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  1. Article ; Online: Senotherapy, cancer, and aging.

    Balducci, Lodovico / Falandry, Claire / Silvio Monfardini

    Journal of geriatric oncology

    2023  , Page(s) 101671

    Abstract: Introduction: We aimed to highlight the effects of senotherapy on the prevention and treatment of cancer in older individuals. The aim of senotherapy is to eliminate senescent cells. These cells express the senescence-associated secretory phenotype ( ... ...

    Abstract Introduction: We aimed to highlight the effects of senotherapy on the prevention and treatment of cancer in older individuals. The aim of senotherapy is to eliminate senescent cells. These cells express the senescence-associated secretory phenotype (SASP). With production of inflammatory cytokines, growth factors, and different type of proteases, the SASP is responsible for aging-associated disability and diseases. All mammalian cells experience senescence. The main agents of aging include fibroblasts and adipose cells. Senescent tumor cells may undergo genomic reprogramming and re-enter cell cycle with a stem cell phenotype.
    Materials and methods: We conducted a Medline search for the following key words: senotherapy, senolysis, senomorphic agents. We provide a narrative review of the finding.
    Results: Different agents may eliminate senescent cells from cell cultures and murine models. These include metformin, rapamycin, desatinib, quercitin, fisetin, ruloxitinib, and BCL2 inhibitors. A randomized controlled study of metformin in 3,000 patients aged 65-79 without glucose intolerance aiming to establish whether senotherapy may prevent or reverse disability and aging associated diseases, including cancer, is ongoing. Senotherapy prolongs the life span and decreases the incidence of cancer in experimental animal models, as well as delays and reverses disability. Senescent tumor cells are found prior to treatment and after chemotherapy and radiation. These elements may be responsible for tumor recurrence and treatment refractoriness.
    Discussion: Senotherapy may have substantial effects on cancer management including decreased incidence and aggressiveness of cancer, improved tolerance of antineoplastic treatment, and prevention of relapse after primary treatment. Senotherapy may ameliorate several complications of cancer chemotherapy.
    Language English
    Publishing date 2023-11-15
    Publishing country Netherlands
    Document type Journal Article ; Review
    ZDB-ID 2556813-9
    ISSN 1879-4076 ; 1879-4068
    ISSN (online) 1879-4076
    ISSN 1879-4068
    DOI 10.1016/j.jgo.2023.101671
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  2. Article ; Online: A Proactive Approach to Prevent Hematopoietic Exhaustion During Cancer Chemotherapy in Older Patients: Temporary Cell-Cycle Arrest.

    Balducci, Lodovico / Falandry, Claire / List, Alan

    Drugs & aging

    2023  Volume 40, Issue 3, Page(s) 263–272

    Abstract: 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 ... ...

    Abstract 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.
    MeSH term(s) Humans ; Aged ; Small Cell Lung Carcinoma/drug therapy ; Small Cell Lung Carcinoma/etiology ; Tumor Suppressor Protein p53/therapeutic use ; Antineoplastic Agents/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Lung Neoplasms/drug therapy ; Cell Cycle Checkpoints ; Clinical Trials, Phase II as Topic ; Randomized Controlled Trials as Topic ; Clinical Trials, Phase I as Topic
    Chemical Substances Tumor Suppressor Protein p53 ; Antineoplastic Agents
    Language English
    Publishing date 2023-01-30
    Publishing country New Zealand
    Document type Journal Article ; Review
    ZDB-ID 1075770-3
    ISSN 1179-1969 ; 1170-229X
    ISSN (online) 1179-1969
    ISSN 1170-229X
    DOI 10.1007/s40266-022-01005-1
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    Zs.A 3481: Show issues Location:
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  3. Article ; Online: Cell cycle arrest: A breakthrough in the supportive care of older cancer patients.

    Falandry, Claire / List, Alan / Balducci, Lodovico

    Journal of the American Geriatrics Society

    2023  Volume 71, Issue 7, Page(s) 2297–2307

    Abstract: Background: Age is a major risk factor for the acute and chronic complications of cancer chemotherapy. The current approach to the prevention of these complications is reactive and involves the reduction of the doses and the delay of treatment which may ...

