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The management strategy should consider various patient characteristics, including the patient’s fitness for treatment and TNM staging. In patients with early-stage
cancer T1/2 with no disseminated disease or involvement of other structures,
esophageal resection with curative intent remains the primary treatment strategy.
Early tumors may be amenable to endoscopic removal, whereas advanced or progressive diseases are likely to require additional interventions alongside surgery.
Advanced EC is often treated with chemotherapy, chemoradiotherapy, surgical
resection, and/or an amalgamation of these. Inoperable EC is treated with systemic
palliative chemo- and/or radiotherapy (Lordick et al. 2016).
Treatment intent should be considered and determined as an MDT whether the
patient is suitable for curative treatment is vital. Curative treatment is typically
provided to patients who are fit to undergo significant surgical resection and in
addition to limited disease burden.
4 Survival
Curative treatment (surgical intervention +/- neoadjuvant chemotherapy) for EC is
feasible. Although, in the past, postoperative survivorship was poor, advances in
surgical techniques and neoadjuvant chemotherapy have extended the survival rate
of patients suitable for esophagectomy. In addition, the advancement of healthcare
systems and technologies has resulted in improved operative and oncological
outcomes. The 5-year survival rate for localized EC has increased to 47% in recent
years, due to earlier diagnosis and improved intervention as outlined above (2019).
5 Weight Loss and Nutritional Compromise in All Stages
of Esophageal Cancer (EC)
Weight loss and nutritional compromise are common in the majority of patients with
EC throughout the course of the disease process. At the time of diagnosis, over 80%
of patients with EC have experienced unintentional, clinically significant weight loss
(>10%) resulting in compromised nutritional status (Steenhagen 2019). This phenomenon begins with the onset of cancer-rela ted symptoms and may persist throughout all stages of disease management whether it be for curative or palliative intent.
The effects of nutritional compromise are of particular importance given that
malnutrition has been identified as an independent risk factor in predicting survival
in patients with cancer and can negatively impact treatment plans, including
delaying or even precluding surgery or other treatment modalities in some cases
(Steenhagen 2019). Dysphagia, defined as difficulty in swallowing, is generally
progressive and is rarely an isolated symptom. Its effects on weight loss are
exacerbated by additional symptoms, including anorexia, early satiety, regurgitation,
and odynophagia, which are often observed in patients with EC. By the time patients
present with clinical symptoms suggestive of EC, many have already lost a significant amount of weight. The mechanical symptoms secondary to EC are often further
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exacerbated by the effect of systemic carcinomatosis and cancer cachexia, resulting
in additional weight and lean body loss. Furthermore, these problems may be
accelerated by the side effects of treatments such as perioperative chemo-/
radiotherapy, which are delivered as a standard of care for most pati ents. Within
this context, although treatment regimens are highly variable, the emetogenic effects
of oxaliplatin-based chemotherapy are profound. Radiotherapy is also associated
with a high incidence of side effects, including nausea, vomiting, reflux esophagitis,
as well as diarrhea.
6 The Impact of Esophagectomy on Nutritional Status
Nutritional compromise following esophagectomy is common. In patients following
esophagectomy, between 65% and 70% have inadequate intakes of energy and
protein at the time of discharge (Ryan et al. 2006). Furthermore, 25% of patients
fail to meet their caloric intake targets at 6 and 12 months after surgery (Haverkort
et al. 2012). Changes in nutritional status are most prominent in the first 6 months
following surgery, with weight loss ranging from 5% to 12% at this time point
(Baker et al. 2016). There is often a plateau in the nutritional deterioration trajectory
observed at 6–12 months post-esophagectomy, with weight stabilizing at a new,
lower baseline (Baker et al. 2017). By 3 years, in those with no recurrence, nearly
one-third of patients have lost more than 15% of their preoperative total body weight
(Martin and Lagergren 2009).
Body mass index (BMI) at the time of diagnosis has been identifi ed as an
important predictor of postoperative unintentional weight loss (Schandl et al.
