RESUMO
G-quadruplex ligands exert their antiproliferative effects through telomere-dependent and telomere-independent mechanisms, but the inter-relationships among autophagy, cell growth arrest and cell death induced by these ligands remain largely unexplored. Here, we demonstrate that the G-quadruplex ligand 20A causes growth arrest of cancer cells in culture and in a HeLa cell xenografted mouse model. This response is associated with the induction of senescence and apoptosis. Transcriptomic analysis of 20A treated cells reveals a significant functional enrichment of biological pathways related to growth arrest, DNA damage response and the lysosomal pathway. 20A elicits global DNA damage but not telomeric damage and activates the ATM and autophagy pathways. Loss of ATM following 20A treatment inhibits both autophagy and senescence and sensitizes cells to death. Moreover, disruption of autophagy by deletion of two essential autophagy genes ATG5 and ATG7 leads to failure of CHK1 activation by 20A and subsequently increased cell death. Our results, therefore, identify the activation of ATM by 20A as a critical player in the balance between senescence and apoptosis and autophagy as one of the key mediators of such regulation. Thus, targeting the ATM/autophagy pathway might be a promising strategy to achieve the maximal anticancer effect of this compound.
Assuntos
Apoptose/efeitos dos fármacos , Proteínas Mutadas de Ataxia Telangiectasia , Autofagia/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Quadruplex G , Neoplasias/patologia , Células A549 , Animais , Apoptose/genética , Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Autofagia/genética , Linhagem Celular Tumoral , Senescência Celular/genética , Dano ao DNA/efeitos dos fármacos , Células HeLa , Humanos , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Neoplasias/genética , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The benefit of radiotherapy (RT) after chemotherapy in limited-stage diffuse large B-cell lymphoma (DLBCL) remains controversial. We conducted a randomized trial in patients with nonbulky limited-stage DLBCL to evaluate the benefit of RT after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Patients were stratified according to the modified International Prognostic Index, including lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, age, and disease stage. The patients received 4 or 6 consecutive cycles of R-CHOP delivered once every 2 weeks, followed or not by RT at 40 Gy delivered 4 weeks after the last R-CHOP cycle. All patients were evaluated by fluorodeoxyglucose-positron emission tomography scans performed at baseline, after 4 cycles of R-CHOP, and at the end of treatment. The primary objective of the trial was event-free survival (EFS) from randomization. The trial randomly assigned 165 patients in the R-CHOP arm and 169 in the R-CHOP plus RT arm. In an intent-to-treat analysis with a median follow-up of 64 months, 5-year EFS was not statistically significantly different between the 2 arms, with 89% ± 2.9% in the R-CHOP arm vs 92% ± 2.4% in the R-CHOP plus RT arm (hazard ratio, 0.61; 95% confidence interval [CI], 0.3-1.2; P = .18). Overall survival was also not different at 92% (95% CI, 89.5%-94.5%) for patients assigned to R-CHOP alone and 96% (95% CI, 94.3%-97.7%) for those assigned to R-CHOP plus RT (P = not significant). R-CHOP alone is not inferior to R-CHOP followed by RT in patients with nonbulky limited-stage DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT00841945.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/radioterapia , Anticorpos Monoclonais Murinos/administração & dosagem , Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Doxorrubicina/uso terapêutico , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prednisona/uso terapêutico , Intervalo Livre de Progressão , Estudos Prospectivos , Rituximab , Resultado do Tratamento , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Vincristina/uso terapêuticoRESUMO
PURPOSE OF REVIEW: The current review will outline recent data which may improve management of older patients with aggressive lymphoma through comanagement by hematologists and geriatricians. RECENT FINDINGS: Many recent data show that determinants of prognosis differ in older patients with an increased importance of nonlymphoma-related parameters. As a consequence, geriatric assessment parameters are predictive of the outcome in these patients. Data from clinical trials allow for standardization of chemotherapy in diffuse large B-cell lymphoma even in older fit patients. Yet data are missing in vulnerable and frail patients. Recent results show that anthracyclines appear essential also in vulnerable patients although precautions should be considered. Geriatric intervention will be the next step but its potential value remains to be demonstrated. SUMMARY: Although aggressive lymphoma therapy is well standardized, management of vulnerable and frail patients remains complicated because of the accumulation of comorbidities and geriatric syndromes and because they are excluded from clinical trials. Comanagement with hematologists and geriatricians may be the solution to improve outcome but organization of care should reinvented.