    Abstract Background: Age is a major risk factor for the acute and chronic complications of cancer chemotherapy. The current approach to the prevention of these complications is reactive and involves the reduction of the doses and the delay of treatment which may compromise the outcome. There is a limited number of antidotes to chemotherapy toxicity and these have complications of their own. Oldest old and frail patients are mostly excluded from life saving cancer treatment due to the risk of severe and even lethal complications.
    Methods: molecular biology has revealed that different checkpoints control the proliferative cycle of normal and neoplastic cells. Two new drugs, Trilaciclib and ALRN-6924 may cause a temporary cell cycle arrest (CCA) of normal cells without blocking the proliferation of the neoplastic ones and render the normal cells temporarily invulnerable to the toxicity of chemotherapy. We reviewed the publications related to these drugs on the Medline, the published drug information and the presentations to major medical conferences.
    Results: In three randomized controlled phase II trials Trilaciclib proved effective in preventing neutropenia, thrombocytopenia and anemia in patients with non small cell lung cancer with non proficient RB1 gene. Forty-five percent of patients were 65 and older and age did not prevent the effectiveness of the drug. Trilaciclib was approved by the FDA for the management of these patients. ALRN-6924 appeared promising in preventing myelotoxicity in patients whose cancer had deleted or mutated TP53, but failed to show any significant activity in a randomized controlled study. The development of this drug is now on hold CONCLUSIONS: CCA is a novel proactive approach to the toxicity of chemotherapy of special interest to older patients. At the very least it may prevent all forms of myelotoxicity with a single agent, obviating the risk and cost of polypharmacy. It allows to avoid the complications of myelopoietic growth factors which include severe pain, stem cell competition, bone marrow exhaustion, and hematological malignancies. It may allow the treatment of frail patients with full chemotherapy doses. It is also reasonable to expect that may complications other common and sometimes lethal complications of chemotherapy such as stomatitis, esophagitis, diarrhea and dehydration.
    MeSH term(s) Aged, 80 and over ; Humans ; Carcinoma, Non-Small-Cell Lung ; Lung Neoplasms ; Antineoplastic Agents/adverse effects ; Thrombocytopenia/chemically induced ; Cell Cycle Checkpoints ; Randomized Controlled Trials as Topic ; Clinical Trials, Phase II as Topic
    Chemical Substances Antineoplastic Agents
    Language English
    Publishing date 2023-04-10
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 80363-7
    ISSN 1532-5415 ; 0002-8614
    ISSN (online) 1532-5415
    ISSN 0002-8614
    DOI 10.1111/jgs.18350
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  4. Article ; Online: Correction to: New Advances in Supportive Care: Chemoprotective Agents as Novel Opportunities in Geriatric Oncology.

    Balducci, Lodovico / Falandry, Claire / List, Alan

    Current oncology reports

    2022  Volume 24, Issue 12, Page(s) 1885–1886

    Language English
    Publishing date 2022-11-03
    Publishing country United States
    Document type Published Erratum
    ZDB-ID 2057359-5
    ISSN 1534-6269 ; 1523-3790
    ISSN (online) 1534-6269
    ISSN 1523-3790
    DOI 10.1007/s11912-022-01336-7
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  5. Article ; Online: Impact of Age on Poly(ADP-Ribose) Polymerase Inhibitor (PARPi)-Induced Lymphopenia: A Scoping Review of the Literature and Internal Analysis of a Retrospective Database.

    Antherieu, Gabriel / Heiblig, Maël / Freyer, Gilles / Ghesquieres, Hervé / Falandry, Claire

    Drugs & aging

    2023  Volume 40, Issue 5, Page(s) 397–405

    Abstract: Background: Poly(ADP-ribose) polymerase inhibitors (PARPi) are increasingly used in oncology; their hematological toxicities affect classically red, platelet and neutrophil lineages, but some opportunistic infections have been reported concomitantly to ... ...

