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Chapter III: Impact of cancer cachexia
Florian Strasser and Egidio Del Fabbro
With an estimated 14.1 million new cases of cancer and 8.2 million cancer deaths occurring worldwide in 2012, cancer represents a leading cause of morbidity and mortality (Ferlay et al., 2013; Torre et al., 2015; World Health Organization, 2015). The occurrence of cancer, and thus cancer cachexia, is increasing due to the growth and aging of the population; a predicted 21.7 million new cases of cancer will be diagnosed in 2030 (Ferlay et al., 2013). The prevalence of cancer cachexia is unknown, but it has been estimated that cachexia affects 50–80% of cancer patients and accounts for 20% of cancer deaths (reviewed in Argiles et al., 2014). von Haehling and Anker, 2014, estimated that the absolute number of patients with cancer cachexia in Europe in 2014 was 1 million, with a 1-year mortality rate of 20–60%.
The prevalence of cachexia varies considerably according to different definitions/diagnostic criteria (Couch et al., 2015; Fox et al., 2009; Thoresen et al., 2013; Wallengren et al., 2013). Weight loss is a key clinical feature of cachexia and also of malnutrition (Bozzetti, 2013); however, cachexia is more complex, involving for example inflammation and muscle wasting (Fearon and Strasser et al., 2011; Fearon et al., 2006; Fearon et al., 2012); therefore, caution may be needed when interpreting cachexia prevalence data based solely on weight loss (reviewed in von Haehling and Anker, 2010) because it may reflect patients with malnutrition but not cachexia. There are several definitions of cancer cachexia, which incorporate various features of cachexia, including a consensus definition from the European Palliative Care Research Collaborative (EPCRC) in 2011 (Fearon and Strasser et al., 2011); the Cancer Cachexia Study Group (CCSG) definition from 2006 (Fearon et al., 2006); and a generic definition for all types of cachexia from Evans et al. (2008) that is not cancer specific (these definitions are described in more detail in Chapter IV [Table 2] and in Table 1).
As shown in Table 1, in Thoresen et al., 2013, 22% to 55% of the colorectal cancer patients had cachexia according to the CCSG and EPCRC criteria, respectively; in Wallengren et al., 2013, the prevalence of cachexia diagnosis varied from 12% to 85% according to criteria from the CCSG, the EPCRC, Evans et al. 2008, and using criteria of weight loss >2%, fatigue >3 (on a 1–10 scale), and CRP >10 mg/L. In a large (n=8541), but slightly older study by Fox et al., 2009, the prevalence ranged from 2.4% to 14.7% using one of four different definitions: ICD-9 diagnostic code of 799.4 (cachexia); ICD-9 diagnosis of cachexia, anorexia, abnormal weight loss, or feeding difficulties; prescription indicative of cancer cachexia (megestrol acetate, oxandrolone, somatropin, or dronabinol); or ≥5% weight loss.
The prevalence of cancer cachexia also depends on the cancer site and stage. In Fox, et al., 2009, cancer cachexia (defined according to any one of 4 definitions of cachexia) was frequent in esophageal, gastric, head and neck, pancreatic, lung, colorectal and breast cancers (Table 1). Sun et al., 2015, recently reported that in 390 patients with advanced cancer, 140 (35.9%) had cachexia (based on the EPCRC consensus definition; see Chapter IV). The prevalence was highest in pancreatic cancer (88.9%), followed by gastric cancer (76.5%) and esophageal cancer (52.9%). As reviewed by Bozzetti, 2013, estimates of the prevalence of malnutrition (defined using a variety of different methodologies, including weight loss as the sole parameter) are: up to 9% in urological cancer patients, up to 15% in gynecological cancers, up to 33% in colorectal cancer patients, up to 46% in lung cancer patients, up to 67% in head and neck cancer patients, up to 57–80% in patients with esophageal or gastrointestinal cancers, and up to 85% in pancreatic cancer patients. Overall it is evident that the prevalence of cancer cachexia is high in advanced cancer patients.
