**2. Nutritional status**

#### **2.1. Malnutrition rates and weight loss**

Esophageal cancer patients often suffer from malnutrition, the manifestation of which is strongly linked to the stage of the disease and therapeutic regimens. Excessive weight loss is partly attributed to the disease process itself and is often deteriorated due to chemotherapy/ radiotherapy treatment [11]. Malnutrition occurs in 60–85% of esophageal cancer patients, which is one of the highest reported rates when compared to other malignancies, such as lung, head and neck, stomach, and pancreatic cancers [12]. According to recent publications, 32% of patients who underwent esophagectomy experienced more than 10% weight loss preoperatively [13], while 90% of patients had a 5% weight loss at 3 months postoperatively [14]. It is noteworthy that in many patients weight loss persists for at least 3 years after surgi‐ cal intervention [15]. Another study revealed that 43.8% of patients with esophageal cancer were underweight based on BMI values, 29.7% of patients were undernourished as indicated from anthropometric measurements and 69% had weight loss within 2 weeks before hos‐ pital admission [16]. Chemotherapy and radiotherapy affect nutritional status by promot‐ ing weight loss and muscle wasting. More specifically, malnutrition developed in 83.8% of patients after the end of radiotherapy [17] and the number of patients requiring nutritional intervention increased from 56 to 75% during induction chemotherapy [10]. These facts high‐ light the need of nutritional assessment at several time points in order to identify patients who are candidates for nutritional support.

#### **2.2. Methods of nutritional assessment and impact on clinical outcome**

Excess alcohol consumption and consumption of hot food and beverages increase the risk of esophageal squamous cell carcinoma, whereas many components of Western type diet, such as red and processed meat increase the risk of esophageal adenocarcinoma [2–4]. Moreover, obesity, especially central type, and gastroesophageal reflux disease are risk factors toward developing esophageal adenocarcinoma [5, 6]. On the other hand, healthy dietary habits could be a shield against some types of esophageal cancer [7], while nutritional support could

Esophageal cancer is commonly associated with malnutrition and impaired nutritional intake. Nutritional management of these patients may differ according to the type of therapy and stage of disease, in order to alleviate symptoms, ameliorate nutritional status, and improve quality of life. Furthermore, cancer cachexia affects a great percentage of esophageal can‐ cer patients emerging as a significant factor the multidisciplinary team should deal with [8]. Regarding the perioperative care, the proper type of feeding (i.e. enteral/parenteral nutrition (EN/PN), immunonutrition, oral supplements, etc.) as well as the right time of feeding is a matter of controversy due to lack of consistent evidence for patients undergoing esophagec‐ tomy [9]. Special nutritional needs in the long run are also of great significance for patients with both resectable and unresectble disease, bearing in mind that the majority of these patients strive to meet their caloric and protein needs. Considering the treatment approach, nutritional screening and assessment leads to early detection of malnourished patients in need of nutritional support. Taking into account patient's specific needs helps to choose the most suitable routes of delivering nutritional support (nutritional counseling and artificial nutrition). Personalized nutritional support could modify poor nutritional status resulting in reduced postoperative complications and improved survival. Moreover, the implementation of nutritional protocols could reduce toxicity of treatment regimens and in conjunction with nutritional monitoring could have impact on patients' daily living [10]. Therefore, nutritional therapy should be an essential part of a multidisciplinary approach in the clinical setting, in

The aim of the current review is to focus on the etiology of malnutrition, review the various methods of nutritional assessment, and analyze the aspects of nutritional management of

Esophageal cancer patients often suffer from malnutrition, the manifestation of which is strongly linked to the stage of the disease and therapeutic regimens. Excessive weight loss is partly attributed to the disease process itself and is often deteriorated due to chemotherapy/ radiotherapy treatment [11]. Malnutrition occurs in 60–85% of esophageal cancer patients, which is one of the highest reported rates when compared to other malignancies, such as lung, head and neck, stomach, and pancreatic cancers [12]. According to recent publications, 32% of patients who underwent esophagectomy experienced more than 10% weight loss

esophageal cancer patients as a fundamental part of multimodality therapy.

be beneficial for the management of these patients after cancer diagnosis.

order to improve short‐ and long‐term outcomes.

