It is possible that\nthe benefits of high-LET CIRT may make radiosensitizing chemotherapy unnecessary. We therefore implemented a\nphase I/II clinical trial to address these questions and present our methodology and results.\nMethods and design: The maximal tolerated dose (MTD) of re-treatment using raster-scanning CIRT plus concurrent\ncisplatin will be determined in the phase I, dose-escalating stage of this study. CIRT dose escalation from 52.5 to\n65 GyE (2.5 GyE Ã?â?? 21ââ?¬â??26 fractions) will be delivered, with the primary endpoints being acute and subacute toxicities.\nEfficacy in terms of overall survival (OS) and local progression-free survival of patients after concurrent chemotherapy\nplus CIRT at the determined MTD will then be studied in the phase II stage of the trial. We hypothesize that CIRT plus\nchemotherapy can improve the 2-year OS rate from the historical 50% to at least 70%.\nConclusions: Re-treatment of locally recurrent NPC using photon radiation techniques, including IMXT, provides\nmoderate efficacy but causes potentially severe toxicities. Improved outcomes in terms of efficacy and toxicity profile\nare expected with CIRT plus chemotherapy. However, the MTD of CIRT used concurrently with cisplatin-based chemotherapy\nfor locally recurrent NPC remains to be determined. In addition, whether the addition of chemotherapy to CIRT is needed remains unknown. These questions will be evaluated in the dose-escalating phase I and randomized\nphase II trials....
Background: Recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN) has a poor prognosis and\nthe combination of cisplatin and cetuximab, with or without 5-fluorouracil, is the gold standard treatment in this stage.\nThus, the concomitant use of novel compounds represents a critical strategy to improve treatment results. Histone\ndeacetylase inhibitors (HDACi) enhance the activity of several anticancer drugs including cisplatin and anti-Epidermal\nGrowth Factor Receptor (anti-EGFR) compounds. Preclinical studies in models have shown that vorinostat is able to\ndown regulate Epidermal Growth Factor Receptor (EGFR) expression and to revert epithelial to mesenchimal transition\n(EMT). Due to its histone deacetylase (HDAC) inhibiting activity and its safe use as a chronic therapy for epileptic\ndisorders, valproic acid (VPA) has been considered a good candidate for anticancer therapy. A reasonable option may\nbe to employ the combination of cisplatin, cetuximab and VPA in recurrent/metastatic SCCHN taking advantage of the\npossible positive interaction between histone deacetylase inhibitors, cisplatin and/or anti-EGFR.\nMethod/Design: V-CHANCE is a phase 2 clinical trial evaluating, in patients with recurrent/metastatic squamous cell\ncarcinoma of the head and neck never treated with first-line chemotherapy, the concomitant standard administration\nof cisplatin (on day 1, every 3 weeks) and cetuximab (on day 1, weekly), in combination with oral VPA given daily from\nday âË?â??14 with a titration strategy in each patient (target serum level of 50ââ?¬â??100 Ã?¼g/ml). Primary end point is the\nobjective response rate measured according to Response Evaluation Criteria in Solid Tumors (RECIST). Sample size,\ncalculated according to Simon 2 stage minimax design will include 21 patients in the first stage with upper limit\nfor rejection being 8 responses, and 39 patients in the second stage, with upper limit for rejection being 18\nresponses. Secondary endpoints are time to progression, duration of response, overall survival, safety.\nObjectives of the translational study are the evaluation on tumor samples of markers of treatment efficacy/resistance (i.e. Ã?³H2AX, p21/WAF, RAD51, XRCC1, EGFR, p-EGFR, Ki-67) and specific markers of VPA HDAC inhibitory\nactivity (histones and proteins acetylation, Histone deacetylase isoforms) as well as valproate test, histones and\nproteins acetylation of peripheral blood mononuclear cell, tested on blood samples at baseline and at different\ntime points during treatment.\nDiscussion: Overall, this study could provide a less toxic and more effective first-line chemotherapy regimen in\npatients with recurrent/metastatic squamous cell carcinoma of the head and neck by demonstrating the feasibility and\nefficacy of cisplatin/cetuximab plus valproic acid. Moreover, correlative studies could help to identify responder\npatients, and will add insights in the mechanism of the synergistic interaction between these agents....
Background: Adding bevacizumab to chemotherapy improves response rates and progression-free survival (PFS) in\nmetastatic breast cancer (mBC). We aimed to demonstrate decreased toxicity with metronomic chemotherapy/\nbevacizumab compared with paclitaxel/bevacizumab.\nMethods: This multicenter, randomized phase III trial compared bevacizumab with either paclitaxel (arm A) or daily\noral capecitabine-cyclophosphamide (arm B) as first-line treatment in patients with HER2-negative advanced breast\ncancer. The primary endpoint was the incidence of selected grade 3ââ?¬â??5 adverse events (AE) including: febrile\nneutropenia, infection, sensory/motor neuropathy, and mucositis. Secondary endpoints included objective response\nrate, disease control rate, PFS, overall survival (OS), quality of life (QoL), and pharmacoeconomics. The study was\nregistered prospectively with ClinicalTrials.gov, number NCT01131195 on May 25, 2010.\nResults: Between September 2010 and December 2012, 147 patients were included at 22 centers. The incidence of\nprimary endpoint-defining AEs was similar in arm A (25 % [18/71]; 95 % CI 15ââ?¬â??35 %) and arm B (24 % [16/68]; 95 %\nCI 13ââ?¬â??34 %; P = 0.96). Objective response rates were 58 % (42/73; 95 % CI 0.46ââ?¬â??0.69) and 50 % (37/74; 95 % CI 0.39ââ?¬â??\n0.61) in arms A and B, respectively (P = 0.45). Median PFS was 10.3 months (95 % CI 8.7ââ?¬â??11.3) in arm A and 8.\n5 months (95 % CI 6.5ââ?¬â??11.9) in arm B (P = 0.90). Other secondary efficacy endpoints were not significantly different\nbetween study arms. The only statistically significant differences in QoL were less hair loss and less numbness in\narm B. Treatment costs between the two arms were equivalent.Conclusion: This trial failed to meet its primary endpoint of a reduced rate of prespecified grade 3ââ?¬â??5 AEs with\nmetronomic bevacizumab, cyclophosphamide and capecitabine....
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