Granocyte-colony Stimulating Factor (G-CSF) Has Significant Efficacy as Secondary Prophylaxis of Chemotherapy-induced Neutropenia in Patients with Solid Tumors: Results of a Prospective Study

Abstract. Aim: To carry out a prospective, multicenter and observational study describing prophylactic strategies [cycle delay, dose-reduction, (G-CSF) Neutropenia is a common side-effect of cancer chemotherapy in patients with solid tumors. Febrile neutropenia (FN), defined by grade 4 neutropenia and >38.0˚C fever is the complication of most concern. It is associated with severe morbidity and increased risk of mortality (1-3). A correlation between the dose/dosing schedule and neutropenia has been established for most cytotoxic agents (4, 5). However the risk of developing life-threatening complications after an episode of severe neutropenia (i.e. FN) is variable from one patient to another due to individual risk factors. Some risk factors can be considered in predicting the risk of neutropenia and are well-established in international guidelines in the primary prophylaxis setting (5, 6). These are: age (>65 years old and older), advanced disease, altered patient condition [poor performance status (PS) and/or nutritional status], preexisting condition (active infection, open wound, recent surgery), previous FN, previous irradiation to pelvis, and impaired renal or liver function. Granulocyte colony stimulating factors (G-CSF) reduce the severity and duration of neutropenia and F

Chemotherapeutic errors in hospitalised cancer patients: attributable damage and extra costs

<p>Abstract</p> <p>Background</p> <p>In spite of increasing efforts to enhance patient safety, medication errors in hospitalised patients are still relatively common, but with potentially severe consequences. This study aimed to assess antineoplastic medication errors in both affected patients and intercepted cases in terms of frequency, severity for patients, and costs.</p> <p>Methods</p> <p>A 1-year prospective study was conducted in order to identify the medication errors that occurred during chemotherapy treatment of cancer patients at a French university hospital. The severity and potential consequences of intercepted errors were independently assessed by two physicians. A cost analysis was performed using a simulation of potential hospital stays, with estimations based on the costs of diagnosis-related groups.</p> <p>Results</p> <p>Among the 6, 607 antineoplastic prescriptions, 341 (5.2%) contained at least one error, corresponding to a total of 449 medication errors. However, most errors (n = 436) were intercepted before medication was administered to the patients. Prescription errors represented 91% of errors, followed by pharmaceutical (8%) and administration errors (1%). According to an independent estimation, 13.4% of avoided errors would have resulted in temporary injury and 2.6% in permanent damage, while 2.6% would have compromised the vital prognosis of the patient, with four to eight deaths thus being avoided. Overall, 13 medication errors reached the patient without causing damage, although two patients required enhanced monitoring. If the intercepted errors had not been discovered, they would have resulted in 216 additional days of hospitalisation and cost an estimated annual total of 92, 907€, comprising 69, 248€ (74%) in hospital stays and 23, 658€ (26%) in additional drugs.</p> <p>Conclusion</p> <p>Our findings point to the very small number of chemotherapy errors that actually reach patients, although problems in the chemotherapy ordering process are frequent, with the potential for being dangerous and costly.</p

Traitement du cancer de l'ovaire au stage avancé chez la femme de plus de 70 ans (l'expérience du GINECO)

LYON1-BU Santé (693882101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Cancer de l'ovaire de la femme agée (influence de la composition corporelle sur la survie et la toxicité au traitement)