**2. Nutritional status**

90 Esophageal Abnormalities

**2.1. Malnutrition rates and weight loss**

There are various methods of nutritional assessment in the clinical setting providing cli‐ nicians with tools for the evaluation of the nutritional status and the estimation of nutri‐ tional needs of esophageal cancer patients. One commonly used criterion of malnutrition is the percentage of weight loss in a certain period of time. Α weight loss of more than 5% in the previous month or more than 10% in the last 3–6 months is considered significant malnutrition [18]. One retrospective study concluded that weight loss <10% and BMI>18 kg/m<sup>2</sup> were significantly correlated with a better response to chemoradiotherapy, while BMI>18 kg/m<sup>2</sup> was predictive of survival at both univariate and multivariate analysis [19]. Other anthropometric measurements, such as mid‐arm circumference and mid upper‐arm muscle area can give information about the nutritional status and body composition of these patients.

Biochemical markers, such as plasma proteins are often used as nutritional markers. For instance, albumin is commonly used for the assessment of protein status, but given its long half‐life (14–20 days), it has a slow response to dietary interventions and cannot detect subtle changes in nutritional status. Furthermore, albumin reflects an acute phase response and is not always a reliable marker of malnutrition [20]. However, albumin is an independent risk factor for complications after esophagectomy, since patients with hypoalbuminemia have twice the risk of postoperative infection and increased incidence of acute respiratory distress syndrome [21]. A recent review examined the association of serum albumin with postop‐ erative complications in patients undergoing esophagectomy, suggesting that low serum albumin does increase the risk of postoperative complications, but there is still conflicting evidence regarding the prognostic value of this biomarker [22].

Other methods of nutritional assessment include questionnaires that incorporate many factors that impede adequate nutritional intake, as well as laboratory parameters, and unintentional weight loss. For example, Subjective Global Assessment (SGA), a question‐ naire based on four parameters of patient's history (percentage of weight loss, changes in habitual diet, presence of significant gastrointestinal symptoms, and changes in patient's functional capacity) and three elements of their physical examination (loss of subcutane‐ ous fat, muscle wasting, and presence of edema or ascites) is one the most commonly used tool for nutritional screening in malnourished hospital patients with cancer. SGA is strongly correlated with performance status in esophageal cancer patients [16] as well as with The Glasgow prognostic score and with complications during cancer treatment [23]. Other tools that have been studied in cancer patients is the Prognostic Nutritional Index (PNI), the Nutritional Risk Screening 2002 (NRS 2002), the Controlling Nutritional Status (CONUT) and the Nutritional Risk Index (NRI). Esophagectomized patients with a high Prognostic Nutritional Index—a tool which includes serum albumin and absolute peripheral lymphocyte count—had a higher prevalence of postoperative complications [24]. These results are in accordance with later studies, indicating that nutritional status preoperatively, expressed as PNI, was significantly related with the occurrence of severe complications and was a predictive factor for long‐term survival [25, 26]. Nevertheless, Han‐Geurts et al. showed that PNI was not associated with postoperative infectious com‐ plications in patients who underwent esophageal resection for malignancy [27]. NRS‐2002 is recommended by the European Society for Clinical Nutrition and Metabolism as a stan‐ dard tool for the assessment of surgical patients [28], but it is not tailored to esophageal cancer patients, thus limiting its prognostic value in this population. The CONUT score, which is calculated by serum albumin concentration, total peripheral lymphocyte count, and total cholesterol concentration, was developed as a screening tool for early detec‐ tion of patients at risk of malnutrition [29]. Patients classified preoperatively as moderate or severe malnourished had a higher incidence of pulmonary and other severe morbidi‐ ties, surgical site infections, and reoperation. Consequently, the duration of hospital stay in patients with moderate or severe malnutrition was significantly longer compared to well‐nourished or slightly malnourished patients [30]. Similarly, Hirahara et al. [31] and Toyokawa et al. [32] demonstrated that CONUT was significantly associated with cancer death and poorer disease‐free survival in patients with resectable esophageal squamous cell carcinoma. NRI is another tool used for the assessment of malnutrition based on serum albumin concentration and weight loss. Ιncreased nutritional risk, derived from NRI, is associated with reduced survival in esophageal cancer patients treated with definitive chemoradiotherapy [10, 33], but is not associated with postoperative infectious complica‐ tions in patients treated with esophagectomy [27]. The Geriatric Nutritional Risk Index (GNRI) is a new index recently introduced for the assessment of nutritional status of elderly patients. Patients diagnosed with poor nutritional status according to GNRI had significantly higher rate of respiratory complications after esophagectomy and gastric tube reconstruction [34]. In conclusion, there are several nutrition assessment tools for esopha‐ geal cancer patients, but since many of the studies mentioned above are of retrospective nature, the gold standard for the evaluation of nutritional status in this cancer subpopula‐ tion is yet to be determined (**Table 1**).