Assuntos
Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos como Assunto , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Idoso Fragilizado , Avaliação Geriátrica/métodos , Humanos , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prognóstico , Rituximab/administração & dosagem , Rituximab/efeitos adversos , Vincristina/administração & dosagem , Vincristina/efeitos adversosRESUMO
Faced with the lack of evidence-based medicine concerning the efficacy and tolerance of cancer treatments in the extremely heterogeneous elderly population, and with no standardised geriatric evaluation in geriatric oncology clinical trials, the intergroup Dialog set itself the objective of establishing a minimal standardised geriatric evaluation for clinical trials. The evaluation must be simple, short and effective. It must comprise validated and reproducible measurement tools. The Geriatric Core Dataset, made up of seven items, has been formalised and validated by national and international experts.
Assuntos
Ensaios Clínicos como Assunto , Conjuntos de Dados como Assunto , Avaliação Geriátrica , Neoplasias/terapia , Idoso , HumanosRESUMO
The treatment of low-tumour burden follicular lymphoma (LTBFL) remains a challenge. Rituximab-based strategies may be improved by adding chemotherapy. This Lymphoma Study Association multicentre phase II study assessed rituximab and bendamustine in 63 patients with untreated LTBFL who were aged over 60 years old and had a follicular lymphoma International Prognostic Index (FLIPI) score ≥2. Induction comprised 4 weekly cycles of rituximab 375 mg/m2 intravenously combined with 2 cycles of bendamustine 90 mg/m2 days 1-2 with a 28-day interval, followed by twelve cycles of 375 mg/m2 rituximab maintenance therapy every 8 weeks. The primary endpoint was complete response (CR)/unconfirmed CR (CRu), at 12 weeks. Median age was 67·4 years and median FLIPI was 3. Ultimately, 18 patients (29%) had high tumour burden according to Groupe d'Etude des Lymphomes Folliculaires criteria. The 12-week CR/CRu rate was 54·0% and the overall response rate was 93·7%. Surprisingly, 3 patients died during maintenance (2 sepsis, 1 neoplasm). Progression-free survival was 85·4% at 24 months. In LTBFL patients with FLIPI ≥2, two cycles of rituximab and bendamustine result in a CR rate of 54·0%. However, the treatment-related deaths observed do not allow this regimen to be recommended for LTBFL patients aged over 60 years. EudraCT: 2010-020757-14; ClinicalTrials.gov: NCT01313611.
Assuntos
Cloridrato de Bendamustina/administração & dosagem , Linfoma Folicular/tratamento farmacológico , Rituximab/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Humanos , Linfoma Folicular/mortalidade , Quimioterapia de Manutenção/métodos , Quimioterapia de Manutenção/mortalidade , Masculino , Pessoa de Meia-Idade , Indução de Remissão/métodos , Análise de Sobrevida , Resultado do Tratamento , Carga TumoralRESUMO
BACKGROUND: Cancer management in the elderly is often considered as suboptimal, highly variable, and rarely evidence-based. Data are needed to understand decision-making processes in this population. MATERIALS AND METHODS: A survey was performed in France to describe decision-making in gynaecologic patients over 70. It followed a three-step method: (1) 101 representative physicians questioned about treatment decision criteria; (2) simplified individual data were collected; (3) as well as detailed data patients receiving chemotherapy. This analysis refers to breast cancer subgroup of patients. RESULTS: Main decision criteria were performance status, comorbidities, and renal function. In adjuvant setting, the main concern was life expectancy, whereas it was quality of life in metastatic setting. Of the 631 patients entered in the simplified analysis, 41% had been evaluated by a geriatrician, 67% received chemotherapy. In the detailed analysis, patients older than 75 were more likely to receive a monochemotherapy and to be treated with weekly/divided dose. In adjuvant setting, respectively, 19, 55, and 26% of the patients were treated with regimen validated in the elderly, validated in a younger population, and not validated. A G-CSF was prescribed in 48% of the patients, as primary prophylaxis in 78 and in 41% of patients with a risk of febrile neutropenia < 10%. CONCLUSION: Geriatric covariates become an increasing concern in the decision-making process. This survey also suggests an insufficient use of validated chemotherapy regimens. To date, age remains a risk factor for heterogeneity in oncologic practice justifying a persistent effort for elaborating and disclosing specific recommendations.