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OBJECTIVES: Nutrition impact symptoms (NIS) are associated with weight loss (WL), and decreased energy intake in cross-sectional studies. We aimed to ascertain associations between changes in NIS burden, energy intake and WL over time in patients with advanced cancer. METHODS: Adult patients from an observational radiotherapy study for painful bone metastases self-reported NIS and WL using the Patient-Generated Subjective Global Assessment tool (PG-SGA) at baseline and week eight (W8). NIS burden, the sum of NIS per patient, categorised as 0, 1-2 and ≥3 with changes defined as 2-point differences from baseline to W8 were used. Energy intake was assessed by 24-hour recall interviews. RESULTS: 111 patients (72.1%) were analysed and grouped by NIS burden; 0 NIS (44.1%), 1-2 NIS (30.6%) and ≥3 NIS (25.2%). Patients with NIS burden of ≥3 reported higher baseline WL compared with those with 1-2 or 0 NIS (46.4% vs 18.2% vs 10.2%, respectively, p=0.002). At W8, 21 patients (19%) reported improved NIS burden, accompanied by a lower proportion of severe (≥5%) new-onset WL (19% vs 42.1%) and higher energy intake (median 29.6 vs 21.2 kcal/kg) than those with worsened NIS burden (17.1%). CONCLUSIONS: NIS management may improve energy intake and prevent WL, emphasising the importance of systematic follow-up and interventions. CLINICALTRIALSGOV REGISTRATION: NCT02107664.
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Regulatory agencies require evidence that endpoints correlate with clinical benefit before they can be used to approve drugs. Biomarkers are often considered surrogate endpoints. In cancer cachexia trials, the measurement of biomarkers features frequently. The aim of this systematic review was to assess the frequency and diversity of biomarker endpoints in cancer cachexia trials. A comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990-2023) was completed. Eligible trials met the following criteria: adults (≥18 years), prospective design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a biomarker(s) as an endpoint. Biomarkers were defined as any objective measure that was assayed from a body fluid, including scoring systems based on these assays. Routine haematology and biochemistry to monitor intervention toxicity were not considered. Data extraction was performed using Covidence, and reporting followed PRISMA guidance (PROSPERO: CRD42022276710). A total of 5975 studies were assessed, of which 52 trials (total participants = 6522) included biomarkers as endpoints. Most studies (n = 29, 55.7%) included a variety of cancer types. Pharmacological interventions (n = 27, 51.9%) were most evaluated, followed by nutritional interventions (n = 20, 38.4%). Ninety-nine different biomarkers were used across the trials, and of these, 96 were assayed from blood. Albumin (n = 29, 55.8%) was assessed most often, followed by C-reactive protein (n = 22, 42.3%), interleukin-6 (n = 16, 30.8%) and tumour necrosis factor-α (n = 14, 26.9%), the latter being the only biomarker that was used to guide sample size calculations. Biomarkers were explicitly listed as a primary outcome in six trials. In total, 12 biomarkers (12.1% of 99) were used in six trials or more. Insulin-like growth factor binding protein 3 (IGFBP-3) and insulin-like growth factor 1 (IGF-1) levels both increased significantly in all three trials in which they were both used. This corresponded with a primary outcome, lean body mass, and was related to the pharmacological mechanism. Biomarkers were predominately used as exploratory rather than primary endpoints. The most commonly used biomarker, albumin, was limited by its lack of responsiveness to nutritional intervention. For a biomarker to be responsive to change, it must be related to the mechanism of action of the intervention and/or the underlying cachexia process that is modified by the intervention, as seen with IGFBP-3, IGF-1 and anamorelin. To reach regulatory approval as an endpoint, the relationship between the biomarker and clinical benefit must be clarified.
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Biomarcadores , Caquexia , Neoplasias , Caquexia/etiologia , Caquexia/diagnóstico , Humanos , Neoplasias/complicações , Ensaios Clínicos como AssuntoRESUMO
Significant variation exists in the outcomes used in cancer cachexia trials, including measures of body composition, which are often selected as primary or secondary endpoints. To date, there has been no review of the most commonly selected measures or their potential sensitivity to detect changes resulting from the interventions being examined. The aim of this systematic review is to assess the frequency and diversity of body composition measures that have been used in cancer cachexia trials. MEDLINE, Embase and Cochrane Library databases were systematically searched between January 1990 and June 2021. Eligible trials examined adults (≥18 years) who had received an intervention aiming to treat or attenuate the effects of cancer cachexia for >14 days. Trials were also of a prospective controlled design and included body weight or at least one anthropometric, bioelectrical or radiological endpoint pertaining to body composition, irrespective of the modality of intervention (e.g., pharmacological, nutritional, physical exercise and behavioural) or comparator. Trials with a sample size of <40 patients were excluded. Data extraction used Covidence software, and reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. This review was prospectively registered (PROSPERO: CRD42022276710). A total of 84 clinical trials, comprising 13 016 patients, were eligible for inclusion. Non-small-cell lung cancer and pancreatic cancer were studied most frequently. The majority of trial interventions were pharmacological (52%) or nutritional (34%) in nature. The most frequently reported endpoints were assessments of body weight (68 trials, n = 11 561) followed by bioimpedance analysis (BIA)-based estimates (23 trials, n = 3140). Sixteen trials (n = 3052) included dual-energy X-ray absorptiometry (DEXA)-based endpoints, and computed tomography (CT) body composition was included in eight trials (n = 841). Discrepancies were evident when comparing the efficacy of interventions using BIA-based estimates of lean tissue mass against radiological assessment modalities. Body weight, BIA and DEXA-based endpoints have been most frequently used in cancer cachexia trials. Although the optimal endpoints cannot be determined from this review, body weight, alongside measurements from radiological body composition analysis, would seem appropriate. The choice of radiological modality is likely to be dependent on the trial setting, population and intervention in question. CT and magnetic resonance imaging, which have the ability to accurately discriminate tissue types, are likely to be more sensitive and provide greater detail. Endpoints are of particular importance when aligned with the intervention's mechanism of action and/or intended patient benefit.