L'essai FAG-3 du groupe GINECO (Groupe d'Investigateurs Nationaux pour l'Etude des Cancers de l'Ovaire) a mis en évidence par l'intermédiaire du score de vulnérabilité gériatrique (GVS) la forte prévalence de la dénutrition et de la perte d'autonomie chez les femmes âgées atteintes de cancer épithélial de l'ovaire de stade avancé, traitées par carboplatine. Selon certaines études, l'étude de la composition corporelle, et notamment la diminution de masse musculaire appelée sarcopénie, apparaît être un facteur prédictif de chimiotoxicité et de mortalité. Notre étude exploratoire réalisée sur 50 patientes des Ill de l'essai FA G-3 n'a pas mis en évidence de lien entre la sarcopénie, survie globale et toxicité chimio-induite dans le cadre du cancer de l'ovaire. Contrairement aux études précédentes dont la dose de chimiothérapie était basée sur la surface corporelle, les patientes de notre étude ont reçu du carboplatine calculé selon la formule de Chatelut. Ce mode de calcul permet indirectement de tenir compte des paramètres nutritionnels en intégrant le poids et la créatininémie. Une corrélation entre masse grasse et toxicité hématologique a été mise en évidence. Il existe à l'heure actuelle très peu de données scientifiques sur ce sujet. Un essai prospectif sur un plus grand nombre de patientes devra confirmer ces résultats. Par ailleurs, nous n'avons pas mis en évidence de corrélation entre la composition corporelle et la perte d'autonomie dans le cancer de l'ovaire de la femme âgée. La mesure de la force musculaire (dynapénie) semble être un facteur mieux corrélé à l'incapacité et à la survie que la diminution de la masse musculaireLYON1-BU Santé (693882101) / SudocSudocFranceF

Is There an Age Threshold for Holding Off on Testing Novel Therapies?

International audiencePurpose of Review We will review the reasons that explain the poor accrual of elderly patients to clinical trials, then we will discuss the relevance of an age threshold for holding off on testing novel therapies. Recent Findings Little progress has been made in enrolling elderly patients in clinical trials. Summary Reasons to hold off on testing novel therapies in elderly patients are mainly explained by exclusion criteria and industrials' reluctance to include elderly patients for fear of negative results. No age threshold should exist for testing novel therapies as long as well-designed clinical trials are developed and requested by regulatory authorities. Furthermore, clinical trials assessing novel anticancer therapies such as targeted therapies or immune checkpoint inhibitors should be developed in elderly patients regardless of age as these therapies may present a favorable benefit-risk profile compared to chemotherapy which is often more toxic and at risk of geriatric deconditioning

Toxicity of Cancer Therapies in Older Patients

International audienceIn clinical practice, older patients are often undertreated due to underrepresentation in clinical trials and fear of toxicity. Our objective was therefore to review toxicities that are specific to older cancer patients, to review risk factors in order to help physicians guide their decisions, and to review interventions that can be implemented in routine clinical practice to prevent toxicity induced by cancer therapies. On the whole, reviews report similar number and frequency as well as similar grade 3 or 4 adverse events between subjects older and younger than 65 years. Yet patients included in clinical trials are often not representative of real-life patients and are often fit older cancer patients. Moreover, tolerance to the additive impact of multiple adverse effects is different between older and younger patients. And specific symptoms such as stomatitis may cause a series of consequences such as dehydration, denutrition, renal insufficiency, and adverse events of renally excreted drugs. Older patients are at high risk of toxicity due to many factors but mainly due to the prevalence of frailty in this population that has been estimated to be around 40% increasing the risk of chemotherapy intolerance. As a consequence, interventions must be implemented according to altered domains of comprehensive geriatric assessment in order to improve anticancer tolerance. These interventions are reviewed here

A Proactive Approach to Prevent Hematopoietic Exhaustion During Cancer Chemotherapy in Older Patients: Temporary Cell-Cycle Arrest