    Abstract Background: Poly(ADP-ribose) polymerase inhibitors (PARPi) are increasingly used in oncology; their hematological toxicities affect classically red, platelet and neutrophil lineages, but some opportunistic infections have been reported concomitantly to deep lymphopenias.
    Objective: This study was designed to provide an external and internal analysis of the crossed impacts of PARPi and age on lymphopenia risk.
    Patients and methods: A scoping review was performed on the PubMed and Embase databases to assess the reporting of lymphocyte rates in original studies on PARPi treatment for adult patients up to 1 April 2022. A retrospective cohort was extracted from the medical charts of all patients treated for gynecological cancer at our institution from 2015 to 2022 in accordance with ethical regulations.
    Results: The scoping review research strategy retrieved 5840 abstracts; 225 studies were selected for full-text analysis. Lymphopenia was reported in 41.8% of the studies; frequency of all-grade and grade ≥ 3 lymphopenia reached 20.5% and 8.9%, respectively. Grade ≥ 3 lymphopenia was significantly higher in studies including older patients (median age ≥ 60 years vs. < 60 years), at 7.5% vs. 10.3% (p < 0.0001). PARIB-OLD-HCL included 46 patients, 19 of whom were aged < 70 years (median 44 years) and 27 of whom were aged ≥ 70 years (median 79 years); the frequency of all-grade and grade ≥ 3 lymphopenia reached 67% (< 70 years: 63%; ≥ 70 years: 70%) and 13% (< 70 years: 5%; ≥ 70 years: 19%), respectively.
    Conclusion: Lymphopenia events were much more frequent in real-life than in previously reported studies, particularly in older patients. Future work is needed to improve patient follow-up and discuss prophylactic strategies.
    MeSH term(s) Humans ; Aged ; Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use ; Retrospective Studies ; Antineoplastic Agents/therapeutic use ; Neoplasms/drug therapy ; Lymphopenia/chemically induced
    Chemical Substances Poly(ADP-ribose) Polymerase Inhibitors ; Antineoplastic Agents
    Language English
    Publishing date 2023-04-20
    Publishing country New Zealand
    Document type Journal Article ; Review
    ZDB-ID 1075770-3
    ISSN 1179-1969 ; 1170-229X
    ISSN (online) 1179-1969
    ISSN 1170-229X
    DOI 10.1007/s40266-023-01023-7
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    Zs.A 3481: Show issues Location:
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  6. Article ; Online: New Advances in Supportive Care: Chemoprotective Agents as Novel Opportunities in Geriatric Oncology.

    Balducci, Lodovico / Falandry, Claire / List, Alan

    Current oncology reports

    2022  Volume 24, Issue 12, Page(s) 1695–1703

    Abstract: Purpose of review: To explore the effectiveness of trilaciclib and ALRN-6924 in the prevention of cancer chemotherapy-induced toxicity in older patients. New chemoprotective agents are necessary because age is the main risk factor for chemotherapy ... ...

