Pharmacoeconomic Evaluations of Oral Anticancer Agents. Thematic Systematic Review

Background: Around 14.1 million new cancer cases and 8.2 million deaths caused by cancer were reported in 2012, expected to rise up to 22 million within the next 2 decades. The parenteral route (intravenous dosage form) has been the most common administration route for chemotherapeutic agents, which is associated with the need for hospitalization and a range of significant adverse drug reaction. A new generation of chemotherapies that is orally administered has been introduced to practices as a superior and more efficient therapeutic alternative. Oral anticancer drugs (OACDs) have shown to be eliminating the need for hospitalization, decreasing the rate of adverse drug reactions and, ultimately, improving patients' quality of life. Economically, this translates into reduction in inpatient hospitalization costs, including several of the associated costs, such as the cost of treating side effects. A disadvantage of OACDs however, is the increased acquisition costs as compared to those for the intravenously administered alternatives. This resulted into resistance to include OACDs by several international insurance schemes and drug formulary practices, including in Qatar. Objectives: The current project sought to analyze the medical literature in relation to published economic evaluations (pharmacoeconomics) of OACDs, especially as compared to the parenteral alternatives. This will identify the decision analytic modeling conducted as well as the variety of methods used. Strengths and weaknesses of study designs will be determined, including gaps in knowledge. Methodology: A thematic systematic review was conducted using the search engines: PubMed, Medline, EconLit, Embase and Economic Evaluation Database. The following 3 categories were considered: (i) therapy (chemotherapy [Mesh]); (ii) dosage form (oral [Mesh]); and (iii) research design (economics [Mesh] OR cost-benefit analysis [Mesh]). These included full-text, English articles incorporating comparative economic evaluations of oral chemotherapies. Excluded studies were: non-comparative, non-economic based models, of secondary indications (not cancer), and/or reviews. This process was followed by two stages of manual exclusion; based on title/abstract content and, then, the full-text article content. A data extraction form was developed and pilot tested for the purpose of data collection. Article inclusion and data collection was conducted twice, each by a different investigator. Included articles were finally summarized according to methodological themes of interest. Results: A total of 235 records were identified. After screening and removing duplicates, only 18 studies were deemed eligible study inclusion. It was found that the pharmacoeconomics evaluations were mostly of cost-utility analyses (13 out of 18), measuring cost per quality adjusted life years (QALY) gained, and from the payer perspective (15 out of 18). Primary sources of clinical and economic data were randomized clinical trials, expert panels and medical charts. Other sources included medicine databases, reimbursement schedules, drug policies and price lists, treatment guidelines, case reports and patient interviews. In 13 out of 18 cases, dominance status was reported in favor of OACDs, in relation to cost and/or clinical effect. Decision analytic modeling was used in the majority of studies, mostly constituting Markov modeling for the simulation of life long use of drugs. Sensitivity analyses were conducted in most studies, mostly constituting one-way sensitivity analysis to ensure robustness of study results. The types of cancers, where the effect of OACDs was studied, were the metastatic renal carcinoma, gastrointestinal tumors, colon cancer, chronic myeloid leukemia and non-small cell lung cancer. Most included articles were published during the last seven years. Most studies were conducted in the UK, US and Europe, while none were conducted in Australia or the Middle East. Conclusion: This is first systematic review of the economic methods used in the evaluation of OACDs. There seems to be a recent increasing interest of this type of research, whereby the QALYs measurement is of priority for the decision making in relation to the comparative value of OACDs in practices. Most important, is that despite the higher acquisition cost, OACDs were demonstrated to be mostly superior over the parenteral alternatives. Furthermore, the decision analytic modeling, mostly constituting Markov modeling, is valued and enables a structured decision analyses of therapies. The pharmacoeconomics research is difficult to generalize, whereby published economic evaluations are locally specific, especially for the purpose of practical interpretation. The current review of literature proposes valuable methods for the local Qatari implementation and guidance of decision makers. This is most relevant to National Center for Cancer Care & Research (NCCCR), which is the only tertiary service provider of cancer therapy in Qatar, where confusion in relation to the use of oral chemotherapies exists, particularly the therapies vinorelbine and capacitabine.qscienc

Kaposi’s Sarcoma Presenting As Lymphadenopathy In An Immunocompetent Patient

Introduction: Kaposi’s sarcoma (KS) is an angioproliferative disorder first described in 1872 by Moritz Kaposi. Four main clinical presentations of KS have been described: classic, endemic, iatrogenic and epidemic. KS involvement of the lymph nodes is extremely uncommon in the classical variant form, especially if it precedes the skin manifestations. We describe the case of an elderly HIV-negative patient presenting with lymphadenopathy who was found to have KS. Case Report: A 67-year-old patient was admitted for exploration of polyadenopathies in the context of a general decline in health. Physical examination revealed an erythematosus left lower limb rash associated with angiomatous nodules and multiple lymphadenopathies. The diagnosis of erysipelas in the left leg was retained and the patient was treated with good evolution of the rash but persistence of the angiomatous nodules and the polyadenopathies. Skin and lymph node biopsies led to a diagnosis of KS. The patient is proposed for polychemotherapy. Conclusion: KS must be suspected in lymphadenopathies despite the absence of typical cutaneous signs of the disease and in immunocompetent patients

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Does isolated myocardial bridge really interfere with coronary blood flow?