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/terapia , Tomada de Decisão Clínica , Avaliação Geriátrica/métodos , Inquéritos Epidemiológicos/estatística & dados numéricos , Fatores Etários , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Neutropenia Febril Induzida por Quimioterapia/etiologia , Neutropenia Febril Induzida por Quimioterapia/prevenção & controle , Comorbidade , Feminino , França , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Ginecologia/métodos , Humanos , Expectativa de Vida , Masculino , Mastectomia , Oncologia/métodos , Seleção de Pacientes , Médicos/estatística & dados numéricos , Qualidade de Vida , Proteínas Recombinantes/uso terapêuticoRESUMO
PURPOSE OF REVIEW: The choice for an optimal treatment in older lymphoma patients is a real challenge for hemato-oncologists. They have to treat a potentially curative lymphoma, and concomitantly protect their patients from unacceptable toxicities. Some recommendations are provided for the major subtypes of lymphomas including the antitumoral treatment and primarily the optimal supportive care. RECENT FINDINGS: All the recent literature data converge to say that the approach of an older patient with a malignant hemopathy is a multistep procedure. This process comprises the appraisal of life expectancy of the patient with or without the disease, the prognostic factors of the tumor, the functional, physiological and cognitive functions evaluation, the socio-economical environment and the patient's expectancy in terms of quality of life. Major progresses have been achieved in the management of diffuse large B cell lymphoma and mantle cell lymphoma in patients up to 80 and above 80 years old. SUMMARY: With all these information in hands, the hematologist will decide if the treatment's objective is the standard treatment with optimal supportive care (fit patients), tailor-made adapted chemotherapy (unfit patients) or preservation of quality of life (frail patients).
Assuntos
Linfoma Difuso de Grandes Células B/tratamento farmacológico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso Fragilizado , Doença de Hodgkin/tratamento farmacológico , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoAssuntos
Neoplasias Oculares/tratamento farmacológico , Linfoma/tratamento farmacológico , Neoplasias da Retina/tratamento farmacológico , Temozolomida/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Neoplasias Oculares/epidemiologia , Neoplasias Oculares/patologia , Feminino , Humanos , Linfoma/epidemiologia , Linfoma/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias da Retina/epidemiologia , Neoplasias da Retina/patologia , Estudos Retrospectivos , Resultado do Tratamento , Corpo Vítreo/patologiaRESUMO
The anti-CD20 mAb, rituximab, is routinely used to treat B cell malignancies. However, a majority of patients relapse. An improvement in the complete response was obtained by combining rituximab with chemotherapy, at the cost of increased toxicity. We reported that rituximab induced the colocalization of both the Orai1 Ca(2+) release-activated Ca(2+) channel (CRAC) and the endoplasmic reticulum Ca(2+) sensor stromal interaction molecule 1 with CD20 and CD95 into a cluster, eliciting a polarized store-operated Ca(2+) entry (SOCE). We observed that blocking this Ca(2+) entry with downregulation of Orai1, pharmacological inhibitors, or reducing calcemia with hypocalcemic drugs sensitized human B lymphoma cell lines and primary human lymphoma cells to rituximab-induced apoptosis in vitro, and improved the antitumoral effect of rituximab in xenografted mice. This revealed that Ca(2+) entry exerted a negative feedback loop on rituximab-induced apoptosis, suggesting that associating CRAC channel inhibitors or hypocalcemic agents with rituximab may improve the treatment of patients with B cell malignancies. The calcium-dependent proteins involved in this process appear to vary according to the B lymphoma cell type, suggesting that CRAC-channel targeting is likely to be more efficient than calcium-dependent protein targeting.