2019). Although no upper BMI has been identified, patients with a higher BMI
lose more weight preoperatively but comparatively less postoperatively (Martin and
Lagergren 2009; Ouattara et al. 2012). Furthermore, the use of neoadjuvant chemotherapy and female sex have also been associated with greater weight loss (Martin
and Lagergren 2009). Given how prevalent and persistent this issue is, an understanding of the mechanisms of weight loss following esophagectomy is important to
the MDT in managing these patients within both the hospital and community
settings. Despite the potential implications for patients, there is a relative paucity
of studies on the topic, with one systematic review of the nutritional implications
of esophagectomy finding that no studies considered the relationship between the
inadequacy of nutritional intake and change in nutritional status postoperatively
(Baker et al. 2016).
Importantly, the implications of these gaps in knowledge can negatively affect
clinical practice. The failure to address the problem of weight loss may have a
negative impact on both recovery and long-term survival. Several high-quality
randomized controlled trials (RCTs) have demonstrated a greater survival benefit
in patients who were able to complete perioperative chemo-/chemoradiotherapy in
conjunction with esophagectomy (Cunningham et al. 2006; Ychou et al. 2011;
Al-Batran et al. 2019; Shapiro et al. 2015). A better understanding of the physiological mechanisms contributing to unintentional weight loss in this context may help us
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adequately address and manage this phenomenon, ultimately supporting patients to
ensure the availability of therapeutic interventions is not limited by compromised
nutritional status.
7 What Are the Consequences of Weight Loss
and Malnutrition Associated with Esophagectomy?
7.1 Negative Impact on Quality of Life
As a consequence of improved perioperative care, surgical techniques, perioperative
chemotherapy, and nutritional support, the 5-year survi val rate for the treatment of
EC has improved substantially over the past 20 years (2019). Population-based
cohort studies have demonstrated that patients who have undergone surgical resection for EC have the poor health-related quality of life in the short and longer term
(Lagergren et al. 2007). This is, in part, reflective of the invasiveness and associated
morbidity of surgical interventions, particularly if major postoperative complications
arise, as well as due to persistent nutritional challenges. A systematic review
identified six studies reporting on changes in nutritional status, which also reported
on the effects of nutrition-related symptoms on quality of life (Baker et al. 2016).
While the evidence is limited for nutrition-related quality of life, there is a general
consensus that the common and long-term (>12 months) GI symptoms following
esophagectomy include early satiety, nausea, dumping syndrome, reflux, dysphagia,
and diarrhea, all of which have implications for weight, lean body mass, and overall
nutritional status.
7.2 Reduced Long-Term Survival due to Inability to Tolerate
Adjuvant Treatments
Perioperative chemotherapy is increasingly becoming the standard of care for
patients undergoing esophagectomy. In patients following esophagectomy, adjuvant
chemotherapy is generally delivered at 75% of the preoperative dose. However,
in patients who are malnourished, there is a greater risk of life-threatening
complications. Failure to complete adjuvant treatments due to systemic side effects,
such as diarrhea, may have implications for long-term survival.
8 Pathophysiological Mechanis ms of Weight Loss Following
Esophagectomy
Valuable insights into the mechanisms which govern weight loss following
esophagectomy have arisen from mechanistic studies. These studies have challenged
the traditional view that postoperative weight loss is largely attributable to a simple
restrictive phenomenon, primarily due to decreased gastric volume. Using a model
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of bariatric surgery has shaped our understanding of GI physiology and, in turn,
informed our current appreciation of the changes following esophagectomy, which
mediate unintentional weight loss (Pournaras et al. 2017). This understanding of gut
hormone changes and their effect on the gut-brain axis may play an important role in
developing novel treatment strategies to preserve or increase weight in patients
following esophagectomy.