**Table 1.** Nutritional assessment of esophageal cancer patients.

#### **2.3. Sarcopenia and cancer cachexia**

used tool for nutritional screening in malnourished hospital patients with cancer. SGA is strongly correlated with performance status in esophageal cancer patients [16] as well as with The Glasgow prognostic score and with complications during cancer treatment [23]. Other tools that have been studied in cancer patients is the Prognostic Nutritional Index (PNI), the Nutritional Risk Screening 2002 (NRS 2002), the Controlling Nutritional Status (CONUT) and the Nutritional Risk Index (NRI). Esophagectomized patients with a high Prognostic Nutritional Index—a tool which includes serum albumin and absolute peripheral lymphocyte count—had a higher prevalence of postoperative complications [24]. These results are in accordance with later studies, indicating that nutritional status preoperatively, expressed as PNI, was significantly related with the occurrence of severe complications and was a predictive factor for long‐term survival [25, 26]. Nevertheless, Han‐Geurts et al. showed that PNI was not associated with postoperative infectious com‐ plications in patients who underwent esophageal resection for malignancy [27]. NRS‐2002 is recommended by the European Society for Clinical Nutrition and Metabolism as a stan‐ dard tool for the assessment of surgical patients [28], but it is not tailored to esophageal cancer patients, thus limiting its prognostic value in this population. The CONUT score, which is calculated by serum albumin concentration, total peripheral lymphocyte count, and total cholesterol concentration, was developed as a screening tool for early detec‐ tion of patients at risk of malnutrition [29]. Patients classified preoperatively as moderate or severe malnourished had a higher incidence of pulmonary and other severe morbidi‐ ties, surgical site infections, and reoperation. Consequently, the duration of hospital stay in patients with moderate or severe malnutrition was significantly longer compared to well‐nourished or slightly malnourished patients [30]. Similarly, Hirahara et al. [31] and Toyokawa et al. [32] demonstrated that CONUT was significantly associated with cancer death and poorer disease‐free survival in patients with resectable esophageal squamous cell carcinoma. NRI is another tool used for the assessment of malnutrition based on serum albumin concentration and weight loss. Ιncreased nutritional risk, derived from NRI, is associated with reduced survival in esophageal cancer patients treated with definitive chemoradiotherapy [10, 33], but is not associated with postoperative infectious complica‐ tions in patients treated with esophagectomy [27]. The Geriatric Nutritional Risk Index (GNRI) is a new index recently introduced for the assessment of nutritional status of elderly patients. Patients diagnosed with poor nutritional status according to GNRI had significantly higher rate of respiratory complications after esophagectomy and gastric tube reconstruction [34]. In conclusion, there are several nutrition assessment tools for esopha‐ geal cancer patients, but since many of the studies mentioned above are of retrospective nature, the gold standard for the evaluation of nutritional status in this cancer subpopula‐

tion is yet to be determined (**Table 1**).

**Table 1.** Nutritional assessment of esophageal cancer patients.

*Biochemical markers* (albumin, prealbumin, total peripheral lymphocyte count)

*Questionnaires and indices:* SGA, NRS2002, CONUT, NRI, PNI, Glasgow Prognostic Score

*Percentage of unintentional* 

92 Esophageal Abnormalities

*weight loss*

Patients with esophageal cancer often witness loss of muscle mass and/or muscle strength, a condition described as sarcopenia. Although there are many different definitions of the term sarcopenia, all of them place emphasis on the impaired physical function following decreased muscle mass [35–37]. Sarcopenia is a component of cancer cachexia, especially in advanced stage cancer patients. Cancer cachexia is a complex syndrome which combines anorexia, early satiety, weakness, anemia, inflammation, weight loss, and loss of muscle mass with or with‐ out loss of fat mass [38]. A recent study pointed out that the prevalence of cancer cachexia in advanced esophageal cancer patients was 52.9% [39]. There is lack of consensus on the defini‐ tion, diagnostic criteria, and classification of cancer cachexia, but the most commonly used definition includes one of the following: Weight loss >5% over past 6 months (in absence of simple starvation); or BMI <20 and any degree of weight loss >2%; or appendicular skeletal muscle index consistent with sarcopenia (males <7.26 kg/m<sup>2</sup> ; females <5.45 kg/m<sup>2</sup> ),and any degree of weight loss >2% [40]. Furthermore, assessment of sarcopenia plays an emerging role in cancer patients owing to the fact that CT scanning is a gold standard imaging method of body composition analysis at the tissue‐organ level [41]. CT scans can identify reduced muscle mass and predict negative cancer outcomes in people with abdominal malignancies, where traditional methods of assessment are less effective [42]. Handgrip strength is another method used to measure muscle strength, which is directly related to the physiologic status of the individual and reflects patient's nutritional status. It could be easily used in patient's nutri‐ tional assessment due to the fact that it is an inexpensive and not time‐consuming method.