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Composição Corporal , Peso Corporal , Caquexia , Neoplasias , Humanos , Caquexia/etiologia , Caquexia/terapia , Neoplasias/complicações , Ensaios Clínicos como AssuntoRESUMO
The use of patient-reported outcomes (PROMs) of quality of life (QOL) is common in cachexia trials. Patients' self-report on health, functioning, wellbeing, and perceptions of care, represent important measures of efficacy. This review describes the frequency, variety, and reporting of QOL endpoints used in cancer cachexia clinical trials. Electronic literature searches were performed in Medline, Embase, and Cochrane (1990-2023). Seven thousand four hundred thirty-five papers were retained for evaluation. Eligibility criteria included QOL as a study endpoint using validated measures, controlled design, adults (>18 years), ≥40 participants randomized, and intervention exceeding 2 weeks. The Covidence software was used for review procedures and data extractions. Four independent authors screened all records for consensus. Papers were screened by titles and abstracts, prior to full-text reading. PRISMA guidance for systematic reviews was followed. The protocol was prospectively registered via PROSPERO (CRD42022276710). Fifty papers focused on QOL. Twenty-four (48%) were double-blind randomized controlled trials. Sample sizes varied considerably (n = 42 to 469). Thirty-nine trials (78%) included multiple cancer types. Twenty-seven trials (54%) featured multimodal interventions with various drugs and dietary supplements, 11 (22%) used nutritional interventions alone and 12 (24%) used a single pharmacological intervention only. The median duration of the interventions was 12 weeks (4-96). The most frequent QOL measure was the EORTC QLQ-C30 (60%), followed by different FACIT questionnaires (34%). QOL was a primary, secondary, or exploratory endpoint in 15, 31 and 4 trials respectively, being the single primary in six. Statistically significant results on one or more QOL items favouring the intervention group were found in 18 trials. Eleven of these used a complete multidimensional measure. Adjustments for multiple testing when using multicomponent QOL measures were not reported. Nine trials (18%) defined a statistically or clinically significant difference for QOL, five with QOL as a primary outcome, and four with QOL as a secondary outcome. Correlation statistics with other study outcomes were rarely performed. PROMs including QOL are important endpoints in cachexia trials. We recommend using well-validated QOL measures, including cachexia-specific items such as weight history, appetite loss, and nutritional intake. Appropriate statistical methods with definitions of clinical significance, adjustment for multiple testing and few co-primary endpoints are encouraged, as is an understanding of how interventions may relate to changes in QOL endpoints. A strategic and scientific-based approach to PROM research in cachexia trials is warranted, to improve the research base in this field and avoid the use of QOL as supplementary measures.
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Caquexia , Neoplasias , Qualidade de Vida , Humanos , Caquexia/etiologia , Caquexia/terapia , Neoplasias/complicações , Neoplasias/psicologia , Ensaios Clínicos como Assunto , Medidas de Resultados Relatados pelo PacienteRESUMO
There is no consensus on the optimal endpoint(s) in cancer cachexia trials. Endpoint variation is an obstacle when comparing interventions and their clinical value. The aim of this systematic review was to summarize and evaluate endpoints used to assess appetite and dietary intake in cancer cachexia clinical trials. A search for studies published from 1 January 1990 until 2 June 2021 was conducted using MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Eligible studies examined cancer cachexia treatment versus a comparator in adults with assessments of appetite and/or dietary intake as study endpoints, a sample size ≥40 and an intervention lasting ≥14 days. Reporting was in line with PRISMA guidance, and a protocol was published in PROSPERO (2022 CRD42022276710). This review is part of a series of systematic reviews examining cachexia endpoints. Of the 5975 articles identified, 116 were eligible for the wider review series and 80 specifically examined endpoints of appetite (65 studies) and/or dietary intake (21 studies). Six trials assessed both appetite and dietary intake. Appetite was the primary outcome in 15 trials and dietary intake in 7 trials. Median sample size was 101 patients (range 40-628). Forty-nine studies included multiple primary tumour sites, while 31 studies involved single primary tumour sites (15 gastrointestinal, 7 lung, 7 head and neck and 2 female reproductive organs). The most frequently reported appetite endpoints were visual analogue scale (VAS) and numerical rating scale (NRS) (40%). The appetite item from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30/C15 PAL (38%) and the appetite question from North Central Cancer Treatment Group anorexia questionnaire (17%) were also frequently applied. Of the studies that assessed dietary intake, 13 (62%) used food records (prospective registrations) and 10 (48%) used retrospective methods (24-h recall or dietary history). For VAS/NRS, a mean change of 1.3 corresponded to Hedge's g of 0.5 and can be considered a moderate change. For food records, a mean change of 231 kcal/day or 11 g of protein/day corresponded to a moderate change. Choice of endpoint in cachexia trials will depend on factors pertinent to the trial to be conducted. Nevertheless, from trials assessed and available literature, NRS or EORTC QLQ C30/C15 PAL seems suitable for appetite assessments. Appetite and dietary intake endpoints are rarely used as primary outcomes in cancer cachexia. Dietary intake assessments were used mainly to monitor compliance and are not validated in cachexia populations. Given the importance to cachexia studies, dietary intake endpoints must be validated before they are used as endpoints in clinical trials.
