Ejercicio para la caquexia del cáncer en adultos
Resumen
Antecedentes
La caquexia del cáncer es un síndrome multifactorial caracterizado por una pérdida progresiva de masa muscular esquelética, con o sin una pérdida de masa de grasa, que provoca deficiencia funcional progresiva. El ejercicio físico puede atenuar los efectos de la caquexia del cáncer mediante varios mecanismos que incluyen la modulación del metabolismo muscular, la sensibilidad a la insulina y los niveles de inflamación.
Objetivos
El objetivo primario fue determinar los efectos del ejercicio comparado con atención habitual o ningún tratamiento sobre la masa corporal magra, el biomarcador principal de caquexia, en adultos con cáncer. Los objetivos secundarios, sujetos a la disponibilidad de los datos, fueron examinar la aceptabilidad y la seguridad del ejercicio en este contexto y comparar los efectos según las características de la intervención con ejercicios o la población de pacientes.
Métodos de búsqueda
Se hicieron búsquedas en las bases de datos CENTRAL (número 6, 2014), MEDLINE (1946 hasta junio de 2014), EMBASE (1974 hasta junio de 2014), DARE y en HTA (número 6, 2014), ISI Web of Science (1900 hasta junio de 2014), LILACS (1985 hasta el 28 de junio de 2014), PEDro (inicio hasta el 28 de junio de 2014), SciVerse SCOPUS (inicio hasta el 28 de junio de 2014), Biosis Previews PreMEDLINE (1969 hasta junio de 2014) y en Open Grey (inicio hasta el 28 de junio de 2014). También se buscaron los estudios en curso, se verificaron las listas de referencias y se estableció contacto con expertos para buscar investigaciones potencialmente relevantes.
Criterios de selección
Se incluyeron los ensayos controlados aleatorios (ECA) en adultos que cumplieron los criterios clínicos para la caquexia del cáncer y que compararon un programa de ejercicios como una intervención única o adjunta con ningún tratamiento o un control activo. No se impuso restricción de idioma.
Obtención y análisis de los datos
Dos revisores evaluaron de forma independiente los títulos y los resúmenes de los artículos para determinar la relevancia y extrajeron datos sobre el diseño del estudio, los participantes, las intervenciones y los resultados de los artículos potencialmente relevantes.
Resultados principales
Se revisaron 3154 referencias individuales, de las cuales se eliminaron 3138 después de la revisión del título y se leyeron completos 16. No se encontraron ensayos que cumplieran los criterios de inclusión.
Conclusiones de los autores
No hay pruebas suficientes para determinar la seguridad y la efectividad del ejercicio en los pacientes con caquexia del cáncer. Se necesitan ensayos controlados aleatorios (es decir, preferentemente ensayos de grupos paralelos o con asignación al azar grupal) para probar la efectividad del ejercicio en este grupo. Hay estudios en curso sobre el tema, por lo que esta revisión se actualizará para incorporar los hallazgos.
PICO
Resumen en términos sencillos
¿Es el ejercicio eficaz en los pacientes con caquexia del cáncer?
Muchos pacientes con cáncer pierden peso (músculo y grasa del cuerpo) como parte del síndrome de caquexia, que puede ser causado por el cáncer y su tratamiento. Lo anterior puede provocar debilidad muscular, fatiga, falta de energía y una reducción en la calidad de vida. El ejercicio es un tratamiento posible para la caquexia del cáncer y puede ayudar a reducir el efecto que provoca en los pacientes. En esta revisión sistemática se efectuaron búsquedas en bases de datos importantes e informes de congresos y se estableció contacto con expertos en este campo para identificar estudios de ejercicios en grupos de pacientes con caquexia del cáncer. La extensa búsqueda en la literatura hasta junio de 2014 no encontró estudios que pudieran incluirse. Por lo tanto, no se encontraron pruebas de ensayos controlados aleatorios disponibles en la bibliografía para determinar el efecto del ejercicio en la caquexia del cáncer. Se necesitan más estudios de investigación. Hay estudios en curso sobre el tema, por lo que esta revisión se actualizará para incorporar los hallazgos.
Authors' conclusions
Background
We conducted this systematic review following the protocol previously published in the Cochrane Database of Systematic Reviews (Grande 2013). For explanations of methodological terms, see the main glossary on The Cochrane Collaboration website (http://www.cochrane.org/glossary).
