Muscle derangement and alteration of the nutritional machinery in NSCLC
Introduction
Lung cancer represents the second common cancer and the leading cause of cancer-related death in developed countries (Siegel et al., 2018). Non-small-cell lung cancer (NSCLC) accounts for more than 80% of all lung cancer cases and usually presents as locally advanced or metastatic disease. The significant improvements in diagnostic tools and treatment options, with crucial advancements in surgery, radiotherapy and chemotherapy, as well as the emergence of innovative therapeutic strategies as targeted therapy and immunotherapy, represent an advantage over the previous care (Planchard et al., 2018). Nevertheless, these patients continue to face relevant nutritional and metabolic consequences, related both to illness process and to treatment-induced adverse events.
Reports from the literature show that patients with NSCLC present a high incidence of malnutrition at diagnosis, with weight loss happening in 54% of them at disease presentation (Tan and Fearon, 2008; Kovarik et al., 2014). Moreover, the nutritional status depletion is not a problem experienced only upon diagnosis, but is also commonly reported during chemotherapy, radiotherapy and, mainly, concurrent chemo-radiotherapy. In detail, NSCLC patients under treatment may experience several symptoms as loss of appetite, taste and smell alterations, nausea, vomiting, dysphagia and esophagitis, potentially affecting treatment schedule and adherence (Belqaid et al., 2014; Kiss, 2016). In this regard, a cross-sectional study by Iyer et al. including 450 patients with advanced NSCLC receiving pharmacological treatment reported that 97% experienced loss of appetite (Iyer et al., 2014). These symptoms adversely affect the ability to achieve adequate nutritional intake, placing these patients at increased risk of malnutrition, especially in advanced or metastatic setting or among the elderly (Gioulbasanis et al., 2011; Zhang et al., 2013).
During recent years, research has particularly focused on the role of the nutritional status as a novel prognostic and predictive factor for NSCLC patients (Kawaguchi et al., 2010). In this regard, data are concordant in suggesting that nutritional deficiency may adversely influence the prognosis of lung cancer patients (Jagoe et al., 2001; Attaran et al., 2012). First of all, as widely known, the loss of appetite and weight loss at disease diagnosis seem to predict unfavorable outcomes for survival in advanced NSCLC (Stanley, 1980). Secondly, weight loss may increase the risk of impaired response to chemo- or radiotherapy, the susceptibility to chemotherapy-induced toxicity, the incidence of post-operative complications and the treatment delays (Dewys et al., 1980; Buccheri and Ferrigno, 2001; Santarpia et al., 2011). Furthermore, patients with a normal nutritional status showed lower levels of perceived pain, anxiety and depression than patients with nutritional disorders (Khalid et al., 2007; Sanchez-Lara et al., 2012; Chabowski et al., 2018).
Nevertheless, variations in weight and body mass index (BMI), a ratio of weight relative to height measured in kilograms per square meters, may have low diagnostic accuracy in identifying patients with malnutrition. In fact, body weight is influenced by several physiological and pathological conditions and, for example, weight loss may be underestimated in patients with a large tumor mass or fluid retention, such as body edema or pleural effusion (Collins et al., 2014). Furthermore, body weight loss does not precisely reflect body composition derangements within the course of the disease (Nattenmuller et al., 2017). In this context, recent evidence utilizing computed tomography (CT) images to assess skeletal muscle mass has recognized that skeletal muscle loss is a prominent feature in cancer patients, even with normal or high BMI (Baracos et al., 2010; Martin et al., 2013). Notably, in NSCLC patients, several recent studies have identified loss of lean body mass, mainly skeletal muscle, both following lung resection of early-stage disease and during cytotoxic chemotherapy in patients with advanced cancer (Takamori et al., 2018; Stene et al., 2015).
Changes in skeletal muscle volume have been reported to have a great impact on clinical outcomes in cancer patients. Low muscle mass may affect muscle function and lead to loss of strength, reduced pulmonary function, increased disability and, thereby, poorer quality of life (Kilgour et al., 2010, 2013). In addition, muscle wasting and low muscle mass have been related to a shorter survival and increased risk of developing dose-limiting toxicity in various cancer types, including NSCLC (Arrieta et al., 2015; Kazemi-Bajestani et al., 2016; Anandavadivelan et al., 2016; Tan et al., 2015; Jung et al., 2015; Sjoblom et al., 2015). Of interest, with the introduction of targeted therapies, recent studies investigated the predictive and prognostic role of low lean body mass in patients with advanced NSCLC treated with epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI), suggesting that the nutritional status should be considered as an important factor also in these patients subgroups (Arrieta et al., 2015; Park et al., 2016; Rossi et al., 2018). To date, although the depletion of muscle mass has emerged as a novel potential prognostic factor that may precede an overt cancer cachexia syndrome (Fearon et al., 2011), few attention has been paid to clarify the pathophysiological mechanisms underlying this complex phenomenon (Blum et al., 2011).
Given these perspectives, we carried out an in-depth review exploring the impact of malnutrition on NSCLC patients’ outcomes, across the available therapies and in light of novel treatment options. We mainly focus the discussion on the lean body mass that has already been suggested as a potential target for tailored therapies. Based on the available published data, we explored molecular and metabolic factors leading to muscle tissue wasting, emphasizing the importance of incorporating into treatment programs a careful and accurate body composition’s assessment, rather than weight measurement alone. The identification of those factors playing a crucial role in promoting nutritional derangements may allow the design of tailored interventions focused on reaching precise nutritional goals, in order to improve quality of life and clinical outcomes in NSCLC patients.