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Apetite , Neoplasias , Humanos , Caquexia/terapia , Caquexia/tratamento farmacológico , Ingestão de Alimentos , Neoplasias/complicações , Estudos Prospectivos , Qualidade de Vida , Estudos Retrospectivos , Ensaios Clínicos como AssuntoRESUMO
BACKGROUND: Effects on anticancer therapy following the integration of palliative care and oncology are rarely investigated. Thus, its potential effect is unknown. AIM: To investigate the effects of the complex intervention PALLiON versus usual care on end-of-life anticancer therapy. DESIGN: Cluster-randomised controlled trial (RCT), registered at ClinicalTrials.gov (No. NCT01362816). The complex intervention consisted of a physician education program enhancing theoretical, clinical and communication skills, a patient-centred care pathway and patient symptom reporting prior to all consultations. Primary outcome was overall use, start and cessation of anticancer therapy in the last 3 months before death. Secondary outcomes were patient-reported outcomes. Mixed effects logistic regression models and Cox proportional hazard were used. SETTING: A total of 12 Norwegian hospitals (03/2017-02/2021). PARTICIPANTS: Patients ⩾18 years, advanced stage solid tumour, starting last line of anticancer therapy, estimated life expectancy ⩽12 months. RESULTS: A total of 616 (93%) patients were included (intervention: 309/control:307); 63% males, median age 69, 77% had gastrointestinal cancers. Median survival time from inclusion was 8 (IQR 3-14) and 7 months (IQR 3-12), and days between anticancer therapy start and death were 204 (90-378) and 168 (69-351) (intervention/control). Overall, 78 patients (13%) received anticancer therapy in the last month (intervention: 33 [11%]/control: 45 [15%]). No differences were found in patient-reported outcomes. CONCLUSION: We found no significant differences in the probability of receiving end-of-life anticancer therapy. The intervention did not have the desired effect. It was probably too general and too focussed on communication skills to exert a substantial influence on conventional clinical practice.
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Neoplasias , Cuidados Paliativos , Masculino , Humanos , Idoso , Feminino , Qualidade de Vida , Neoplasias/patologia , Hospitais , MorteRESUMO
In cancer cachexia trials, measures of physical function are commonly used as endpoints. For drug trials to obtain regulatory approval, efficacy in physical function endpoints may be needed alongside other measures. However, it is not clear which physical function endpoints should be used. The aim of this systematic review was to assess the frequency and diversity of physical function endpoints in cancer cachexia trials. Following a comprehensive electronic literature search of MEDLINE, Embase and Cochrane (1990-2021), records were retrieved. Eligible trials met the following criteria: adults (≥18 years), controlled design, more than 40 participants, use of a cachexia intervention for more than 14 days and use of a physical function endpoint. Physical function measures were classified as an objective measure (hand grip strength [HGS], stair climb power [SCP], timed up and go [TUG] test, 6-min walking test [6MWT] and short physical performance battery [SPPB]), clinician assessment of function (Karnofsky Performance Status [KPS] or Eastern Cooperative Oncology Group-Performance Status [ECOG-PS]) or patient-reported outcomes (physical function subscale of the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaires [EORTC QLQ-C30 or C15]). Data extraction was performed using Covidence and followed PRISMA guidance (PROSPERO registration: CRD42022276710). A total of 5975 potential studies were examined and 71 were eligible. Pharmacological interventions were assessed in 38 trials (54%). Of these, 11 (29%, n = 1184) examined megestrol and 5 (13%, n = 1928) examined anamorelin; nutritional interventions were assessed in 21 trials (30%); and exercise-based interventions were assessed in 6 trials (8%). The remaining six trials (8%) assessed multimodal interventions. Among the objective measures of physical function (assessed as primary or secondary endpoints), HGS was most commonly examined (33 trials, n = 5081) and demonstrated a statistically significant finding in 12 (36%) trials (n = 2091). The 6MWT was assessed in 12 trials (n = 1074) and was statistically significant in 4 (33%) trials (n = 403), whereas SCP, TUG and SPPB were each assessed in 3 trials. KPS was more commonly assessed than the newer ECOG-PS (16 vs. 9 trials), and patient-reported EORTC QLQ-C30 physical function was reported in 25 trials. HGS is the most commonly used physical function endpoint in cancer cachexia clinical trials. However, heterogeneity in study design, populations, intervention and endpoint selection make it difficult to comment on the optimal endpoint and how to measure this. We offer several recommendations/considerations to improve the design of future clinical trials in cancer cachexia.