Assuntos
Apoptose/efeitos dos fármacos , Canais de Cálcio/metabolismo , Cálcio/metabolismo , Linfoma não Hodgkin/tratamento farmacológico , Rituximab/farmacologia , Receptor fas/metabolismo , Animais , Antígenos CD20/imunologia , Antígenos CD20/metabolismo , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Western Blotting , Canais de Cálcio/genética , Linhagem Celular Tumoral , Difosfonatos/farmacologia , Retículo Endoplasmático/metabolismo , Feminino , Células HEK293 , Humanos , Imidazóis/farmacologia , Linfoma não Hodgkin/genética , Linfoma não Hodgkin/patologia , Proteínas de Membrana/metabolismo , Camundongos Knockout , Microscopia Confocal , Proteínas de Neoplasias/metabolismo , Proteína ORAI1 , Interferência de RNA , Rituximab/administração & dosagem , Molécula 1 de Interação Estromal , Ensaios Antitumorais Modelo de Xenoenxerto , Ácido ZoledrônicoRESUMO
We examined the outcome of a cohort of patients with Hodgkin lymphoma (HL) in order to assess if fluorodeoxyglucose (FDG) positron emission tomography-computed tomography (PET/CT) at the end of treatment (end-PET) can be omitted when the interim PET (int-PET) is negative. Seventy-six ABVD(adriamycin, bleomycin, vinblastine, dacarbazine)-treated patients were retrospectively included. No change in treatment was made on the basis of int-PET results. Suspicious foci on end-PET received biopsy confirmation whenever possible. Median follow-up was 58·9 months. Uptake on int-PET higher than liver (scores 4-5) was rated positive according to the Lugano classification, while a positive end-PET corresponded to scores 3, 4 and 5. Fifteen patients had treatment failure. Sensitivity, specificity, positive predictive value (PPV), negative predictive value and accuracy of int-PET were 46·7%, 85·2%, 43·8%, 86·7% and 77·6%, respectively. For end-PET the figures were: 80%, 93·4%, 75%, 95% and 90·8%. Eight patients with negative int-PET had treatment failure; six of them were identified as non-responders with end-PET. The 5-year progression-free survival (PFS) was 87% for patients with negative int-PET versus 56% with positive int-PET. The 5-year PFS was 96% with negative end-PET versus 23% with positive end-PET. The prognostic information from int-PET as regards PFS (log-rank test P = 0·0048) was lower than that provided by end-PET (P < 0·0001). Int-PET predicted only half of the failures. When used in clinical routine, a negative int-PET study cannot obviate the need for end-PET examination.
Assuntos
Doença de Hodgkin/diagnóstico , Tomografia por Emissão de Pósitrons , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bleomicina/uso terapêutico , Terapia Combinada , Dacarbazina/uso terapêutico , Gerenciamento Clínico , Doxorrubicina/uso terapêutico , Feminino , Fluordesoxiglucose F18 , Seguimentos , Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons/métodos , Prognóstico , Reprodutibilidade dos Testes , Falha de Tratamento , Resultado do Tratamento , Vimblastina/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: A multidimensional geriatric assessment (GA) is recommended in older cancer patients to inventory health problems and tailor treatment decisions accordingly but requires considerable time and human resources. The G8 is among the most sensitive screening tools for selecting patients warranting a full GA but has limited specificity. We sought to develop and validate an optimized version of the G8. PATIENTS AND METHODS: We used a prospective cohort of cancer patients aged ≥ 70 years referred to geriatricians for GA (2007-2012: n = 729 [training set]; 2012-2014: n = 414 [validation set]). Abnormal GA was defined as at least one impaired domain across seven validated tests. Multiple correspondence analysis, multivariate logistic regression, and bootstrapped internal validation were performed sequentially. RESULTS: The final model included six independent predictors for abnormal GA: weight loss, cognition/mood, performance status, self-rated health status, polypharmacy (≥ 6 medications per day), and history of heart failure/coronary heart disease. For the original G8, sensitivity was 87.2% (95% confidence interval, 84.3-89.7), specificity 57.7% (47.3-67.7), and area under the receiver-operating characteristic curve (AUROC) 86.5% (83.5-89.6). The modified G8 had corresponding values of 89.2% (86.5-91.5), 79.0% (69.4-86.6), and 91.6% (89.3; 93.9), with higher AUROC values for all tumor sites and stable properties on the validation set. CONCLUSION: A modified G8 screening tool exhibited better diagnostic performance with greater uniformity across cancer sites and required only six items. If these features are confirmed in other settings, the modified tool may facilitate selection for a full GA in older patients with cancer. IMPLICATIONS FOR PRACTICE: Several screening tools have been developed to identify older patients with cancer likely to benefit from a complete geriatric assessment, but none combines appropriate sensitivity and specificity. Based on a large prospective cohort study, an optimized G8 tool was developed, combining a systematic statistical approach with expert judgment to ensure optimal discriminative power and clinical relevance. The improved screening tool achieves high sensitivity, high specificity, better homogeneity across cancer types, and greater parsimony with only six items needed, facilitating selection for a full geriatric assessment.