Background: Myocardial bridge (MB) is defined as a segment of a major epicardial coronary artery the “tunneled artery” that goes intramurally through the myocardium beneath the muscle bridge. Multiple methods have been proposed to assess coronary flow rate among which thrombolysis in acute myocardial infarction frame count was a relatively new semiquantitative method. Objectives: Our goal was to determine incidence of MB in the patients undergoing coronary angiography in Mansoura Specialized Hospital, Cardiac Catheterization Laboratory, also to investigate the hypothesis that slow coronary flow rate may be linked to angina or angina like symptoms in patients with MB without stenotic lesions in epicardial coronary arteries using TFC. Patients and methods: Fifteen patients with MB (group I) were retrospectively collected from Mansoura Specialized Hospital, Cardiac Catheterization Laboratory, we review 3000 cases referred to diagnostic coronary angiography to exclude significant coronary artery disease. Fifteen patients with normal coronary angiography served as control (group II). We review the clinical presentations, risk factors, echocardiographic data for both test and control groups. TFC was calculated using a simple continuous index. Results: The incidence of MB in our study was 0.5%. CTFC in LAD was significantly higher in the patients with MB compared with control. No significant correlation between TFC and echocardiographic parameters. Conclusions: Myocardial bridging must be considered especially in patients at low risk for coronary atherosclerosis but with angina like chest pain or established myocardial ischemia. We suggest that coronary blood flow is decreased in the patients with MB compared with the patients having normal coronary

Dosimetric impact on changes in target volumes during intensity-modulated radiotherapy for nasopharyngeal carcinoma

Background and purposeTo assess anatomic changes during intensity modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) and to determine its dosimetric impact.Patients and methodsTwenty patients treated with IMRT for NPC were enrolled in this study. A second CT was performed at 38Gy. Manual contouring of the macroscopic tumor volumes (GTV) and the planning target volumes (PTV) were done on the second CT. We recorded the volumes of the different structures, D98 %, the conformity, and the homogeneity indexes for each PTV. Volume percent changes were calculated.ResultsWe observed a significant reduction in tumor volumes (58.56 % for the GTV N and 29.52 % for the GTV T). It was accompanied by a significant decrease in the D98 % for the 3 PTV (1.4Gy for PTV H, p=0.007; 0.3Gy for PTV I, p=0.03 and 1.15Gy for PTV L, p=0 0.0066). In addition, we observed a significant reduction in the conformity index in the order of 0.02 (p=0.001) and 0.01 (p=0.007) for PTV H and PTV I, respectively. The conformity variation was not significant for PTV L. Moreover, results showed a significant increase of the homogeneity index for PTV H (+ 0.03, p=0.04) and PTV L (+ 0.04, p=0.01).ConclusionTumor volume reduction during the IMRT of NPC was accompanied by deterioration of the dosimetric coverage for the different target volumes. It is essential that a careful adaptation of the treatment plan be considered during therapy for selected patients

Synthesis and characterization of AgYP2O7 pyrophosphate activated with Tb3+, Sm3+ and Dy3+ ions

International audienceSilver yttrium phosphates AgYP2O7 doped with Tb3+, Sm3+ and Dy3+ (x = 0, 1, 3 5, 10, 15, 20 mol%) were successfully prepared via solid state reaction. The similarity between all diffractograms of prepared phosphors confirm that they are a single pure phase. The Fourier Transform InfraRed (FTIR) analysis are in good agreement with structure type, the characteristic bands of P2O74−groups attributed to the symmetric and asymmetric stretching of P-O-P bridge, respectively are identified. The investigation on luminescence of Tb3+, Sm3+ and Dy3+ ions in this phase is reported. The cross-relaxation phenomenon widely known in phosphors based on Tb3+ is pointed out. A prediction of the nature of the occupied site by the rare earth ion was possible using the predominant intensity in both Sm3+ and Dy3+ ions

Application of spectroscopic properties of Eu3+ ion to predict the site symmetry of active ions in AgLaP2O7: Eu3+ phosphors