Description of the condition
Cancer cachexia is defined as "a multi‐factorial syndrome characterized by an ongoing loss of skeletal muscle mass, with or without a loss of fat mass, that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment" (Fearon 2011). Prevalence varies with cancer type, but is highest in people with cancer arising from the upper gastro‐intestinal tract or lung, where over half of all patients are affected at the point of diagnosis (Fearon 2011; Laviano 2005). The pathophysiology of cancer cachexia is complex and characterised by a negative energy balance and abnormal metabolism (Fearon 2012; Tisdale 2009). The combination of a persistent inflammatory response, tumour‐derived catabolic factors and a stress response leads to reduced food intake, increased resting energy expenditure and an overall loss of skeletal muscle mass; the result of reduced protein synthesis, increased protein breakdown and reduced insulin sensitivity (Evans 2008; Fearon 2011; Tisdale 2009). The loss of lean body mass contributes to a progressive decline in muscle strength and endurance (Stephens 2012; Weber 2009), exercise capacity (England 2012; Jones 2012) and physical activity levels (Dodson 2011; Wilcock 2008), and is associated with increased risk of dose‐limiting chemotherapy toxicities (Prado 2007; Prado 2008; Prado 2009) and poor survival (Antoun 2013; Martin 2013).
Description of the intervention
There are no standard interventions for cancer cachexia and some consider it refractory once established, for example, in patients with progressive disease and a limited prognosis (Fearon 2011). As such, it is recommended that greater emphasis be placed on applying a proactive approach, early in the course of the disease, with the aim being to maintain or slow down the loss of physical function (Fearon 2011; Muscaritoli 2010). Due to the complex nature of the condition, multimodal intervention is also considered necessary as it is unlikely that any single intervention will increase food intake, attenuate the metabolic disturbances and address the imbalance between muscle protein synthesis and breakdown (Fearon 2008). Three main component interventions are being developed alone or in combination (Solheim 2012): nutritional therapies to increase energy and protein intake (Dewey 2007); drug therapies to stimulate appetite and reduce inflammation (Berenstein 2005; Lee 2011; Reid 2012); and exercise therapies.
Exercise is defined by the American College of Sports Medicine as a "planned, structured and repetitive bodily movement done to maintain or improve one or more components of physical fitness" (Thompson 2010). Different types of exercise may use everyday activities, such as walking, or specialist equipment, such as free‐weights, for the purposes of training. Exercise programmes vary widely according to the frequency, intensity and type of training used, as well as contextual factors such as the programme setting and level of supervision. For example, both a hospital‐based programme of twice weekly, high‐intensity, stationary cycling for six weeks, and a home‐based programme of low‐intensity, flexibility training throughout chemotherapy would be defined as exercise (Thompson 2010).
How the intervention might work
Exercise may attenuate the effects of cancer cachexia via several mechanisms, including the modulation of muscle metabolism, insulin sensitivity and levels of inflammation (Maddocks 2012). Resistance exercise is a potent stimulator of muscle protein synthesis, particularly when performed in conjunction with the provision of amino acids (Glover 2010; Marimuthu 2011). Improved insulin action in peripheral tissues following exercise may inhibit muscle protein breakdown (Wang 2006). Exercise also triggers the formation of a cohort of cytokines from muscle fibres, including interleukin‐6, which increases insulin sensitivity and reduces the production of pro‐inflammatory cytokines (Starkie 2003). Repeated exercise has an overall anti‐inflammatory effect, which has been observed in healthy populations (Gleeson 2011) and patients with early stage cancer (Betof 2013). This effect would be beneficial in cancer cachexia as levels of systemic inflammation are associated with reduced weight, exercise capacity and survival (McMillan 2013; Moses 2009; Proctor 2011). Thus, by preventing or slowing down the loss of lean body mass, exercise may ultimately help patients with or at risk of cancer cachexia maintain their independence for longer.
Why it is important to do this review
Despite a growing evidence base for nutritional and drug interventions for cancer cachexia, including Cochrane reviews (Berenstein 2005; Dewey 2007; Payne 2012; Reid 2012), studies of exercise interventions in the field are few in number. Reviews examining the use of exercise in cancer cachexia are generally narrative (Gould 2013), opinion based (Argilés 2012; Maddocks 2011; Maddocks 2012) and/or based on animal models of the condition (Argilés 2012). Nonetheless, there are reports of small studies from conference proceedings as well as ongoing/planned studies. Thus, there is a need to synthesise the evidence for the use of exercise for cancer cachexia and, if data permit, explore the optimal programme characteristics for this group of patients.
Objectives
The primary objective was to determine the effects of exercise, compared to usual care or no treatment, on lean body mass, the main biomarker of cachexia, in adults with cancer. Secondary objectives, subject to the availability of data, were to examine the acceptability and safety of exercise in this setting and to compare effectiveness according to the characteristics of the exercise intervention or patient population.