Impact on patient outcome
A number of clinical parameters associated with cancer cachexia, including weight loss, BMI, sarcopenia, hormones, nutritional status, inflammatory markers, and the modified Glasgow prognostic scale (inflammatory markers combined with albumin) have been reported to impact on various patient outcomes, including survival, anti-cancer treatment response and toxicities, post-operative complications, quality of life (QoL), physical functioning and psychosocial effects, as described in the following sections. As with other aspects of cancer cachexia clinical research, this is an area of complexity, characterized by studies evaluating different patient populations (e.g., tumor types, including site and stage; levels of BMI, obesity [excess adipose tissue], and sarcopenia [low muscle mass]), together with the use of different measurement tools to assess the clinical features of cancer cachexia and the various outcomes. Nevertheless, there is overwhelming evidence that cancer cachexia has serious consequences, impacting heavily on the patient’s health and well-being.
Weight loss has long been indicated as an important prognostic factor for cancer patients (Donohoe et al., 2011). Back in 1980, Dewys et al. reported on the prognostic effect of weight loss prior to chemotherapy using data from 3,047 patients enrolled in 12 chemotherapy protocols of the Eastern Cooperative Oncology Group (ECOG) (Dewys et al., 1980). The frequency of weight loss ranged from 31% for favorable non-Hodgkin’s lymphoma to 87% in gastric cancer. Median survival was significantly shorter in nine protocols for the patients with weight loss compared to the patients with no weight loss. Similar findings of reduced survival in cancer patients experiencing weight loss have been found in several studies of different cancers including non-small cell lung carcinoma (NSCLC) (Buccheri and Ferrigno, 2001), ovarian cancer (Hess et al., 2007), gastro-esophageal cancer (Deans and Wigmore, 2005) and pancreatic cancer (Bachmann et al., 2008).
Cancer cachexia is characterized by a loss of skeletal muscle (sarcopenia), with or without loss of fat mass (Fearon and Strasser et al., 2011). A recent systematic review of the literature reported that sarcopenia at baseline was consistently a predictor of poor survival, regardless of body weight (from 11 studies: Harimoto et al., 2013; Martin et al., 2013; Meza-Junco et al., 2013; Miyamoto et al., 2015; Prado et al., 2008; Prado et al., 2009; Psutka et al., 2014; van Vledder et al., 2012; Veasey Rodrigues et al., 2013; Voron et al., 2015).
Recent studies have analyzed patient outcome, including survival, according to different cancer cachexia criteria/definitions. Wesseltoft-Rao et al., 2015, evaluated survival in unresected pancreatic cancer patients using two different cancer cachexia classifications i.e. a 3-factor classification from the CCSG requiring at least two of the following three factors: weight loss ≥10%, food intake ≤1500 kcal/day, and CRP ≥10 mg/L (Fearon et al., 2006) and the consensus classification from the EPCRC requiring weight loss >5% over the past 6 months, or ongoing weight loss of >2% with BMI <20 kg/m2 or sarcopenia (Fearon and Strasser et al., 2011). Survival was poorer in patients with cachexia compared to non-cachexia patients, defined using either of the classifications. Thoresen et al., 2013, also evaluated survival according to these two cachexia definitions in stage IV colorectal carcinoma patients (n=77), as well as individual parameters including sarcopenia, nutritional risk (assessed using the NRS-2002 questionnaire) and malnutrition (assessed using the Subjective Global Assessment [SGA] questionnaire for determining nutritional status). However, there was a distinct lack of concordance between the results obtained by different assessment criteria, and having cachexia (CCSG definition) was the only variable that reached statistical significance in both unadjusted and adjusted survival analyses. In contrast, Blum and Strasser, 2011, found that, in a large sample of advanced cancer patients (n=861), cachectic patients defined according to the consensus EPCRC definition had significantly higher levels of inflammation, lower nutritional intake and performance status and shorter survival. LeBlanc et al., 2015a, also evaluated patient-centered outcomes according to the consensus definition in patients with advanced NSCLC (n=99), and found that the cachectic group had significantly shorter median survival. All measures of physical function and QoL worsened regardless of cachexia status, however the rate of decline was more rapid in the cachexia group. Wallengren et al., 2013, found that weight loss >2%, fatigue, CRP >10 mg/L and S-albumin <32 g/L were significantly associated with shorter survival. In addition, weight loss >2%, BMI <20 kg/m2, fatigue and CRP>10 mg/L were significantly associated with adverse QoL, function and symptoms. Fatigue, low grip strength and markers of systemic inflammation were significantly associated with short walking distance.
Other features of cancer cachexia that may be considered poor prognostic indicators include: levels of the cachexia-associated hormones leptin and ghrelin (Mondello et al., 2014); sarcopenia combined with inflammatory makers such as high neutrophil-to-lymphocyte ratio (Go et al., 2016), the Glasgow prognostic score (Giannousi et al., 2012) and nutritional status (Giannousi et al., 2012; Gioulbasanis et al., 2011; Gu et al., 2015).