International audienceA suite of AgLa1-xEuxP2O7 (x = 1, 5, 10, 15, 20 and 100%) diphosphates were prepared by solid state reaction at T = 500 °C. Powder X-rays diffraction analysis (XRD) reveal that AgLaP2O7 phase doped with 1, 5, 10, 15 and 20% of Eu3+ are isostructural with AgLaP2O7 (Hami et al., 2018 [1]) while AgLaP2O7:100% Eu3+ is isostructural with AgTbP2O7 diphosphate (Rizzi et al., 2019 [2]). A decreasing trend for unit cell parameters of solid solutions with increasing the Eu3+ content have been observed. The Fourier Transform InfraRed (FTIR) spectra are in good agreement with structure type, highlighting the characteristic bands of P2O74− groups attributed to the symmetric and asymmetric stretching of P-O-P bridge. Spectroscopic properties of Eu3+ have been used to probe the local environment of the Eu3+ ion in AgLaP2O7:Eu3+. The number of components observed for the 5D0 → 7F0–4 transitions is consistent with that predicted by group theory calculations for Cs symmetry. The CIE chromaticity coordinates (x, y) for AgLaP2O7: 10, 15 and 20% Eu samples have been calculated

Synthesis, structural characterization and luminescent properties of Tb 3+ -doped AgLaP 2 O 7 phosphors

Silver lanthanum diphosphates doped with terbium, AgLa1-xTbxP2O7 (x=0%, 1%, 5%, 10%, 15% and 20%), were prepared by solid state reaction at T=500°. The obtained compounds were investigated by means of a multi-methodological approach, involving the Scanning Electron Microscopy (SEM) equipped with energy dispersive X-Ray spectroscopy (EDS) for morphological investigation and semi-quantitative chemical analysis, respectively; powder X-ray diffraction (PXRD) for structural characterization and Rietveld refinement; Fourier Transform InfraRed (FTIR) and Raman spectroscopies for qualitative study. Finally, emission spectra were collected in order to detect the fluorescence properties of the compounds. The unit cell parameters and the space group of all the family members were determined by PXRD data. The compounds crystallize in the orthorhombic Pnma space group, with the AgLaP2O7 cell constants equal to: a = 8.6706(1) Å, b = 5.3218(1) Å, c = 12.8839(1) Å and cell volume V = 594.51(1) Å3. A decreasing trend for unit cell parameters was observed at increase of dopant concentration. For the pure phase, the investigation was completed with the structure solution via Direct Methods and Rietveld refinement. The crystal structure consists of compact layers of LaO9 polyhedra, down the c axis, bridged by P2O7 diphosphate groups and by zig-zag chains of AgO9 polyhedra down b. The FTIR and Raman analysis supports the chemical structure, highlighting the deformation (δPO3) and stretching (νPO3) vibration of PO3 groups, and the characteristic bands of P2O74- groups attributed to the symmetric and asymmetric stretching (νs and νas) of P-O-P bridge, respectively. The luminescence properties of Tb3+ activating ion in AgLa1-xTbxP2O7 (x=1%, 5%, 10%, 15% and 20%) were also examined. No concentration quenching of the main 5D4-→7F5 emission, responsible for the well known green emission of Tb3+ ion, was observed in the studied concentration range, whereas a concentration quenching of the emission from 5D3 level, due to 5D3-→5D4 cross relaxation process, was revealed

Haplotypic classification of dystrophic epidermolysis bullosa in Tunisian consanguineous families: implication for diagnosis

International audienceDystrophic epidermolysis bullosa (DEB) is a rare genodermatosis caused by mutations in the type VII collagen gene COL7A1. Clinical diagnosis of DEB should be confirmed by histopathological and electron microscopy analysis, which is not always accessible. We report here a genetic investigation of DEB consanguineous families in Tunisia. A total of 23 EB families were genotyped with 5 microsatellite markers overlapping the COL7A1 gene. Among these families, 19 presented with the dystrophic form of EB, 9 were diagnosed by histopathological examination, 2 had the simplex form, 1 had a junctional EB, and 1 was affected by an unclassified form of EB. The informativeness of the markers was studied and allowed us to select three markers for genetic testing of DEB in Tunisian families at risk. Haplotype analysis and homozygosity by descent suggest that all families classified clinically as having DEB and the patient who presented with an unclassified form of EB are likely linked to the COL7A1 gene, and showed evidence for exclusion for the simplex and junctional cases. For COL7A1 linked families, two main haplotypes were shared by eight families. For all the other cases, haplotypic heterogeneity was observed, thus suggesting a mutational heterogeneity among Tunisian DEB families. The genetic results matched with the ultrastructural analysis in all the DEB families and with the clinical examination in 94.7% of all studied DEB families. This study is to our knowledge the first genetic investigation of DEB in the Maghrebian population. We propose a selection of informative markers and show the importance of haplotype analysis as a relatively easy and cost and time effective method for carrier screening and prenatal diagnosis of DEB in consanguineous families at risk