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Caquexia , Neoplasias , Humanos , Caquexia/terapia , Caquexia/complicações , Força da Mão , Neoplasias/complicações , Neoplasias/terapia , Qualidade de Vida , Projetos de PesquisaRESUMO
Background: Early integration of oncology and patient-centered palliative care is the recommended clinical practice model for patients with advanced cancer. General and specific communication skills are necessary to achieve integrated patient-centered care, but require organized training to be adequately mastered. Challenges and barriers on several levels, i.e. organizational, professional and individual may, however, hamper implementation. The development, implementation, and evaluation of such an educational program focusing on communication skills contain many steps, considerations and lessons learned, which are described in this article.Methods: A multi-professional faculty developed, implemented, and evaluated an educational program through a 5-step approach. The program was part of a Norwegian cluster-randomized controlled trial aiming to test the effect of early integration of oncology and palliative care for patients with advanced cancer.Results: The result is the PALLiON educational program; a multi-faceted, evidence-based, and learner-centered program with a specific focus on physicians' communication skills. Four modules were developed: lectures, discussion groups, skills training, and coaching. These were implemented at the six intervention hospitals using different teaching strategies. Evaluation in a subgroup of participants showed a positive appraisal of the group discussions and skills training.Conclusion:We present our experiences and reflections regarding implementation and lessons learned, which should be considered in future developments and implementations; (1) Include experienced faculty with various backgrounds, (2) Be both evidence-based and learner-centered, (3) Choose teaching strategies wisely, (4) Expect resistance and skepticism, (5) Team up with management and gatekeepers, (6) Expect time to fly, and (7) Plan thorough assessment of the evaluation and effect.Trial registration: ClinicalTrials.gov identifier: NCT03088202.
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Neoplasias , Médicos , Humanos , Neoplasias/terapia , Oncologia/educação , Cuidados Paliativos , ComunicaçãoRESUMO
BACKGROUND: Telehealth seems feasible for use in home-based palliative care (HBPC). It may improve access to health care professionals (HCPs) at patients' homes, reduce hospital admissions, enhance patients' feelings of security and safety, and increase the time spent at home for patients in HBPC. HBPC requires the involvement of various HCPs such as nurses, physicians, allied health professionals, dietitians, psychologists, religious counselors, and social workers. Acceptance of the use of technology among HCPs is essential for the successful delivery of telehealth in practice. No scoping review has mapped the experiences and perspectives of HCPs regarding the use of telehealth in HBPC. OBJECTIVE: The aim of this review was to systematically map published studies on HCPs' experiences and perspectives on the use of telehealth in HBPC. METHODS: A scoping review was conducted using the methodology of Arksey and O'Malley. The review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for scoping reviews. A systematic search was performed in AMED, CINAHL, Embase, MEDLINE, PsycINFO, and Web of Science for studies published in peer-reviewed journals between January 1, 2000, and August 23, 2022. The reference lists of the included papers were hand searched to identify additional studies. The inclusion criteria were (1) studies using qualitative, quantitative, or mixed methods; (2) studies including HCPs using telehealth with patients in HBPC; (3) studies on HCPs' experiences and perspectives on the use of telehealth in HBPC; (4) studies published between January 1, 2000, and August 23, 2022; and (5) studies published in English, Portuguese, Norwegian, Danish, Swedish, or Spanish. Pairs of authors independently included studies and extracted data. The first 2 stages of thematic synthesis were used to thematically organize the data. RESULTS: This scoping review included 29 papers from 28 studies. Four descriptive themes were identified: (1) easy to use but technological issues undermine confidence, (2) adds value but personal and organizational barriers challenge adoption, (3) potential to provide useful and meaningful patient-reported data, and (4) mutual trust as a prerequisite for interpersonal relationships. CONCLUSIONS: Telehealth in HBPC seems to be easy to use and may improve the coordination of care, time efficiency, clinical assessments, and help build and enhance personal and professional relationships. However, the introduction of technology in HBPC is complex, as it may not align well with the overall aim of palliative care from HCPs' point of view. Further, changes in practice and requirements for HCPs may reduce motivation for the use of telehealth in HBPC. HCPs consider themselves to have central roles in implementing telehealth, and a lack of acceptance and motivation is a key barrier to telehealth adoption. Policy makers and telehealth developers should be aware of this potential barrier when developing or implementing new technology for use in HBPC. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/33305.
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Médicos , Telemedicina , Humanos , Pessoal Técnico de Saúde , Pessoal de Saúde , Cuidados PaliativosRESUMO
BACKGROUND: Telehealth seems feasible for use in home-based palliative care. However, acceptance among health care professionals (HCPs) is essential for the successful delivery of telehealth in practice. No scoping review has mapped the experiences and perspectives of HCPs on the use of telehealth for home-based palliative care. OBJECTIVE: The aim of this review is to systematically map published studies on HCPs' experiences and perspectives on the use of telehealth in home-based palliative care. METHODS: The proposed scoping review will employ the methodology of Arksey and O'Malley. This protocol is guided by the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol (PRISMA-P). A systematic search will be performed in MEDLINE, PsycINFO, EMBASE, CINAHL, Allied and Complementary Medicine (AMED), and Web of Science for studies published between January 2000 and July 5, 2021. We will also hand search the reference lists of included papers to identify additional studies of relevance. The search will be updated in 2022. Pairs of authors will independently assess the eligibility of studies and extract data. The first 2 stages of thematic synthesis will be used to thematically organize the data. Because the scoping review methodology consists of reviewing and collecting data from publicly available materials, this study does not require ethics approval. RESULTS: The database searches; testing of eligibility criteria; and screening of titles, abstracts, and full-text papers will be performed by fall 2021. The results from this scoping review will be presented as a descriptive summary of the results from all included papers, and will be inductively organized into descriptive themes. A frequency table illustrating which papers were included in which descriptive themes will be made. Results are anticipated by the fall of 2022. CONCLUSIONS: A mapping of studies could identify research gaps regarding HCPs' experiences and perspectives on the use of telehealth in home-based palliative care and may determine the value and feasibility of conducting a full systematic review. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/33305.