8.1 Changes in Gut Hormones, Bile Acids, and Gut Microbiota
After Esophagectomy Gut Hormone Changes After
Esophagectomy
Short-term regulation of feeding is mainly under the control of the hypothalamic
gut-brain axis and the enteroendocrine system which modulates appetite, satiety, and
glucose metabolism through a balance of orexigenic and anorectic gut hormones.
Hunger is primarily driven by the secretion of the main orexigenic hormone, ghrelin,
which is produced by Gr-cells in the gastric fundus. Food intake results in an
attenuation of this response with decreased ghrelin production. There is a concurrent
secretion of satiety-promoting or anorectic hormones from the enteroendocrine
L-cells of the large and small intestine in response to the arrival of ingested nutrients,
primarily through interactions with fatty acid bile receptors on their luminal surfaces
(Spreckley and Murphy 2015). In addition to producing a sensation of fullness, these
hormones, particularly glucagon-like peptide 1 (GLP-1), are essential regulators of
nutrient utilization, particularly in their role in promoting insulin secretion and
increasing hepatic and peripheral insulin sensitivity (Carmody et al. 2016). As
previously demonstrated by mechanistic studies looking into the role of gut
hormones in bariatric surgery, the anatomical changes produced by esophagectomy
are thought to result in important changes in enteroendocrine signaling. These
alterations are critical in mediating reduced long-term postoperative food intake.
Key satiety hormones involved in appetite regulation include:
• Glucagon-like peptide 1 (GLP-1).
• Peptide YY (PYY).
• Gastric inhibitory polypeptide (GIP).
• Oxyntomodulin (OXM).
• Pancreatic polypeptide (PP).
• Cholecystokinin (CCK).
The features of these gut peptide hormones in the context of OC surgery are
outlined in Table 3.
Models derived from bariatric surgery have largely shaped our understanding of
the effects of GI surgery on modifying neurohormonal control regulating the
gut-brain axis. In particular, studies characterizing the effects of satiety hormones,
namely, GLP-1 and PYY, have demonstrated their importance in the long-term
regulation of satiety, weight loss, and weight loss maintenance. Both GLP-1 and
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Brief decrease in fasting levels
(Elliott et al. 2019a; Yamamoto
et al. 2013; Miyazaki et al. 2012;
Doki et al. 2006)
Signals fasting, helps initiation
of feeding
" GH, PRL, ACTH, and cortisol
Inflated post-prandial reaction
Post-prandial satiety, ileal brake
Pancreatic exocrine and biliary
secretion
Post-prandial satiety, ileal brake Inflated post-prandial reaction
Decreased post-prandial reaction
Post-prandial satiety, ileal brake
Decreased biliary and
Inflated post-prandial reaction
pancreatic exocrine secretion
Post-prandial satiety, ileal brake
Incretin effect
Cardiac, renal, vascular,
immune effects
Inflated post-prandial reaction
Post-prandial satiety, ileal brake
Decreased pancreatic exocrine
function
Raised energy expenditure
Hormone Primary source Cell Site of action Function Response to upper GI surgery
Orexigenic gut hormones
Table 3 Anatomical and physiological features of the main gut peptide hormones (Murphy 2020)
Ghrelin Stomach Gr-cells Vagal afferent neurons
Hypothalamus
Mesolimbic system
Anorexigenic gut hormones
Brainstem
Hypothalamus
L-cells Vagal afferent neurons
intestine
CCK Proximal small
Gallbladder
Hypothalamus
Brainstem
L-cells Vagal afferent neurons
large intestine
PYY The small and
Brainstem
Hypothalamus
Pancreas PP-cells Vagal afferent neurons
Pancreatic
polypeptide
Hypothalamus
Brainstem
Mesolimbic system
L-cells Vagal afferent neurons
large intestine
GLP-1 The small and
Pancreatic islet
Hepatocytes
L-cells Vagal afferent neurons
OXM The small and
Hypothalamus
Pancreatic islet
Hepatocytes
large intestine
ACTH adrenocorticotropic hormone, CCK cholecystokinin, GH growth hormone, GLP glucagon-like peptide, OXM oxyntomodulin, PRL prolactin,
PYY peptide YY
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PYY are secreted by enteroendocrine L-cells throughout the GI tract, particularly in