Methods
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) with a parallel, single‐stage or cross‐over design, including studies with a quasi‐randomised allocation in cases where allocation concealment was described.
Types of participants
Study participants were adults (≥ 18 years of age) with a histological or clinical diagnosis of cancer, meeting international criteria for cancer cachexia (Fearon 2011) of any stage, which include:
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pre‐cachexia, defined as weight loss ≤ 5% with anorexia and metabolic changes;
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cachexia, defined as weight loss > 5% in the past six months or body mass index (BMI) < 20 kg/m2 and ongoing weight loss > 2% or sarcopenia, anorexia or systemic inflammation; and
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refractory cachexia, defined as active catabolism, ongoing weight loss, not responsive to treatment and life expectancy of less than three months.
Where baseline demographic data were insufficient to assess participants against these criteria, we contacted study authors to seek additional data for this purpose.
We considered studies that were relevant to the review objectives, but which were not performed specifically to address cancer cachexia; e.g. studies in groups with advanced cancer. As such, we included studies in which at least half of the study population fell within the cachexia definitions above. Participants could be studied in any hospital or community setting. We did not include studies relating to participants during or following treatment with curative intent, or with no evidence of current disease.
Types of interventions
Studies examining any programme of exercise offered as a sole intervention or in combination with another intervention were eligible. We considered programmes using aerobic/endurance training, resistance training or a combination of both. We expected programmes to vary in terms of session length (minutes) and frequency (sessions/week), intensity of training (low, moderate, high) and overall duration (weeks). There were no restrictions on these or other programme characteristics including the setting in which the programme is offered (hospital/centre/home) and level of supervision (none, minimal, close). Interventions could be compared to either no treatment, usual care or an active control group, e.g. a nutritional or drug intervention.
Types of outcome measures
Primary outcomes
The primary outcome was lean body mass assessed at the first study time point to the end of a programme of exercise.
Secondary outcomes
Secondary outcomes included adherence to prescribed programmes, occurrence of adverse events and, subject to availability of data, muscle strength and endurance, maximal and submaximal exercise capacity, fatigue and health‐related quality of life.
Search methods for identification of studies
Electronic searches
We developed an electronic search strategy using a combination of terms based on the target population, intervention, comparator and outcomes. The search strategies used can be found in Appendix 1. We adapted these where necessary for the other databases listed below. We searched the following electronic databases from their start date until June 2014:
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CENTRAL (2014, Issue 6);
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MEDLINE (Ovid) 1946 to June 2014;
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EMBASE (Ovid) 1974 to June 2014;
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DARE and HTA ‐ Health Technology Assessments (on The Cochrane Library) (2014, Issue 6);
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ISI Web of Science (SCI‐Expanded and CPCI) 1900 to June 2014;
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LILACS (Latin American and Caribbean Health Sciences) 1985 to 28 June 2014;
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PEDro (the Physiotherapy Evidence Database) 28 June 2014;
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SciVerse SCOPUS 28 June 2014;
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Biosis Previews PreMEDLINE 1969 to June 2014;
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Open Grey (System for Information on Grey Literature) 28 June 2014.
We identified ongoing studies using:
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ClinicalTrials.gov (clinicaltrials.gov/);
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the metaRegister of Controlled Trials (mRCT) (www.controlled‐trials.com/);
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International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/en/);
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Pan African Clinical Trials (www.pactr.org); and
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the EU Clinical Trials Register (www.clinicaltrialsregister.eu/).
Searching other resources
We handsearched the following sources: the Society on Sarcopenia, Cachexia and Wasting Disorders (SCWD); the American Cancer Society; the British Association for Cancer Research (BACR); and the European Clinical Guidelines. We checked reference lists of relevant studies and reports citing all retrieved studies. In addition, we contacted corresponding authors of retrieved studies, experts and organisations in the field to seek potentially relevant research material, including unpublished and ongoing studies.
Data collection and analysis
Selection of studies
We used reference management software to merge results from different electronic databases and remove duplicate studies. Two review authors (AJG, VS or SV) independently assess titles and abstracts of articles for relevance (Higgins 2011a). We obtained full‐text reports of potentially relevant studies for assessment against the inclusion criteria. If missing information impaired the study selection, we contacted the study authors by email to clarify the necessary information. Any disagreement in the selection of studies was discussed and resolved by consensus from both review authors. In cases of persistent disagreement, a third author (MSP or MM) was consulted. We applied no language restrictions in the selection of studies.