Age is associated with the decline of multiple organ systems. In older patients, hematological toxicities associated with chemotherapy are often dose limiting, impairing dose intensity and treatment efficacy. Contrary to the classical path using growth factors to activate tissue regeneration, a novel strategy is emerging to prevent chemotherapy toxicity that involves temporary cell-cycle arrest of normal cells, such as hematopoietic or epithelial precursors. This proactive approach may allow the sparing of the stem cell reserve of these tissues. Two molecules are included in this new category, trilaciclib and ALRN-6924, which induce cell-cycle arrest by two different pathways. Previous approaches, such as the use of myelopoietic growth factors, were reactive and they might even have accelerated the depletion of stem cells by enhancing the commitment of these elements. Trilaciclib causes cell-cycle arrest by CDK 4/6 inhibition and ALRN-6924 by p53 activation. In a pooled analysis of three randomized phase II studies of patients with small cell lung cancer, trilaciclib prevented neutropenia, thrombocytopenia, and anemia. Similar chemoprotective results were observed with ALRN-6924 in an open-label phase Ib study of patients with p53-mutated small cell lung cancer. Trilaciclib is now approved as a myelopreservation agent in patients with extensive-stage small cell lung cancer. ALRN-6924 is currently in phase Ib clinical development in patients with p53-mutated cancer. In addition to preserving the normal hemopoietic pool, these drugs promise to preserve the stem cell reserve of other normal tissues with high turnover, preventing potentially other dose-limiting toxicities, such as mucositis and diarrhea. An "ex vivo" study provided early evidence that ALRN-6924 may prevent chemotherapy-induced alopecia. By affording protection from multiple toxicities with a single drug, trilaciclib and ALRN-6924 have the potential to transform the current standards of supportive care for oncology patients and may prevent the depletion of tissue stem cells already compromised with age

The biology of aging and lymphoma: a complex interplay

International audienceThe probability to develop non-Hodgkin lymphoma grows with age. The biological links between aging and lymphoma are not well described in the literature, and different hypothesis may be raised to explain this complex relationship. First, the impact of chronological age favoring the accumulation of genetic alterations can contribute to the multisteps proces of lymphomagenesis. Then, the age-related defects in cancer protection and the age-related clonal restriction in hematopoietic stem cell may also promote lymphoma development. Finally, the senescent and immunosenescence phenotype might represent a key process explaining this link. In this review, we will explore the current available clinical data and their ability to apply to age-related regulation pathways

New Advances in Supportive Care: Chemoprotective Agents as Novel Opportunities in Geriatric Oncology