the terminal ileum and large intestine in response to both nutrients and bile (De Silva
and Bloom 2012). Crossing the blood-brain barrier, they act on the arcuate nucleus
of the hypothalamus, inhibiting further food intake by stimulating the anorectic
pro-opiomelanocortin neurons while simultaneously inhibiting the orexigenic
agouti-related peptide and neuropeptide Y neurons (Turton et al. 1996). Following
esophagectomy, there is an exaggerated GLP-1 response, which, unlike the ghrelin
response, remains altered long term. Although the mechanisms underlying this
change have yet to be elucidated, it has been suggested that alterations in nutrient
delivery and bile flow due to anatomical changes may lead to enteroendocrine cell
hyperstimulation resulting in raised GLP-1 levels (Elliott et al. 2017). Postoperative
weight loss and fat loss following esophagectomy can be predicted by the magnitude
of the GLP-1 response (Elliott et al. 2019c). Evidence supporting the key role of
satiety hormones in mediating weight loss following esophagectomy has prompted a
further study to investigate the possible therapeutic role of somatostatin analogs and
specific GLP-1 receptor antagonists in regulating the exaggerated gut hormone
response (Elliott et al. 2019b; Murphy et al. 2021).
Ghrelin is the primary orexi genic hormone secreted by the Gr-cells of the gastric
fundus in response to hunger. Total circulating ghrelin levels have an inverse
relationship with body weight, with patients who have experienced diet-induced
weight loss demonstrating increased levels of ghrelin (Elliott et al. 2016). The
orexigenic effects of ghrelin are mediated centrally as the hormone is able to cross
the blood-brain barrier. In the brain, it stimulates the arcuate nucleus neuropeptide Y
(NPY) and agouti-related peptide expression, enhancing appetitive behavior while
simultaneously modifying dietary preferences toward carbohydrate intake. Given
the anatomical changes involving the gastric fundus with gastric conduit formation
during esophagectomy, it has been postulated that decreases in ghrelin may play a
role in weight loss post-esophagectomy. Studies have consistently demonstrated a
significant reduction in ghrelin levels in the early postoperative period. However,
these changes have been shown to be transient with a return to baseline by as early as
3 months (Koizumi et al. 2011). A return to normal hunger scores with persistent
weight loss, in conjunction with normalization of ghrelin levels, suggests that this is
not the primary mediator of long-term weight loss following esophagectomy but that
it may play a role in decreased hunger in the early postoperative period (Elliott et al.
2019a).
8.2 Alterations in Bile Acid Signaling Following Esophagectomy
Extensive changes in bile acid signaling, which are importan t mediators of weight
loss, occur following bariatric surgery, suggesting there may be similar mechanisms
involved following esophagectomy (Pournaras et al. 2012). Both of the most
commonly performed bariatric procedures, sleeve gastrectomy (SG) and Roux-enY gastric bypass (RYGB), produce a substantial increase in circulating bile acids
(Myronovych et al. 2014; Patti et al. 2009). Although bile acids are primarily thought
to mediate their effects in the digestion of lipids, they may also play an important role
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in directly regulating metabolism, primarily through their interaction with the
nuclear receptor FXR. Studies looking at FXR knock-out mice showed a substantially reduced response following SG for both weight loss and glucose tolerance
compared to wild-type mice, supporting the role of bile acid signaling in postoperative weight loss (Ryan et al. 2014). Further supporting this hypothesis, in rodent
models simulating the effect of RYGB, studies have demonstrated that alterations in
bile flow to the terminal ileum resulted in increased plasma bile acids, gut satiety
hormone response, reduced food intake, and weight loss (Pournaras et al. 2012).
Although this has yet to be specifically examined in patients following
esophagectomy, investigating the possible role of bile acids in postoperative weight
loss merits further investigation.