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BACKGROUND: Despite robust evidence from randomized controlled trials (RCTs) demonstrating clinical and patient-reported benefits of integrated oncology and palliative care, the tumour-centred focus is predominant. This single-centre process evaluation monitors documentation of required patient-centred variables during an RCT. METHODS: Performance status, patient self-reported symptoms, weight and summaries to general practitioners were assessed from June 2017 to July 2020 in three consultation types: first oncological after study inclusion and palliative and oncological consultations during chemotherapy. Descriptive statistics were used to monitor if the pre-defined program fulfilment of ≥85% documentation was reached. RESULTS: 435 consultations were monitored in 76 patients; 60.5% males, 86.8% with GI cancers; 76 (17.5%) were from the first oncological consultations, 87 (20.0%) and 272 (62.5%) from palliative or subsequent oncological consultations. Program fulfilment differed across consultation types with 94.8% in the palliative consultations (83.3-100%), relative to 65.8% (62.5-75.0%) and 69.2% (57.0-84.3%) for first and subsequent oncological consultations over time, respectively. Use of self-reported symptoms was consistently lower in the oncological consultations. CONCLUSIONS: The documentation level of required core variables was not satisfactory, notwithstanding their high clinical relevance and continuous reminders during study. Pre-trial optimization strategies are paramount to promote integration and reduce professional and personal barriers towards a more patient-centred focus.
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Detection of tumour-specific circulating cell-free DNA in plasma (ctDNA) fails in a significant number of cases depending on the clinical context. The primary aim was to investigate clinicopathological factors associated with detection of ctDNA in patients with RAS-/BRAF-mutated metastatic colorectal cancer (mCRC) prior to first-line therapy. A secondary aim was to evaluate the prognostic impact of ctDNA compared to other biomarkers. Patients were included from the NORDIC-VII study (N = 253). ctDNA was sampled prior to treatment and analysed for hotspot tissue mutations (KRAS, NRAS, and BRAF) using droplet digital PCR. Multivariable regression models were constructed to predict the probability of mutation detection and survival. Increasing radiological size of target lesions by increments of 1 cm (odds ratio [OR] = 1.18; 95% confidence interval [CI] 1.09-1.27; P < .001), intact primary tumour (OR = 3.17; 95% CI 1.22-8.22; P = .018) and more than one metastatic site (OR = 3.08; 95% CI 1.32-7.19; P = .009) were associated with mutation detection in plasma. Metastatic involvement of the lung was associated with non-detection (OR = 0.26; 95% CI 0.12-0.58; P = .001). Preanalytical and analytical factors modulated detection. High allele frequencies of ctDNA indicated poor prognosis independently of CEA and CA19-9 (hazard ratio [HR] = 2.38; 95% CI 1.74-3.26; P < .001; N = 206). Clinicopathological characteristics should be carefully considered when evaluating ctDNA results from mCRC patients, especially when confronted with a plasma negative result. ctDNA may prove to be a clinically useful marker in the evaluation of mCRC treatment.
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Neoplasias Colorretais/genética , GTP Fosfo-Hidrolases/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/secundário , Proteínas de Membrana/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Neoplasias Colorretais/sangue , Neoplasias Colorretais/patologia , Feminino , Frequência do Gene , Humanos , Modelos Logísticos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/patologia , Masculino , Prognóstico , Análise de SobrevidaRESUMO
BACKGROUND: Several publications have addressed the need for a systematic integration of oncological care focused on the tumor and palliative care (PC) focused on the patient with cancer. The exponential increase in anticancer treatments and the high number of patients living longer with advanced disease have accentuated this. Internationally, there is now a persuasive argument that introducing PC early during anticancer treatment in patients with advanced disease has beneficial effects on symptoms, psychological distress, and survival. METHODS: This is a national cluster-randomized trial (C-RCT) in 12 Norwegian hospitals. The trial investigates effects of early, systematic integration of oncology and specialized PC in patients with advanced cancer in six intervention hospitals compared with conventional care in six. Hospitals are stratified on the size of local catchment areas before randomization. In the intervention hospitals, a three-part complex intervention will be implemented. The backbone of the intervention is the development and implementation of patient-centered care pathways that contain early, compulsory referral to PC and regular and systematic registrations of symptoms. An educational program must be completed before patient inclusion. A total of 680 patients with advanced cancer and one caregiver per patient are included when patients come for start of last line of chemotherapy, defined according to national treatment guidelines. Data registration, clinical variables, and patient- and caregiver-reported outcomes take place every 2 months for 1 year or until death. The primary outcome is use of chemotherapy in the last 3 months of life by comparing the proportion of patients who receive this in the intervention and control groups. Primary outcome is use of chemotherapy in the last 3 months before death, i.e. number of patients. Secondary outcomes are initiation, discontinuation and number of cycles, last 3 months of life, administration of other medical interventions in the last month of life, symptom burden, quality of life (QoL), satisfaction with information and follow-up, and caregiver health, QoL, and satisfaction with care. DISCUSSION: Results from this C-RCT will be used to raise the awareness about the positive outcomes of early provision of specialized palliative care using pathways for patients with advanced cancer receiving medical anticancer treatment. The long-term clinical objective is to integrate these patient-centered pathways in Norwegian cancer care. The specific focus on the patient and family and the organization of a predictable care trajectory is consistent with current Norwegian strategies for cancer care. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03088202. Registered on 23 March 2017.