Data extraction and management
We planned for two review authors (AJG and VS or SV) to independently extract data from the included studies. We developed an online extraction form to store data relating to the study source and eligibility, methods and bias (study design, sequence generation, allocation sequence concealment, blinding), participants (number, age, sex, ethnicity, diagnosis, disease severity, setting) and intervention (exercise type and intensity, session length and frequency, and overall programme duration), adherence to the exercise programme (either self reported or objective) and the occurrence of any adverse events. We planned to discuss and resolve disagreements by consensus.
Outcome data collected at baseline, immediately following a programme of exercise and at first follow‐up, were to include:
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lean body mass, generally assessed by anthropometry, e.g. skin fold thickness, or imaging, e.g. dual x‐ray absorptiometry, and expressed as a weight (e.g. kilograms, kg), cross‐sectional area (square centimetres, cm2) or volume (cubic centimetres, cm3) normalised to height;
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muscle strength, either isometric or isotonic, generally assessed using myometry and expressed as a measure of force (e.g. kilograms, kg, or Newton metres, Nm);
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muscle endurance, generally assessed as time or number of repetitions to a specified decline in muscle performance;
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maximal and submaximal exercise capacity, generally assessed by a walking or cycling test and expressed as a measure of oxygen uptake (VO2) or performance, e.g. distance walked in metres (m);
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fatigue, generally assessed on a numerical or categorical scale with a higher score representing more severe fatigue;
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health‐related quality of life, generally assessed on a numerical or categorical scale with a higher score representing a better quality of life. We examined the content items and known psychometric properties of the instruments used.
Assessment of risk of bias in included studies
We planned for two authors (AJG and VS or SV) to assess independently each study for risk of bias using The Cochrane Collaboration's tool, which addresses seven specific domains: sequence generation, allocation concealment, blinding of study participants and personnel, blinding of outcome assessment, completeness of outcome data, selective reporting and other potential sources of bias, for example carry‐over or blocking, where bias may be introduced. For each domain, the tool first identifies what is reported to have happened in the study. Where it was unclear, we sought information to aid this assessment from additional study reports, protocols, published comments and personal contact with study authors. Thereafter, we made a judgement as to the level of risk of bias for that domain: low, high or unclear (Higgins 2011b).
Measures of treatment effect
For the review objectives and outcomes, we may have extracted count, dichotomous, categorical and continuous data. We would have analysed outcome data as continuous when possible. We would have calculated the mean difference (MD) or standardised mean difference (SMD) in outcome between the intervention and control group with 95% confidence intervals (CI) (Deeks 2011).
Unit of analysis issues
In parallel‐group randomised controlled trials, we would have considered the individual patient as the unit of analysis. If we included cross‐over randomised controlled trials, we would have analysed both periods, separated by periods and together. If we included cluster‐randomised trials, we would have considered the group as the unit of analysis.
Dealing with missing data
We contacted authors by email if studies did not report the outcome measures of interest, did not describe randomisation or intention‐to‐treat analysis or had missing data.
Assessment of heterogeneity
We planned to assess clinical heterogeneity using the I2 statistic (Higgins 2002; Higgins 2003), to quantify inconsistency across trial conditions and its impact on the meta‐analysis. Ideally we would have used an inverse variable fixed‐effect model to estimate the overall direction, size and consistency of an effect from exercise immediately post‐programme. If considerable (I2 > 50%) or substantial clinical heterogeneity (I2 > 75%) was confirmed, we would have applied a random‐effects model or separate fixed‐effect model calculation to estimate an effect from exercise by subgroup (see below) (Deeks 2011).
Assessment of reporting biases
If there were 10 or more included studies, we would have conducted a funnel plot test for asymmetry to assess for any evidence of reporting bias.
Data synthesis
Where there were sufficient data and consistent or comparable outcomes, we planned to perform a meta‐analysis using an inverse variable fixed‐effect model to estimate the overall direction, size and consistency of an effect from exercise immediately post‐programme. For other types of data, likely to arise from secondary outcomes, we would have described findings from individual studies or presented them in tabular form (RevMan 2012).
Subgroup analysis and investigation of heterogeneity
Where sufficient data were available, we planned to use descriptive comparisons to consider differences in effect between subgroups according to the following participant characteristics: type of cancer (lung, pancreatic, etc.); stage of cachexia (pre‐cachexia, cachexia, refractory cachexia (Fearon 2011)), and intervention characteristics: type of exercise (aerobic, resistance, combined); intensity of exercise (light, moderate, high); duration of exercise programme (four weeks, 12 weeks, etc.).
Sensitivity analysis
Where sufficient data were available, we planned to perform a sensitivity analysis to consider the difference in pooled effect when studies at high or unclear risk of bias, or those with substantial (> 20%) missing data, were omitted from analyses.