Sarcopenia and cachexia are prognostic factors for surgical complications, decreased survival, and poor response to chemotherapy. More specifically, patients with weak handgrip strength had higher risk of complications and mortality after elective esophagectomy [43]. Decreased muscle mass, assessed by preoperative computed tomography scans, seems to be an indepen‐ dent predictor of both overall survival (**Figure 1**) [44] and disease‐free survival, as significant as tumor stage, in patients following esophagectomy [45, 46]. In addition, sarcopenic patients who underwent esophagectomy had significantly higher rate of respiratory complications compared to nonsarcopenic subjects, but there was no difference in the incidence of overall complications between the two groups [47–49]. Sarcopenia has also impact on chemotherapy outcome since decreased muscle mass is associated with dose‐limiting toxicity and patho‐ logical chemotherapy response in patients receiving neoadjuvant chemotherapy [50–52]. Therefore, it is imperative to estimate patients' muscle mass not only preoperatively but also before the οnset of chemotherapy, bearing in mind that sarcopenia is frequently masqued by obesity making it more difficult to define patients' needs for intervention.

#### **2.4. Mechanisms of malnutrition**

Malnutrition, as mentioned above, affects a great percentage of esophageal cancer patients. Most patients are not able to achieve a positive energy balance and in many cases, initial body weight cannot even be maintained. This is ascribed mainly to impaired metabolism and side effects caused by esophagectomy or chemotherapy/radiation treatment. Dysphagia is a very common mechanical cause of malnutrition and is accompanied by dietary changes in order to

**Figure 1.** Example of CT scan analysis by the Slice‐O‐Matic software. Lumbar vertebrae 3 slice with Hounsfield units used to measure area of skeletal muscle, subcutaneous fat and visceral fat. White outer ring, subcutaneous fat; Light grey inner ring, muscle; Dark grey central area, visceral fat. Reproduced from Gibson et al. [42].

avoid foods that worsen symptoms leading to inadequate intake of calories. The surgical pro‐ cedure often causes deficiencies in macronutrients and micronutrients, with the most prevail‐ ing side effects being postprandial dumping syndrome, dysphagia, anorexia, reflux, and early satiety [53–55]. Furthermore, chemotherapy affects rapidly proliferating cells preferentially and, consequently, affects the cells of the gastrointestinal tract. Chemotherapy‐related causes of reduced food intake include nausea, vomiting, diarrhea, mucositis, and decreased appetite. Radiotherapy also contributes to malnutrition, and combined with chemotherapy exacerbates patients' nutritional status. Common side effects of radiotherapy include mucositis, esopha‐ gitis, odynophagia, mouth and throat soreness, and hypogeusia [56]. Tumor‐related causes of malnutrition are also of great significance, but the mechanisms involved are still under inves‐ tigation. Cancer‐induced anorexia may result from circulating factors produced by the tumor or by the host in response to the tumor. For instance, cytokines, such as interleukins (IL) and tumor necrosis factor‐alpha (TNF‐α) cause anorexia [57], whereas other tumor‐secreted fac‐ tors promote central‐ and peripheral‐mediated cancer cachexia. Tumor growth results in the secretion of pro‐inflammatory factors that promote cachexia by signaling anorexia, muscle wasting, and white adipose tissue atrophy. Tumors also secrete both the proteolysis‐inducing factor and activin, which promote skeletal muscle degradation and sarcopenia [58, 59].

Even though the mechanisms behind muscle wasting have been widely studied, less is known about the factors implicated in adipose tissue loss in cancer cachectic patients, such as lipid‐ mobilizing factor, as well as about the derangement in the neuroendocrine regulation of food intake and anorexia [60]. Additionally, changes in carbohydrate, lipid, and protein metabo‐ lism account for altered substrate metabolism. Changes in resting energy expenditure (REE) are considered one of the causes of nutritional depletion in cancer. In particular, measured REE by indirect calorimetry (IC) was elevated in patients with newly detected esophageal cancer, compared to healthy individuals [61]. A cross‐sectional study involved 30 patients admitted with a diagnosis of squamous cell carcinoma who underwent IC before starting cancer therapy. The basal energy expenditure (BEE) was evaluated using IC and was also estimated using the Harris‐Benedict Equation (HBE). The results showed that BEE of patients with squamous cell carcinoma was underestimated when using the HBE [62]. However, cur‐ rent evidence is inconsistent, since some studies suggest that REE is normal and is not affected by stage of disease [63–65]. Consequently, more research should be conducted in order to shed light on this controversial field.