    Abstract Purpose of review: To explore the effectiveness of trilaciclib and ALRN-6924 in the prevention of cancer chemotherapy-induced toxicity in older patients. New chemoprotective agents are necessary because age is the main risk factor for chemotherapy complications that account largely for the poorer outcome of cancer in the elderly. Trilaciclib and ALRN-6924 cause a reversible block of the proliferation of normal cells through cell cycle arrest (CCA). With this mechanism, they may prevent the toxicity of cycle-active cancer treatment including neutropenia, anemia, thrombocytopenia, lymphopenia, mucositis, and alopecia.
    Recent findings: Myelopoietic growth factors may prevent neutropenia in the aged, but they may cause severe bone pain, may aggravate thrombocytopenia and anemia, and may cause myelodysplasia and acute leukemia as a late complication. The prevention of thrombocytopenia, anemia, mucositis, and alopecia is unsatisfactory at present. These complications may jeopardize the treatment outcome as they require a reduction of treatment dose/intensity and because many patients find the resulting symptoms intolerable. In three studies of patients with extensive disease small cell lung cancer (ES-SCLC), trilaciclib reduced the severity and duration of neutropenia and thrombocytopenia as well as the need for blood transfusions. In addition, it produced a significant expansion of T-cell clones. Trilaciclib received FDA approval for the prevention of chemotherapy-induced myelosuppression in patients with ES-SCLC. ALRN-6924 is currently studied in phase II study of ES-SCLC. In a phase IB of 38 patients, ALRN-6924 prevented myelosuppression to an extent comparable with trilaciclib. Both drugs proved as effective in patients 65 and older as they were in the younger ones. In an "ex vivo" study, ALRN-6924 protected the epithelial stem cells of hair follicles from taxanes and promised to prevent alopecia. The possibility that CCA of tumor cells may reduce the effectiveness of cycle-active chemotherapy is a major concern. For this reason, the use of trilaciclib, an inhibitor of CDK 4/6, should be limited to tumors with inactivated RB1, and the use of ALRN-6924, an inhibitor of P53, should be limited to tumors with inactivated P53. Chemotherapy-related toxicities limit dose intensity and contribute to significant morbidity and mortality in elderly cancer patients. Trilaciclib and ALRN-6924 are of particular interest to geriatric oncologists because of their novel mechanism of action. Ameliorating chemotherapy-induced toxicities holds the promise of transforming the practice of geriatric oncology by enabling chemotherapeutic regimens that are currently not feasible for this patient population. Specifically, these agents may prevent chemotherapy-induced neutropenia and thrombocytopenia, perhaps the most life-threatening complications of cytotoxic chemotherapy, thereby obviating the need for the use of rescue strategies such as hematopoietic growth factors. In addition, these agents offer the potential for broad tissue protection from other chemotherapy-related toxicities, including mucositis, diarrhea, and alopecia, which historically have been poorly managed. Importantly, by preventing a spectrum of chemotherapy-related toxicities, these agents may permit the administration of chemotherapy at full-dose intensity, prevent functional decline, and grant maintenance of resilience to older cancer patients. As a result, the successful prevention of chemotherapy-induced side effects may not only mitigate the costs of care but also improve patient outcomes and quality of life. Finally, chemoprotective strategies offer the opportunity to apply geriatric principles to clinical trials of cancer treatment. In particular, they may allow the testing of prolongation of "active life expectancy" as a major goal of clinical trials in elderly patients. They may also enable novel and more practical forms of clinical trials. By assessing the risk of chemotherapy-related toxicity with the Chemotherapy Risk Assessment Scale for High Age Patients (CRASH) or the Cancer and Aging Research Group (CARG) instruments, these agents may permit researchers to utilize patients as their own controls and endorse the approval of supportive care drugs based upon the risk profile of individual patients.
    MeSH term(s) Aged ; Humans ; Quality of Life ; Mucositis/chemically induced ; Mucositis/drug therapy ; Tumor Suppressor Protein p53 ; Antineoplastic Agents/adverse effects ; Small Cell Lung Carcinoma/drug therapy ; Neutropenia/chemically induced ; Neutropenia/drug therapy ; Neutropenia/prevention & control ; Lung Neoplasms/drug therapy ; Thrombocytopenia ; Alopecia/chemically induced ; Alopecia/drug therapy ; Clinical Trials, Phase II as Topic
    Chemical Substances Tumor Suppressor Protein p53 ; Antineoplastic Agents
    Language English
    Publishing date 2022-08-20
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 2057359-5
    ISSN 1534-6269 ; 1523-3790
    ISSN (online) 1534-6269
    ISSN 1523-3790
    DOI 10.1007/s11912-022-01324-x
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  7. Article ; Online: What Is the Optimal Treatment for Vulnerable Older Women With Ovarian Cancer?-Reply.

    Falandry, Claire / Freyer, Gilles / Pujade-Lauraine, Eric

    JAMA oncology

    2021  Volume 7, Issue 11, Page(s) 1727

    MeSH term(s) Aged ; Carcinoma, Ovarian Epithelial ; Female ; Humans ; Ovarian Neoplasms/drug therapy
    Language English
    Publishing date 2021-08-23
    Publishing country United States
    Document type Letter ; Comment
    ISSN 2374-2445
    ISSN (online) 2374-2445
    DOI 10.1001/jamaoncol.2021.4131
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  8. Article ; Online: Real-world experience with CDK4-6 inhibition in the old and oldest old with a diagnosis of breast cancer.

    Sobrini-Morillo, Paula / Ravot, Christine / Herlédan, Chloé / Sánchez-Castellano, Carmen / Cruz-Jentoft, Alfonso J / Falandry, Claire

    Seminars in oncology

    2024  

    Abstract: This study describes characteristics, toxicity and survival in old patients with HR+/HER2-breast cancer (BC) treated with CDK4/6 inhibitors. Retrospective observational study that included patients ≥ 75 years with HR+/HER2-BC treated with CDK4/6 ... ...