International audienceExplorer l'efficacité du trilaciclib et de l'ALRN-6924 dans la prévention de la toxicité induite par la chimiothérapie anticancéreuse chez les patients âgés. De nouveaux agents chimioprotecteurs sont nécessaires car l'âge est le principal facteur de risque des complications de la chimiothérapie qui expliquent en grande partie les moins bons résultats du cancer chez les personnes âgées. Le trilaciclib et l'ALRN-6924 provoquent un blocage réversible de la prolifération des cellules normales par arrêt du cycle cellulaire (CCA). Grâce à ce mécanisme, ils peuvent prévenir la toxicité du traitement anticancéreux à cycle actif, notamment la neutropénie, l'anémie, la thrombocytopénie, la lymphopénie, la mucosite et l'alopécie.Découvertes récentes : Les facteurs de croissance myélopoïétiques peuvent prévenir la neutropénie chez les personnes âgées, mais ils peuvent provoquer des douleurs osseuses sévères, peuvent aggraver la thrombocytopénie et l'anémie, et peuvent entraîner une myélodysplasie et une leucémie aiguë comme complication tardive. La prévention de la thrombocytopénie, de l'anémie, de la mucosite et de l'alopécie est actuellement insatisfaisante. Ces complications peuvent compromettre le résultat du traitement car elles nécessitent une réduction de la dose/de l'intensité du traitement et parce que de nombreux patients trouvent les symptômes qui en résultent intolérables. Dans trois études portant sur des patients atteints d'un cancer du poumon à petites cellules (ES-SCLC) extensif, le trilaciclib a réduit la gravité et la durée de la neutropénie et de la thrombocytopénie ainsi que le besoin de transfusions sanguines. De plus, il a produit une expansion significative des clones de lymphocytes T. Le trilaciclib a reçu l'approbation de la FDA pour la prévention de la myélosuppression induite par la chimiothérapie chez les patients atteints de ES-SCLC. ALRN-6924 est actuellement étudié dans le cadre de l'étude de phase II de l'ES-SCLC. Dans une phase IB de 38 patients, ALRN-6924 a empêché la myélosuppression dans une mesure comparable au trilaciclib. Les deux médicaments se sont avérés aussi efficaces chez les patients de 65 ans et plus que chez les plus jeunes. Dans une étude "ex vivo", ALRN-6924 a protégé les cellules souches épithéliales des follicules pileux des taxanes et a promis de prévenir l'alopécie. La possibilité que le CCA des cellules tumorales puisse réduire l'efficacité de la chimiothérapie cyclique est une préoccupation majeure. Pour cette raison, l'utilisation de trilaciclib, un inhibiteur de CDK 4/6, doit être limitée aux tumeurs avec RB1 inactivé, et l'utilisation d'ALRN-6924, un inhibiteur de P53, doit être limitée aux tumeurs avec P53 inactivé. Les toxicités liées à la chimiothérapie limitent l'intensité de la dose et contribuent à une morbidité et une mortalité importantes chez les patients âgés atteints de cancer. Le trilaciclib et l'ALRN-6924 intéressent particulièrement les oncologues gériatriques en raison de leur nouveau mécanisme d'action. L'amélioration des toxicités induites par la chimiothérapie promet de transformer la pratique de l'oncologie gériatrique en permettant des régimes chimiothérapeutiques qui ne sont actuellement pas réalisables pour cette population de patients. Plus précisément, ces agents peuvent prévenir la neutropénie et la thrombocytopénie induites par la chimiothérapie, peut-être les complications les plus potentiellement mortelles de la chimiothérapie cytotoxique, évitant ainsi la nécessité d'utiliser des stratégies de sauvetage telles que les facteurs de croissance hématopoïétiques. De plus, ces agents offrent le potentiel d'une large protection tissulaire contre d'autres toxicités liées à la chimiothérapie, y compris la mucosite, la diarrhée et l'alopécie, qui ont toujours été mal gérées. Il est important de noter qu'en prévenant un éventail de toxicités liées à la chimiothérapie, ces agents peuvent permettre l'administration de la chimiothérapie à pleine dose, prévenir le déclin fonctionnel et assurer le maintien de la résilience aux patients âgés atteints de cancer. Par conséquent, la prévention réussie des effets secondaires induits par la chimiothérapie peut non seulement atténuer les coûts des soins, mais également améliorer les résultats pour les patients et la qualité de vie. Enfin, les stratégies chimioprotectrices offrent la possibilité d'appliquer les principes gériatriques aux essais cliniques de traitement du cancer. En particulier, ils peuvent permettre de tester la prolongation de "l'espérance de vie active" en tant qu'objectif majeur des essais cliniques chez les patients âgés. Ils peuvent également permettre des formes nouvelles et plus pratiques d'essais cliniques

Biology of cancer and aging: a complex association with cellular senescence

International audienceOver the last 50 years, major improvements have been made in our understanding of the driving forces, both parallel and opposing, that lead to aging and cancer. Many theories on aging first proposed in the 1950s, including those associated with telomere biology, senescence, and adult stem-cell regulation, have since gained support from cumulative experimental evidence. These views suggest that the accumulation of mutations might be a common driver of both aging and cancer. Moreover, some tumor suppressor pathways lead to aging in line with the theory of antagonist pleiotropy. According to the evolutionary-selected disposable soma theory, aging should affect primarily somatic cells. At the cellular level, both intrinsic and extrinsic pathways regulate aging and senescence. However, increasing lines of evidence support the hypothesis that these driving forces might be regulated by evolutionary-conserved pathways that modulate energy balance. According to the hyperfunction theory, aging is a quasi-program favoring both age-related diseases and cancer that could be inhibited by the regulation of longevity pathways. This review summarizes these hypotheses, as well as the experimental data that have accumulated over the last 60 years linking aging and cancer