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Neoplasias/terapia , Cuidados Paliativos/métodos , Educação de Pacientes como Assunto/métodos , Cuidado Transicional , Adaptação Psicológica , Cuidadores/educação , Cuidadores/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Pessoal de Saúde/educação , Humanos , Oncologia , Estudos Multicêntricos como Assunto , Neoplasias/patologia , Neoplasias/psicologia , Noruega , Satisfação do Paciente , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Encaminhamento e Consulta , Fatores de TempoRESUMO
BACKGROUND & AIMS: Prognostication in hepatocellular carcinoma (HCC) is demanding. Not only tumour extent and performance status are to be considered, but also liver function, which is often limiting for both survival itself and for treatment possibilities. This study was conducted to assess whether patient-reported questionnaires containing general and liver-specific questions could improve prognostication of survival. METHODS: 185 patients with hepatocellular carcinoma in Norway and Sweden were prospectively included. Patients completed the quality-of-life questionnaires EORTC QLQ C30 and HCC18, and clinical, radiological and laboratory parameters were registered. Multivariate Cox regression and Harrell's C-statistics were used to identify the model that best predicted mortality. RESULTS: Quality-of-life data were prognostic for overall survival. Fatigue and nutrition scales were prognostic in the multivariable analyses alone and in combination with clinical parameters. The prognostic value of established scoring systems was increased by the addition of QoL data. The best prognostic power was achieved by combining HCC18 nutrition scale with selected background parameters. CONCLUSION: Quality-of-life questionnaires can prognosticate mortality in HCC patients. When combined with established scoring systems, both the general cancer questionnaire EORTC QLQ C30, and the additional liver cancer-specific HCC18 increased the prognostic accuracy slightly.
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Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/mortalidade , Qualidade de Vida , Idoso , Carcinoma Hepatocelular/fisiopatologia , Fadiga , Feminino , Humanos , Neoplasias Hepáticas/fisiopatologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Noruega , Estado Nutricional , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Índice de Gravidade de Doença , Inquéritos e Questionários , SuéciaRESUMO
PURPOSE: The PI3K/Akt/mTOR signaling pathway is aberrantly activated in many cancers. Combining ridaforolimus, an mTOR inhibitor, with MK-2206, an Akt inhibitor, may more completely block the PI3K pathway and inhibit tumor growth. EXPERIMENTAL DESIGN: This phase I study assessed dose-limiting toxicities (DLT) and maximum tolerated dose (MTD) for the combination of oral ridaforolimus plus oral MK-2206 in patients with advanced solid tumors. Efficacy was evaluated in patients with biomarker-identified estrogen receptor-positive breast cancer (low RAS gene signature and high Ki67 index) or castration-resistant prostate cancer (PTEN deficiency) with PI3K pathway addiction. RESULTS: Thirty-five patients were enrolled: 11 patients in part A (three breast cancer) and 24 biomarker-eligible patients in part B (16 breast cancer, eight prostate cancer). One patient with breast cancer from part A was also found to be biomarker-eligible when tested after she had clinical response. The MTD was 10 mg/d ridaforolimus 5 d/wk + 90 mg/wk MK-2206; 1 of 17 patients experienced DLT (grade 3 rash) at this dose. The most common adverse events at MTD were rash (44.4%), stomatitis (38.9%), diarrhea (27.8%), and decreased appetite (27.8%). By investigator assessment, 2 of 16 (12.5%) evaluable patients with breast cancer had partial response; by central assessment, 2 of 14 (14.3%) evaluable patients had complete response. Two patients had durable stable disease (SD) for 416 and 285 days, respectively. No patients with prostate cancer responded; one patient had SD for ≥ 6 months. CONCLUSIONS: Combination ridaforolimus and MK-2206 showed promising activity and good tolerability in heavily pretreated patients with hormone-positive and -negative breast cancer exhibiting PI3K pathway dependence.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Feminino , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias/diagnóstico , Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/administração & dosagem , Retratamento , Transdução de Sinais/efeitos dos fármacos , Sirolimo/administração & dosagem , Sirolimo/análogos & derivados , Serina-Treonina Quinases TOR/antagonistas & inibidores , Resultado do Tratamento , Adulto JovemRESUMO
There is no universally accepted definition of cancer cachexia. Two classifications have been proposed; the 3-factor classification requiring ≥ 2 of 3 factors; weight loss ≥ 10%, food intake ≤ 1500 kcal/day, and C-reactive protein ≥ 10 mg/l, and the consensus classification requiring weight loss >5% the past 6 mo, or body mass index <20 kg/m(2) or sarcopenia, both with ongoing weight loss >2%. Precachexia is the initial stage of the cachexia trajectory, identified by weight loss ≤ 5%, anorexia and metabolic change. We examined the consistency between the 2 classifications, and their association with survival in a palliative cohort of 45 (25 men, median age of 72 yr, range 35-89) unresected pancreatic cancer patients. Computed tomography images were used to determine sarcopenia. Height/weight/C-reactive protein and survival were extracted from medical records. Food intake was self-reported. The agreement for cachexia and noncachexia was 78% across classifications. Survival was poorer in cachexia compared to noncachexia (3-factor classification, P = 0.0052; consensus classification, P = 0.056; when precachexia was included in the consensus classification, P = 0.027). Both classifications showed a trend toward lower median survival (P < 0.05) with the presence of cachexia. In conclusion, the two classifications showed good overall agreement in defining cachectic pancreatic cancer patients, and cachexia was associated with poorer survival according to both.