Assuntos
Doença das Coronárias/epidemiologia , Avaliação Geriátrica , Neoplasias/epidemiologia , Idoso , Idoso de 80 Anos ou mais , Doença das Coronárias/complicações , Doença das Coronárias/patologia , Feminino , Idoso Fragilizado , Humanos , Masculino , Neoplasias/complicações , Neoplasias/patologia , Prognóstico , Inquéritos e QuestionáriosRESUMO
BACKGROUND: In the general geriatric population, programs linking geriatric evaluation with interventions are effective for improving functional status and survival of the patients. Whether or not these interventions improve health related quality of life (HRQoL) or overall survival (OS) in older patients with cancer is not yet clear. Indeed, randomized data on the effect of such interventions on survival and HRQoL are rare and conflicting. We describe the rationale and design of a phase III multicenter trial aimed at assessing the efficacy of geriatric intervention in the management of elderly patients with cancer. METHODS/DESIGN: Approximately 1200 patients, 70 years and older, considered in need of a geriatric intervention based on the G8 screening tool will be randomized into two intervention arms. The 'Usual-care' arm involves standard oncological care based on pre-defined oncological protocols. In addition to the standard oncological care, the 'Case-management' arm involves a multidimensional geriatric assessment and interventions tailored for the patient. Efficacy will be assessed using a co-primary endpoint encompassing OS and HRQoL. DISCUSSION: This trial has been designed to assess whether focused geriatric case management can either improve OS or HRQoL in elderly cancer patients considered in need of geriatric assessment. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT02704832 .
Assuntos
Protocolos Clínicos , Neoplasias/terapia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Humanos , Projetos de PesquisaAssuntos
Infecções por Coronavirus , Neoplasias , Betacoronavirus , COVID-19 , Humanos , Pandemias , Pneumonia Viral , SARS-CoV-2RESUMO
In patients with follicular lymphoma treated with single-agent rituximab, single nucleotide polymorphisms in the FCGR3A gene are known to influence response and progression-free survival. The prognostic role of FCGR3A and FCGR2A polymorphisms in patients with follicular lymphoma treated with rituximab and chemotherapy combination remains controversial and has not been evaluated in the context of rituximab maintenance. FCGR3A and FCGR2A single nucleotide polymorphisms were evaluated in, respectively, 460 and 455 patients treated in the PRIMA study to investigate whether these were associated with response rate and patient outcome after rituximab chemotherapy induction and 2-year rituximab maintenance. In this representative patient cohort, complete and unconfirmed complete responses after rituximab chemotherapy were observed in 65%, 67%, 66% (P = .86) and 60%, 72%, 66% (P = .21) of FCGR3A VV, VF, FF and FCGR2A HH, HR, RR carriers, respectively. After 2 years of rituximab maintenance (or observation), response rates did not differ among the different genotypes. Progression-free survival measured from either treatment initiation or randomization to observation or maintenance was not influenced by these polymorphisms. These data indicate that FCGR3A and FCGR2A polymorphisms do not influence response rate and outcome when rituximab is combined with chemotherapy or used as maintenance treatment. The PRIMA study is registered at www.clinicaltrials.gov as NCT00140582.
Assuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores de IgG/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Agências Internacionais , Linfoma Folicular/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Indução de Remissão , Rituximab , Taxa de SobrevidaRESUMO
BACKGROUND: The approval of epoetin biosimilars in the European Union requires extensive scientific evaluation and stringent regulatory procedures, including post-marketing studies. The ORHEO (place of biOsimilaRs in the therapeutic management of anaemia secondary to chemotherapy in HaEmatology and Oncology) study was an observational, longitudinal, multicentre study performed in France to evaluate the efficacy and safety of biosimilar epoetins for the treatment of chemotherapy-induced anaemia (CIA) in the clinical setting. METHODS: Patients >18 years with CIA (haemoglobin [Hb] <11 g/dL) in association with solid tumours, lymphoma or myeloma and eligible for treatment with an epoetin biosimilar were included in this study. Patient characteristics were recorded at baseline along with anaemia-related information, such as observed and target Hb (as chosen by the treating clinician), brand and dose of epoetin biosimilar prescribed, and details of any other treatments. Patients were then followed-up at 3 and 6 months. The primary endpoint was Hb response (defined as Hb reaching ≥10 g/dL, an increase of Hb ≥1 g/dL since inclusion visit or reaching physician-defined target Hb, with no blood transfusions in the 3 weeks prior to measurement). Other endpoints included adverse events, achievement of target Hb and associated treatments. RESULTS: Overall, 2333 patients >18 years (mean age 66.5 years) with CIA (haemoglobin [Hb] <11 g/dL) in association with solid tumours, lymphoma or myeloma and eligible for biosimilar epoetin treatment were included. 99.9% of patients received epoetin zeta (median dose 30,000 IU/week). Mean baseline Hb was 9.61 g/dL, with 35.6% of patients having moderate anaemia (Hb 8-9.5 g/dL). Hb response was achieved in 81.6% and 86.5% of patients at 3 and 6 months, respectively. Overall mean change in Hb level was 1.52 ± 1.61 and 1.72 ± 1.61 g/dL at 3 and 6 months, respectively. Transfusion and thromboembolic event rates were 9.4% and 2.4% at 3 months, and 5.8% and 1.5% at 6 months, respectively. CONCLUSIONS: Epoetin zeta was effective and well tolerated in the management of CIA in patients with solid tumours, lymphoma and myeloma. TRIAL REGISTRATION NUMBER: NCT02140736 (date of registration: 14 May 2014).
Assuntos
Anemia/tratamento farmacológico , Medicamentos Biossimilares/administração & dosagem , Eritropoetina/administração & dosagem , Neoplasias Hematológicas/tratamento farmacológico , Adulto , Idoso , Anemia/induzido quimicamente , Medicamentos Biossimilares/efeitos adversos , Eritropoetina/efeitos adversos , Feminino , França , Neoplasias Hematológicas/complicações , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversosRESUMO
SUMMARY: Cellular senescence has paradoxical effects on cancer emergence, progression, and therapeutic response. We herein identify four lessons that emerged from studying senescence interaction with cancer and emphasize four bottlenecks in the therapeutic manipulation of cellular senescence to prevent or cure cancer.
Assuntos
Senescência Celular , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genéticaRESUMO
INTRODUCTION: In cancer care, symptom monitoring during treatment results in improved clinical outcomes such as improved quality of life, longer survival, and fewer hospital admissions. However, as the majority of patients with cancer are older and have multimorbidity, they may benefit from monitoring of additional symptoms. The aim of this study was to identify a core set of symptoms to monitor in older patients with multimorbidity treated for cancer, including symptoms caused by treatment side effects, destabilization of comorbidities, and functional decline. MATERIALS AND METHODS: During a scoping literature search, 17 quality of life questionnaires were used to select 53 possible symptoms to monitor. An expert panel of cancer and geriatrics specialists was asked to participate in multiple online surveys to indicate whether these symptoms were not relevant to monitor, only relevant to monitor in a specific patient group, or relevant to monitor in all patients. In a subsequent round the list was reduced and the panel indicated how frequently these symptoms should be monitored during cancer treatment and after cancer treatment completion. Finally, a digital consensus meeting was organised to decide when symptoms had to trigger a recommendation to the patient to get in touch with their medical team. RESULTS: In total, 30 healthcare professionals participated in the online surveys. After two rounds, a dataset of 19 symptoms related to cancer, cancer treatment, functional decline, and destabilization of comorbidities was agreed upon for monitoring. Five symptoms were selected for daily monitoring during treatment, seven for weekly, and seven for monthly. After treatment completion, the panel agreed upon less frequent reporting. Additionally, nine symptoms to be monitored only in patients with specific cancer types or treatment types were chosen, such as "cough up blood" in lung cancer. DISCUSSION: This study is the first to identify a core set of symptoms to monitor in older patients with multimorbidity treated for cancer. Future research is needed to investigate whether the monitoring of these symptoms is feasible and improves clinical outcomes in older patients with multimorbidity treated for cancer.