Cancer cachexia and obesity
The prevalence of overweight or obesity has been rapidly increasing in recent decades (World Health Organization, 2016). The significance of obesity in the prognosis of patients is complex: an “obesity paradox” has been described whereby obesity at the time of diagnosis may confer a survival advantage (Kalantar-Zadeh et al., 2007), however the simultaneous loss of skeletal muscle and gain of adipose tissue (i.e sarcopenic obesity) has an adverse effect on survival in cancer patients (Kazemi-Bajestani et al., 2016; Martin et al., 2013; Prado et al., 2008). This means that definitions of clinically significant weight loss in patients with cancer are increasingly unclear, and there is a need to take into account the rate of weight loss and the level of depletion of body reserves (Fearon and Strasser et al., 2011). Current weight loss grading schemes do not take into account the potential benefit of higher initial body weight in risk assessment of patients with cancer- or treatment-associated weight loss. Therefore, Martin et al., 2015, has suggested a robust grading system incorporating the independent prognostic significance of both BMI and percentage weight loss, which takes into account the impact of high versus low initial BMI in the risk assessment of patients with weight loss. Both percentage weight loss and BMI predict survival independently of conventional prognostic factors including cancer site, stage, and performance status. This system could therefore be used in conjunction with assessing other cancer cachexia parameters such as inflammation, anorexia and muscle wasting (sarcopenia).
In particular, the assessment of body composition (using e.g. CT or MRI), which enables the evaluation of skeletal muscle loss, is becoming more significant in this age of rising levels of obesity (Martin et al., 2013). Low levels of muscle are not only seen in patients who appear thin or cachectic, but also in those who are overweight or obese (Kazemi-Bajestani et al., 2016), and obesity can mask the presence of skeletal muscle loss (Martin et al., 2013). Sarcopenic obesity has a strong association with poor survival compared with non-sarcopenic obesity, as shown by several studies (Cooper et al., 2015; Iritani et al., 2015; Prado et al., 2008; Tan et al., 2009) identified in a recent review by Kazemi-Bajestani et al., 2016. With this in mind, the quantification of muscle and fat may be important for prognostication (Kazemi-Bajestani et al., 2016; Prado et al., 2008).
Anti-cancer treatment response and toxicities
Chemotherapy toxicity is a serious and distressing event that can result in dose reductions or treatment termination, and severe toxic events can even be life threatening. It has long been recognized that weight loss is a prognostic factor for poor treatment response during chemotherapy, which in turn is a determinant of survival. In a study by Andreyev et al. cancer patients with weight loss received lower chemotherapy doses initially; however, despite this they developed more frequent and more severe dose limiting toxicity (DLT) than patients without weight loss, and therefore they received on average one month less treatment (Andreyev et al., 1998). Accordingly, the poorer outcome in cancer patients with weight loss may, at least in part, be due to receiving significantly less chemotherapy and developing more toxicity (Andreyev et al., 1998).
There is also mounting evidence of an association between muscularity and treatment toxicity (Antoun et al., 2010). A recent systematic review by Kazemi-Bajestani et al., 2016 found that sarcopenia was associated with increased incidence of DLT or severe toxicity in the vast majority of identified studies regardless of cancer site or type of systemic therapy (Antoun et al., 2010; Barret et al., 2014; Cousin et al., 2014; Cushen et al., 2014; Huillard et al., 2013; Massicotte et al., 2013; Mir et al., 2012; Parsons et al., 2012; Prado et al., 2007; Prado et al., 2009; Prado et al., 2011; Tan et al., 2015; Wong et al., 2014).
Sarcopenia is also associated with increased risks of postoperative infections, inpatient rehabilitation care and consequently a longer length of stay in hospital (Lieffers et al., 2012). Esophageal and gastro-esophageal junction cancer patients who show signs of sarcopenia on preoperative CT images have reduced survival outcome after surgery (Tamandl et al., 2016). However, in contrast, Tegels et al., 2015, found that in gastric cancer surgical patients, although sarcopenia was prevalent, it was not associated with postoperative morbidity or mortality. Low muscle mass in patients undergoing surgery for colorectal cancer is associated with an increased postoperative inflammatory response, which may be a reason for the high incidence of postoperative complications in sarcopenic patients (Reisinger et al., 2016).