Assuntos
Caquexia/classificação , Neoplasias Pancreáticas/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Caquexia/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: It is important to understand the mechanisms by which the cells integrate signals from different receptors. Several lines of evidence implicate epidermal growth factor (EGF) receptor (EGFR) in the pathophysiology of hepatocarcinomas. Data also suggest a role of prostaglandins in some of these tumours, through their receptors of the G protein-coupled receptor (GPCR) family. In this study we have investigated mechanisms of interaction between signalling from prostaglandin receptors and EGFR in hepatocarcinoma cells. METHODS: The rat hepatocarcinoma cell line MH1C1 and normal rat hepatocytes in primary culture were stimulated with EGF or prostaglandin E2 (PGE2) and in some experiments also PGF2α. DNA synthesis was determined by incorporation of radiolabelled thymidine into DNA, phosphorylation of proteins in signalling pathways was assessed by Western blotting, mRNA expression of prostaglandin receptors was determined using qRT-PCR, accumulation of inositol phosphates was measured by incorporation of radiolabelled inositol, and cAMP was determined by radioimmunoassay. RESULTS: In the MH1C1 hepatocarcinoma cells, stimulation with PGE2 or PGF2α caused phosphorylation of the EGFR, Akt, and ERK, which could be blocked by the EGFR tyrosine kinase inhibitor gefitinib. This did not occur in primary hepatocytes. qRT-PCR revealed expression of EP1, EP4, and FP receptor mRNA in MH1C1 cells. PGE2 stimulated accumulation of inositol phosphates but not cAMP in these cells, suggesting signalling via PLCß. While pretreatment with EP1 and EP4 receptor antagonists did not inhibit the effect of PGE2, pretreatment with an FP receptor antagonist blocked the phosphorylation of EGFR, Akt and ERK. Further studies suggested that the PGE2-induced signal was mediated via Ca2+ release and not PKC activation, and that it proceeded through Src and shedding of membrane-bound EGFR ligand precursors by proteinases of the ADAM family. CONCLUSION: The results indicate that in MH1C1 cells, unlike normal hepatocytes, PGE2 activates the MEK/ERK and PI3K/Akt pathways by transactivation of the EGFR, thus diversifying the GPCR-mediated signal. The data also suggest that the underlying mechanisms in these cells involve FP receptors, PLCß, Ca2+, Src, and proteinase-mediated release of membrane-associated EGFR ligand(s).
Assuntos
Carcinoma Hepatocelular , Dinoprostona/administração & dosagem , Fator de Crescimento Epidérmico/administração & dosagem , Receptores ErbB , Neoplasias Hepáticas , Animais , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Linhagem Celular Tumoral , Dinoprostona/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Gefitinibe , Regulação Neoplásica da Expressão Gênica , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinazolinas/administração & dosagem , Ratos , Transdução de Sinais/efeitos dos fármacosRESUMO
PURPOSE: The NORDIC-VII multicenter phase III trial investigated the efficacy of cetuximab when added to bolus fluorouracil/folinic acid and oxaliplatin (Nordic FLOX), administered continuously or intermittently, in previously untreated metastatic colorectal cancer (mCRC). The influence of KRAS mutation status on treatment outcome was also investigated. PATIENTS AND METHODS: Patients were randomly assigned to receive either standard Nordic FLOX (arm A), cetuximab and FLOX (arm B), or cetuximab combined with intermittent FLOX (arm C). Primary end point was progression-free survival (PFS). Overall survival (OS), response rate, R0 resection rate, and safety were secondary end points. RESULTS: Of the 571 patients randomly assigned, 566 were evaluable in intention-to-treat (ITT) analyses. KRAS and BRAF mutation analyses were obtained in 498 (88%) and 457 patients (81%), respectively. KRAS mutations were present in 39% of the tumors; 12% of tumors had BRAF mutations. The presence of BRAF mutations was a strong negative prognostic factor. In the ITT population, median PFS was 7.9, 8.3, and 7.3 months for the three arms, respectively (not significantly different). OS was almost identical for the three groups (20.4, 19.7, 20.3 months, respectively), and confirmed response rates were 41%, 49%, and 47%, respectively. In patients with KRAS wild-type tumors, cetuximab did not provide any additional benefit compared with FLOX alone. In patients with KRAS mutations, no significant difference was detected, although a trend toward improved PFS was observed in arm B. The regimens were well tolerated. CONCLUSION: Cetuximab did not add significant benefit to the Nordic FLOX regimen in first-line treatment of mCRC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cetuximab , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/secundário , Análise Mutacional de DNA , Intervalo Livre de Doença , Esquema de Medicação , Europa (Continente) , Feminino , Fluoruracila/administração & dosagem , Humanos , Estimativa de Kaplan-Meier , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Mutação , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Modelos de Riscos Proporcionais , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras) , Medição de Risco , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Proteínas ras/genéticaRESUMO