Section snippets
Prevalence and implications of malnutrition in NSCLC
Patients affected by NSCLC report a high prevalence of co-occurring symptoms that may contribute to a reduction in nutrients availability and increase the risk of malnutrition, often diagnosed before the treatment start. As reported in a study involving 220 lung cancer patients, fatigue, nausea, weakness, appetite loss and vomiting form a cluster of common symptoms already described at disease presentation (Gift et al., 2004). A retrospective study by Ross et al., analysing 418 NSCLC patients,
The influence of nutritional status and body weight on NSCLC patients’ outcomes
In term of disease prevention, high BMI has been related to a reduced risk of lung cancer, especially among smokers. Conversely, waist circumference and waist-hip ratio (WHR) were associated with increased lung cancer risk, regardless of sex, smoking status, follow-up time and tumor histology (Yu et al., 2018).
At disease diagnosis, poor nutritional status is an independent negative prognostic variable in NSCLC. Considering patients who underwent major surgical resection for early-stage NSCLC,
The particular prognostic significance of weight preservation or gain
Although most of the attention in literature was focused on weight loss, small retrospective studies proposed also the weight gain as a potential prognostic factor in advanced NSCLC. In this regard, the largest analysis retrospectively examined data from three phase III clinical trials, including 2,301 stage IIIb or IV NSCLC patients. A significant association between superior median OS and > 5% weight gain during treatment (16.7 versus 10.7 months, p < 0.001) was reported. Likewise, patients
The detection of body composition derangements in patients with NSCLC
Overall, these recent data suggested that poor nutritional status is related to a shortened survival and may predict chemotherapy-induced toxicities. Interestingly, a higher BMI seems to carry a paradoxical relationship with better outcomes in surgically resected lung cancer, as well as in advanced NSCLC, introducing the intriguing clinical phenomenon of the obesity paradox. Additionally, small studies proposed that NSCLC patients who maintained or gained weight during treatment survived
The preeminent role of skeletal muscle mass loss in NSCLC
The loss of skeletal muscle mass represents an independent predictor of poor prognosis in several malignancies with ample supportive evidence (Villasenor et al., 2012; Levolger et al., 2015; Shachar et al., 2016). Among NSCLC patients, those with muscle mass depletion, even having a high BMI as sarcopenic obese patients, had a significantly worse outcome (HR = 4.2; p < 0.0001) (Prado et al., 2008). Focusing on patients with early-stage lung cancer, the available studies suggested that skeletal
The impact of nutritional status and body composition in the era of the new therapies in NSCLC
The introduction of targeted agents and immune-checkpoint inhibitors radically changed the therapeutical perspectives and the prognosis of a proportion of NSCLC patients. Considering their relatively recent availability in clinical practice, only limited data focusing on the assessment and impact of nutritional status on the outcome of NSCLC patients treated with these innovative therapies are present. A retrospective analysis, conducted in a small cohort of 65 advanced NSCLC patients, compared
Mechanisms underlying NSCLC muscle wasting
The malnutrition in NSCLC patients is driven by a combination of reduced food intake and metabolic derangements, which may be either host- or tumor-derived. However, the molecular mechanisms underlying NSCLC-related muscle wasting have not yet been fully elucidated. The candidate signaling networks involved in lung cancer-induced cachexia in three different cell types (muscle cells, adipocytes and adipose tissue-derived mesenchymal stem cells) and the proposed targeting approaches are presented
New scenarios and opportunities for prevention and treatment of muscle loss
Given the multifactorial complex pathogenesis of muscle wasting in NSCLC, both preventive and therapeutical options should be part of an integrated support program, based on different and multidimensional approaches, including early, targeted and specialized nutritional supports, personalized exercise programs and pharmacological agents (Molfino et al., 2016). In particular, ongoing research exploring the molecular mechanisms underlying muscle loss in NSCLC allowed the identification of some
Nutritional interventions as an essential step for a multimodal approach against cancer-related muscle wasting
An early, adequate and comprehensive nutritional support, based on the tailored energy and proteins intake needed for a specific patient (according to the gender) is necessary to slow and ideally antagonize the NSCLC-related muscle wasting process (Frega et al., 2019). This implies that every single patient should be nutritionally assessed and monitored since cancer diagnosis (Kiss, 2016; Aversa et al., 2017). In detail, specific attention should be paid to the role of dietary protein intake to
Conclusion and suggestions for future research
Increasing evidence is available to support the role of nutritional status on patients’ quality of life, morbidity and mortality. Particularly, muscle mass loss is related to reduced survival and an increased likelihood of dose-limiting anticancer-related drug toxicity. In this regard, its detection and monitoring may allow more accurate drug dose calculation than body surface area or flat-fixed dosing and could be helpful for evaluating the risk assessment of anticancer treatment, even in
Author contributions
Conception and design: All authors.
Manuscript writing: Ilaria Trestini, Anastasios Gkountakos, Sara Pilotto, Emilio Bria.
Drafting the article and revising it for important intellectual content: All authors.
Final approval of manuscript: All authors.
Declaration of Competing Interest
S.P. received honoraria or speakers’ fee from Astra-Zeneca, Eli-Lilly, BMS, Boehringer Ingelheim, Roche, MSD and Istituto Gentili, outside the submitted work. E.B. received honoraria or speakers’ fee from MSD, Astra-Zeneca, Celgene, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis, and Roche, outside the submitted work. A.S. received speaker fee from Astra-Zeneca and Ypsen, outside the submitted work. All remaining authors have declared no conflicts of interest.
Acknowledgments
This work was supported by a grant from L.I.L.T. (Lega Italiana per la Lotta contro i Tumori). S.P. and E.B. were supported by the Italian Association for Cancer Research - My First AIRC Grant 2013 n° 14282 and are supported by AIRC-IG 20583.
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Equally contributors (S.P and E.B. share the last co-authorship).