In patients undergoing an esophagectomy for the resection of esophageal squamous cell cancer, pulmonary complications occurred more frequently in the low BMI group (BMI <18.5 kg/m2 ) than in the normal BMI group (BMI ≥18.5 kg/m2 ). Furthermore, the 5-year overall survival rate and disease-free survival rate was higher in the normal BMI group than the low BMI group (Kamachi et al., 2016). Fiorelli et al., 2014, also reported that BMI <18.5 kg/m2 and weight loss of >5% before lung cancer resection were independent risk factors for 1-year mortality. In pancreatic cancer, evidence suggests that underweight but not obese patients have a poor outcome after pancreatoduodenectomy; patients with low BMI had a greater 90-day mortality and a trend toward greater complication rates and in-hospital mortality, despite a greater comorbidity in obese patients, whereas patients with large amounts of abdominal wall fat had fewer intra-abdominal abscesses, lower in-hospital and 90-day mortality rates, and better long-term survival (Pausch et al., 2012).
Physical function and quality of life
Patients with cancer cachexia can suffer from pain, fatigue, reduced appetite, and declining mobility, together with an impaired ability to perform daily activities and reduced physical activity, all of which can severely impact on their QoL (Cancer Cachexia Hub (a); Vaughan et al., 2013). In fact, some patients find that weight loss, poor nutritional status and the consequent inability to perform physical activities impact on their QoL more than the cancer itself (Ravasco et al., 2004). Furthermore, QoL in patients with advanced cancer was identified to be most significantly affected by symptoms associated with pain, fatigue and reduced appetite (Caissie et al., 2011). Features of cancer cachexia – including weight loss, fatigue, systemic inflammation, and signs of malnutrition (alone or in combination) – have been strongly associated with adverse QoL and reduced functional abilities (Fearon et al., 2006; LeBlanc et al., 2015a; Thoresen et al., 2012; Wallengren et al., 2013).
Psychosocial effects and quality of life
The physical manifestations of cancer cachexia including involuntary weight loss and sarcopenia, often accompanied by symptoms such as anorexia, fatigue and reduced physical functioning, are a cause for enormous emotional, social and physical suffering (Hopkinson, 2014). Secondary nutritional impact symptoms, such as nausea and pain, also compound the weight loss in cancer patients (Hopkinson, 2014). Eating-related distress, the characteristics of which include obstruction to eating, poor and changeable appetite, and an inability to gain weight despite continuous eff orts to eat (Strasser et al., 2007), commonly affects patients with cancer cachexia and their family members (Amano et al., 2016a; Amano et al., 2016b; Strasser et al., 2007). Indeed, family members can experience greater anguish than the patients themselves (Poole and Froggatt, 2002; Strasser et al., 2007). Eating related distress impacts on daily activities and relationships (Strasser et al., 2007), including conflict over food in families, carer fear of patient wasting away, and carer perception of health professional neglect (Hopkinson, 2010). Patients, family members/carers and the interaction between the two should be considered to alleviate weight- and eating-related distress (Hopkinson, 2016).
As determined by a recent systematic review by Oberholzer et al., 2013, aspects that lead to psychosocial effects include the inability to eat, physical changes of weight and muscle loss such as protruding bones, weakness and reduced activity, leading to a loss of independence and possibly social isolation (Hinsley and Hughes, 2007; Hopkinson and Corner, 2006; Strasser et al., 2007). In addition, the response of carers (e.g. being too forceful because they believe that poor nutritional care is the problem) (Hawkins, 2000; Holden, 1991) and a lack of acknowledgement from healthcare professionals (Orrevall et al., 2004; Reid et al., 2009a; Reid et al., 2010) also contribute to psychosocial effects. Relationship changes due to no longer being able to eat socially, cook or shop for food, are also important aspects (Holden, 1991; Meares, 1997; Orrevall et al., 2004; Souter, 2005; Strasser et al., 2007). These leads to many different negative emotions like sadness, anxiety and distress (Holden, 1991; Meares, 1997). In addition, carers can feel incompetent, powerless, and personally rejected leading to relational conflicts (McClement et al., 2004). Adverse events include patients withdrawing from their families and carers by ignoring carers’ comments or pretending to be sleeping (Hopkinson, 2007; Meares, 1997; Reid et al., 2009b; Strasser et al., 2007). In addition, eating just to please their carers occasionally can cause pain, nausea, anticipation of emesis, and, in some extreme cases, a danger of aspiration and choking, for which healthcare practitioners were blamed (Holden, 1991; McClement et al., 2004). Oberholzer et al. reported that the condition was often not managed constructively. This is an area where healthcare professionals can be of immense help, listening and providing information and education about cancer cachexia. In this way patients and carers can understand that cachexia is a real physical disease, which is not due to psychological causes or poor nutritional care. An acceptance of the limitations of nutritional intake can help patients and carers to cope and reduce conflict (McClement et al., 2003). Oberholzer et al. also proposed a model of psychosocial effects of cancer cachexia (Figure 7), which may help healthcare professionals understand the psychosocial effects that patients and carers are experiencing and thus serve as a starting point for interventions.