Assuntos
Multimorbidade , Neoplasias , Idoso , Humanos , Consenso , Eletrônica , Neoplasias/terapia , Qualidade de Vida , Autorrelato , Inquéritos e QuestionáriosRESUMO
As the global population ages, so does the number of older people being diagnosed, treated and surviving cancer. Challenges to providing appropriate healthcare management stem from the heterogeneity common in this population. Although malnutrition is highly prevalent in older people with cancer, ranging between 30 % and 80 % according to some analyses, is associated with frailty, and has been shown to be a major risk factor for poor treatment response and worse overall survival, addressing nutrition status is not always a priority among oncology healthcare providers. Evaluation of nutritional status is a two-step process: screening identifies risk factors for reduced nutritional intake and deficits that require more in-depth assessment. Screening activities can be as simple as taking weight and BMI measurements or using short nutritional questionnaires and asking the patient about unintentional weight loss to identify potential nutritional risk. Using geriatric assessment, deficits in the nutritional domain as well as in others reveal potentially reversible geriatric and medical problems to guide specific therapeutic interventions. The authors of this paper are experts in the fields of geriatric medicine, oncology, and nutrition science and believe that there is not only substantial evidence to support regularly performing screening and assessment of nutritional status in older patients with cancer, but that these measures lead to the planning and implementation of patient-centered approaches to nutrition management and thus enhanced geriatric-oncology care. This paper presents rationale for systematic nutrition screening and assessment in older adults with cancer.
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OBJECTIVES: Early palliative care improves the quality of life of older patients with cancer. This work aimed to analyse the effect of sociodemographic, geriatric, and tumour-related determinants on hospital-based palliative care (HPC) referral in older patients with cancer, taking into account competing risk of death. METHODS: Older adults with diagnosed cancer from 2014 to 2018 according to the general cancer registry of Gironde (French department) were identified in three population-based cohorts on ageing (PAQUID, 3C - Three City, AMI). Cause-specific Cox models focused on 10 usual determinants in geriatric oncology and palliative care: age, gender, living alone, place of residency, tumour prognosis, activities of daily living (ADL) and instrumental-ADL (IADL) limitations, cognitive impairment, depressive disorders, and polypharmacy. RESULTS: 131 patients with incident cancer (mean age: 86.2 years, men: 62.6%, poor cancer prognosis: 32.8%) were included, HPC occurring for 26 of them. Unfavourable cancer prognosis was a key determinant for HPC referral (HR 7.02, 95% CI 2.86 to 17.23). An altered IADL score was associated with precocious (first year) referral (HR 3.21, 95% CI 1.20 to 8.64, respectively). Women had a higher rate immediately (first week) after diagnosis (HR 8.64, 95% CI 1.27 to 87.27). CONCLUSIONS: Cancer prognosis, functional decline and gender are independent factors of HPC referral in older patients with cancer. These findings may help for a better anticipation of the healthcare pathway.
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As older adults with cancer are underrepresented in randomized clinical trials (RCT), there is limited evidence on which to rely for treatment decisions for this population. Commonly used RCT endpoints for the assessment of treatment efficacy are more often tumor-centered (e.g., progression-free survival). These endpoints may not be as relevant for the older patients who present more often with comorbidities, non-cancer-related deaths, and treatment toxicity. Moreover, their expectation and preferences are likely to differ from younger adults. The DATECAN-ELDERLY initiative combines a broad expertise, in geriatric oncology and clinical research, with interest in cancer RCT that include older patients with cancer. In order to guide researchers and clinicians coordinating cancer RCT involving older patients with cancer, the experts reviewed the literature on relevant domains to assess using patient-reported outcomes (PRO) and patient-related outcomes, as well as available tools related to these domains. Domains considered relevant by the panel of experts when assessing treatment efficacy in RCT for older patients with cancer included functional autonomy, cognition, depression and nutrition. These were based on published guidelines from international societies and from regulatory authorities as well as minimum datasets recommended to collect in RCT including older adults with cancer. In addition, health-related quality of life, patients' symptoms, and satisfaction were also considered by the panel. With regards to tools for the assessment of these domains, we highlighted that each tool has its own strengths and limitations, and very few had been validated in older adults with cancer. Further studies are thus needed to validate these tools in this specific population and define the minimum clinically important difference to use when developing RCTs in this population. The selection of the most relevant tool should thus be guided by the RCT research question, together with the specific properties of the tool.