    Abstract This study describes characteristics, toxicity and survival in old patients with HR+/HER2-breast cancer (BC) treated with CDK4/6 inhibitors. Retrospective observational study that included patients ≥ 75 years with HR+/HER2-BC treated with CDK4/6 inhibitors between 2017 and 2021. Patients' general and cancer-related data were collected. Comprehensive Geriatric Assessment scales were gathered. Adverse events reported before each cycle were included. At the end of the follow-up period, mortality was retrospectively registered from medical records. All 19 patients (94.7% women, median age 77.9 ± 10.1) were at risk of frailty (G8 ≤ 14) and malnutrition (MNA-SF ≤ 11). Most were independent (52.7% Lawton ≥ 6), had no cognitive impairment (89.5%, MMSE ≥ 24), poor physical performance (70%, SPPB < 8; 62.5% TUG ≥ 12'') and polypharmacy (72.2%). Almost half had stage IV disease (47.1%). Palbociclib+letrozole was the most frequently prescribed treatment (36.8%). All patients developed some toxicity (94.7% hematologic, 36.8% renal) but except one, grade ≤ 2. Over the 42-month follow-up period, 10 reported progression and 8 died. The median survival time was 19.9 ± 3.4 months. Five months after starting treatment, the probability of survival was 73%. At 30 months, 53% of patients survived. We found a high risk of frailty and drug toxicity in this small sample. Most patients presented hematologic toxicity but to a low degree. The probability of survival increases with treatment.
    Language English
    Publishing date 2024-02-22
    Publishing country United States
    Document type Journal Article
    ZDB-ID 189220-4
    ISSN 1532-8708 ; 0093-7754
    ISSN (online) 1532-8708
    ISSN 0093-7754
    DOI 10.1053/j.seminoncol.2024.01.003
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  9. Article: Multi-Disciplinary Care Planning of Ovarian Cancer in Older Patients: General Statement-A Position Paper from SOFOG-GINECO-FRANCOGYN-SFPO.

    Bengrine, Leila / Bakrin, Naoual / Rousseau, Frédérique / Lavoué, Vincent / Falandry, Claire

    Cancers

    2022  Volume 14, Issue 5

    Abstract: In this position paper the Société Francophone d'OncoGériatrie (SOFOG; French-speaking oncogeriatric society), the Société Française de Pharmacie Oncologique (SFPO, French society for oncology pharmacy), the Groupe d'Investigateurs Nationaux pour l'Étude ...

    Abstract In this position paper the Société Francophone d'OncoGériatrie (SOFOG; French-speaking oncogeriatric society), the Société Française de Pharmacie Oncologique (SFPO, French society for oncology pharmacy), the Groupe d'Investigateurs Nationaux pour l'Étude des Cancers de l'Ovaire et du sein (GINECO, National Investigators' Group for Studies in Ovarian and Breast Cancer) and the Groupe Français de chirurgie Oncologique et Gynécologique (FRANCOGYN) propose a multi-disciplinary care planning of ovarian cancer in older patients. The treatment pathway is based on four successive decisional nodes (diagnosis, resectability assessment, operability assessment, adjuvant, and maintenance treatment decision) implying multidisciplinarity and adaptation of the treatment plan according to the patient's geriatric covariates and her motivation towards treatment. Specific attention must be paid to geriatric intervention, supportive care and pharmaceutical conciliation. Studies are needed to prospectively evaluate the impact of geriatric vulnerability parameters at each step of the treatment agenda and the impact of geriatric interventions on patient outcomes.
    Language English
    Publishing date 2022-03-02
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2527080-1
    ISSN 2072-6694
    ISSN 2072-6694
    DOI 10.3390/cancers14051295
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  10. Article ; Online: Is There an Age Threshold for Holding Off on Testing Novel Therapies?

    Le Saux, Olivia / Falandry, Claire

    Current oncology reports

    2018  Volume 20, Issue 1, Page(s) 6

    Abstract: Purpose 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 ... ...

    Abstract Purpose 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. 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.
    MeSH term(s) Age Factors ; Aging/drug effects ; Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Humans ; Molecular Targeted Therapy/methods ; Neoplasms/drug therapy
    Chemical Substances Antineoplastic Agents
    Language English
    Publishing date 2018-02-07
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2057359-5
    ISSN 1534-6269 ; 1523-3790
    ISSN (online) 1534-6269
    ISSN 1523-3790
    DOI 10.1007/s11912-018-0663-4
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