BACKGROUND: Neurotensin has been found to promote colon carcinogenesis in rats and mice, and proliferation of human colon carcinoma cell lines, but the mechanisms involved are not clear. We have examined signalling pathways activated by neurotensin in colorectal and pancreatic carcinoma cells. METHODS: Colon carcinoma cell lines HCT116 and HT29 and pancreatic adenocarcinoma cell line Panc-1 were cultured and stimulated with neurotensin or epidermal growth factor (EGF). DNA synthesis was determined by incorporation of radiolabelled thymidine into DNA. Levels and phosphorylation of proteins in signalling pathways were assessed by Western blotting. RESULTS: Neurotensin stimulated the phosphorylation of both extracellular signal-regulated kinase (ERK) and Akt in all three cell lines, but apparently did so through different pathways. In Panc-1 cells, neurotensin-induced phosphorylation of ERK, but not Akt, was dependent on protein kinase C (PKC), whereas an inhibitor of the ß-isoform of phosphoinositide 3-kinase (PI3K), TGX221, abolished neurotensin-induced Akt phosphorylation in these cells, and there was no evidence of EGF receptor (EGFR) transactivation. In HT29 cells, in contrast, the EGFR tyrosine kinase inhibitor gefitinib blocked neurotensin-stimulated phosphorylation of both ERK and Akt, indicating transactivation of EGFR, independently of PKC. In HCT116 cells, neurotensin induced both a PKC-dependent phosphorylation of ERK and a metalloproteinase-mediated transactivation of EGFR that was associated with a gefitinib-sensitive phosphorylation of the downstream adaptor protein Shc. The activation of Akt was also inhibited by gefitinib, but only partly, suggesting a mechanism in addition to EGFR transactivation. Inhibition of PKC blocked neurotensin-induced DNA synthesis in HCT116 cells. CONCLUSIONS: While acting predominantly through PKC in Panc-1 cells and via EGFR transactivation in HT29 cells, neurotensin used both these pathways in HCT116 cells. In these cells, neurotensin-induced activation of ERK and stimulation of DNA synthesis was PKC-dependent, whereas activation of the PI3K/Akt pathway was mediated by stimulation of metalloproteinases and subsequent transactivation of the EGFR. Thus, the data show that the signalling mechanisms mediating the effects of neurotensin involve multiple pathways and are cell-dependent.
Assuntos
Neoplasias do Colo/metabolismo , Receptores ErbB/metabolismo , Neurotensina/farmacologia , Proteína Quinase C/metabolismo , Transdução de Sinais , Animais , Cálcio/metabolismo , Linhagem Celular Tumoral , Neoplasias do Colo/enzimologia , Replicação do DNA/efeitos dos fármacos , Ativação Enzimática , Células HCT116 , Células HT29 , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacosRESUMO
Prostaglandins (PGs) such as PGE2 enhance proliferation in many cells, apparently through several distinct mechanisms, including transactivation of the epidermal growth factor (EGF) receptor (EGFR) as well as EGFR-independent pathways. In this study we found that in primary cultures of rat hepatocytes PGE2 did not induce phosphorylation of the EGFR, and the EGFR tyrosine kinase blockers gefitinib and AG1478 did not affect PGE2-stimulated phosphorylation of ERK1/2. In contrast, PGE2 elicited EGFR phosphorylation and EGFR tyrosine kinase inhibitor-sensitive ERK phosphorylation in MH1C1 hepatoma cells. These findings suggest that PGE2 elicits EGFR transactivation in MH1C1 cells but not in hepatocytes. Treatment of the hepatocytes with PGE2 at 3 h after plating amplified the stimulatory effect on DNA synthesis of EGF administered at 24 h and advanced and augmented the cyclin D1 expression in response to EGF in hepatocytes. The pretreatment of the hepatocytes with PGE2 resulted in an increase in the magnitude of EGF-stimulated Akt phosphorylation and ERK1/2 phosphorylation and kinase activity, including an extended duration of the responses, particularly of ERK, to EGF in PGE2-treated cells. Pertussis toxin abolished the ability of PGE2 to enhance the Akt and ERK responses to EGF. The results suggest that in hepatocytes, unlike MH1C1 hepatoma cells, PGE2 does not transactivate the EGFR, but instead acts in synergism with EGF by modulating mitogenic mechanisms downstream of the EGFR. These effects seem to be at least in part G(i) protein-mediated and include upregulation of signaling in the PI3K/Akt and the Ras/ERK pathways.