Wheelwright et al., 2016, conducted a systematic review to establish QoL domains for a model of the impact of cancer cachexia, so as to identify opportunities for intervention. Similar themes to the systematic review by Oberholzer et al. were identified in this review, including identity (change in identity and body image); food and eating (“You want to eat but you can’t eat. I could go with a wee taste of soup of something, but I’ve no real appetite” (Reid et al., 2010)); loss of control (for example loss of independence); knowledge (healthcare professional input and knowledge to understand. “No-one explained why you lose weight. You would then not have to destroy yourself psychologically with: I must eat, even if I am not hungry, if I don’t like the taste.” (Strasser et al., 2007)); physical decline; relationships (for example carer conflicts, changes to social life (“Taking liquidized food is not the sort of thing you want to do with family and friends” (Hopkinson and Corner, 2006)); emotions (negative emotions, continuum of hope, sense of failure); and coping (acceptance and adaptation, taking control, and the denial).
These studies confirm that relationships, coping and knowledge of the condition are important components of psychosocial interventions. As described in Chapter V, providing support to alleviate weight-related distress and psychosocial effects should be included in the multimodal approach to treating cancer cachexia (Fearon and Strasser et al., 2011; Hopkinson, 2014, 2016; Hopkinson et al., 2013; Radbruch et al., 2010; Reid, 2014).
As described in Chapter IV, there are a range of questionnaires that are available to assess QoL and other subjective symptoms in cancer cachexia patients. In particular, the Functional Assessment of Anorexia/Cachexia Treatment (FAACT) and its anorexia-cachexia subscale (ACS) has been reported to be a valid approach to identify patients with advanced NSCLC who are likely to have significantly inferior survival, physical function and QoL (LeBlanc et al., 2015a; LeBlanc et al., 2015b). In addition, because QoL issues are not sufficiently explored by the commonly used generic cancer instruments such as the EORTC QLQ-C30, a cancer cachexia module (EORTC QLQ-CAX24) is being developed to supplement the QLQ-C30 in the assessment of QoL for cancer patients with cachexia (EORTC QOL Module for Cancer Cachexia (QLQ-CAX24)).
Impact on healthcare resources
There are very few studies on the additional costs to the healthcare system associated with cancer cachexia. Cachexia is also a serious consequence of many other chronic diseases, including COPD, HIV, and kidney disease.
Looking at cachexia associated with all diseases, Arthur et al., 2014, recently estimated an annual prevalence of cachexia-related inpatient admissions (according to ICD-9 codes) to community hospitals in the USA to be 161,898 cases. When compared with patients without cachexia, cachexic patients had twice the number of inpatient days (6 versus 3 days), and double the hospitalization costs (average costs per stay $4641.30 greater). Cachexia patients also experienced greater loss of function than those admitted with other diagnoses and over 12% of patients with cachexia died during their hospitalization (compared to 1.88% of patients without cachexia).
Malignancy was the most common comorbidity in patients with cachexia, occurring in 34.40% (n=11,055) of these patients. This study gives an idea of the added burden that cachexia imposes to the healthcare system, both in terms of costs and resources.
In conclusion, cancer cachexia is a frequent condition with a serious negative impact on patient outcome and QoL of patients, families and carers. Consequently, there is an added burden on healthcare resources and costs. There is a need for raised awareness of all aspects of cachexia among healthcare professionals – diagnosis, the physical and psychosocial effects, and management and treatment. In turn, healthcare professionals will then be able to provide the necessary information, advice and support to the patients and their families/carers. As discussed in the following chapters, the early identification of cachexia, in a pre-cachexia stage, together with improved treatments, will also be vital in reducing the burden of this disease.