Muscle derangement and alteration of the nutritional machinery in NSCLC

Abstract

Weight loss and depletion of nutritional status are frequent presentation hallmarks in non-small cell lung cancer (NSCLC). Decline in muscle mass is a major component in weight loss and may have both a prognostic and predictive value for survival and treatment-related toxicities. Recent findings suggest that weight and skeletal muscle mass gain during treatment may represent surrogate markers for outcome in advanced NSCLC patients. Herein we present an in-depth view of the impact of nutritional status derangements on NSCLC patients’ outcome, focusing on lean body mass variations during disease course. We explored the impact of malnutrition with a major attention on novel treatment options. We reviewed molecular, metabolic and immunological mechanisms underlying muscle-wasting condition, which may exhibit a meaningful targeting potential. Incorporating a specialized and accurate body composition assessment into a comprehensive, patient-centered and tailored intervention will facilitate the achievement of nutritional goals and optimal care for lung cancer patients.

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.