Results
Description of studies
No studies met the inclusion criteria. In Figure 1 we present the study selection process.
Flow diagram: study selection process.
Results of the search
We identified 4786 references from the initial search (see Figure 1). There were a total of 3154 references after duplicates were removed, of which we removed 3138 after title screening. We viewed the remaining 16 references as potentially relevant and retrieved the full‐text studies. We excluded all articles for the reasons shown in ‘Excluded studies’.
Included studies
Following an extensive literature search we found no studies that could be included in this systematic review.
Excluded studies
Sixteen studies examined an exercise intervention in groups of patients with cancer and may have collected data on cachexia domains (Battaglini 2010; Carnaby‐Mann 2012; Cheville 2010; Courneya 2009; Elter 2009; Fouladiun 2007; Irwin 2009; Kuehr 2014; Litterini 2013; Mantovani 2010; Oldervoll 2006; Oldervoll 2011; Op den Kamp 2012; Saarto 2012; Schwartz 2007; Zatarain 2013). We attempted to contact corresponding authors via email to determine the proportion of the sample meeting pre‐cachexia or cachexia criteria. Most authors did not explore this concept (Battaglini 2010; Courneya 2009; Elter 2009; Irwin 2009; Kuehr 2014; Mantovani 2010; Oldervoll 2006; Oldervoll 2011; Schwartz 2007; Zatarain 2013), and others did not respond (Carnaby‐Mann 2012; Cheville 2010; Litterini 2013; Saarto 2012).
Risk of bias in included studies
We did not identify any suitable studies for inclusion.
Effects of interventions
In the absence of any suitable randomised controlled trials in cancer cachexia, we were unable to perform a meta‐analysis.
Discussion
Using a comprehensive and systematic search strategy, we identified no randomised controlled trials (RCTs) that examined exercise as an intervention for patients with cancer cachexia. In studies where exercise interventions were delivered to patients with cancer, characteristics that could be used to classify patients' nutritional stores and intake, muscle mass and physical function (as cachexia domains) were seldom reported, and it was not possible to determine the proportion of patients meeting pre‐cachexia or cachexia criteria. The lack of studies in this field is at odds with the strong rationale for exploring exercise as a therapeutic intervention. Systematic and narrative reviews have outlined the potential for exercise to impact favourably on muscle mass and strength (Lowe 2009; Stene 2013), inflammatory markers (Jones 2012; Maddocks 2012; Wilcock 2008) and physical function (Spence 2011), all of which are important domains of cancer cachexia and mediate its impact on the patient.
It is plausible that the lack of consensus on a definition and classification for cachexia has hindered study in the field. Without criteria for cachexia diagnosis and staging, the prevalence and impact of cancer cachexia has been difficult to assess, and interventions may have been trialled in cachectic populations without formal recognition, as may be the case for studies of exercise in advanced cancer (Cheville 2010; Oldervoll 2006; Oldervoll 2011). In this regard, the classification system proposed by Fearon and colleagues, Fearon 2011, is an important step forwards, and the system has recently been validated in a large international cohort of patients with advanced cancer (Blum 2014). Weight loss and low body mass index could be used to distinguish between non‐cachectic and cachectic patients, the latter having significantly higher levels of inflammation, lower nutritional intake and performance status and shorter survival. Additional criteria, e.g. muscle mass or level of inflammation, help to differentiate patients further, establishing their importance in the classification models (Blum 2014).
We identified two studies that may have included patients meeting cancer cachexia criteria, for example trials of exercise in those with advanced cancer. The first RCT had 231 patients with incurable and metastatic cancer and compared physical exercise with usual care for eight weeks. The exercise group had 60 minutes of exercise twice a week and showed some benefits in handgrip strength, sit‐to‐stand and maximal stepping; no adverse effects were found in the study (Oldervoll 2011). The second RCT had a multidisciplinary intervention approach, which included cognitive, emotional, social and spiritual dimensions in eight sessions of 90 minutes. The researchers recruited 115 patients undergoing radiation therapy for advanced cancer. Self assessed physical well‐being was improved in the experimental group, however no quantitative benefits in physical function were seen; no adverse effects were found (Cheville 2010).
We also identified ongoing studies targeting cancer cachexia, most notably a randomised feasibility trial of a six‐week multimodal intervention comprising nutritional supplementation, home‐based exercise and anti‐inflammatory treatment for patients with advanced non‐small cell lung or pancreatic cancer (NCT01419145). The findings are awaited and may pave the way for other complex targeted interventions. Other ongoing studies are NCT01681654 and ACTRN12611000870954 (see Characteristics of ongoing studies).
Flow diagram: study selection process.