8.3 Alterations to Gut Microbiota Following Esophagectomy
Similar to bile acids, studies looking at changes following bariatric surgery demonstrate that there are changes in gut microbiota in the postoperative period, which may
also hold true following esophagectomy; however, the evidence for this remains
limited. Following bariatric surgery, significant changes can be seen in the gut
microbiota of both humans and rodents (Tremaroli et al. 2015). A decrease in
bacterial families (Archaea, Firmicutes, and Prevotellaceae) is observed, while
there is an increase in the ratio of Bacteroidetes to Prevotella. Esophagectomy
may lead to similar microbial changes (Li et al. 2011; Zhang et al. 2009; Furet
et al. 2010). At present, the exact mechanisms resulting in these changes and their
clinical significance, particularly in the context of weight loss, remain unclear.
Fecal transplant studies have provided evidence that altered gut microbiota may
play an instrumental role in weight loss after upper GI surgery. However, there
remain many confounders to this hypothesis, including perioperative antibiotic
use and other mechanisms of weight loss as previously discussed throughout this
chapter, and the extent to which microbial change contributes overall is unclear (Guo
et al. 2018 ).
9 Parallel Contributory Factors to Weight Loss
Post-esophagectomy
In addition to the pathophysiological changes discussed above, a number of additional factors may act in a synergistic manner to contribute toward post-surgical
weight loss and nutritional compromise.
9.1 Surgical Technique
Traditional surgical approaches to esophagectomy involved large open incisions,
such as a laparotomy often combined with a thoracotomy, which is highly invasive
and associated with significant postoperative morbidity. More recently, there have
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been advances in techniques with the adoption of minimally invasive approac hes,
which are generally associated with a decreased systemic inflammatory response
syndrome (SIRS) and faster recovery. Robotic surgery represents the latest advance
in the minimally invasive approaches, and although this may limit the magnitude of
surgical insult, the benefits may be offset by an increased risk of significant perioperative complications.
9.2 Appetitive Behavior
Appetitive behavior can be defined as the amount of effort a patientis prepared to use
to obtain food. Alterations in appetitive behavior are common and profound following esophagectomy. Early satiety in the postoperative period also contributes to this
effect, which ultimately reduces caloric consumption, resulting in weight loss and
nutritional decline.
Appetitive symptoms may be predictive of long-term weight loss after
esophagectomy, e.g., appetite loss and altered desire to eat. In some individuals,
cognitive behavior therapy has been shown to have a positive effect on counteracting
these changes. In many patients, there is a well-described rebound increase in
appetitive behavior following an initial period of decreased intake in the early
postoperative period. Interestingly, this compensatory change is typically not seen
in patients following esophag ectomy even when the inflammatory response has
subsided, suggesting there are additional postoperative changes contributing to
sustained weight loss in this context, including prolonged changes in gut hormones
(Elliott et al. 2019b).
9.3 Systemic Inflammatory Response
Esophagectomy is classified as a major plus intervention according to WHO
definitions. The catabolic effects resulting from the SIRS following surgical intervention are a well-characterized phenomenon. The SIRS response is believed to be
particularly profound in esophagectomy for several reasons, specifically the invasiveness of the two-compartment nature of the surgery as well as profound physiological stress induced by single lung ventilation. Similar to other major surgery,
following esophagectomy, there is an increase in basal metabolic rate due to the
surgery-related immune-driven inflammatory response (Anandavadivelan and
Lagergren 2016; Heneghan et al. 2015).
9.4 Cancer Cachexia
Cancer cachexia is a disease-specificinflammatory process resulting in malnutrition
in patients with underlying malignancy that is frequently seen in patients with EC
(Anandavadivelan and Lagergren 2016). It is characterized by sarcopenia occurring
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with or without the loss of adipose tissue, ultimately culminating in unintentional
weight loss and resultant physical and functional decline. Although this is part of a
disease spectrum, at more advanced stages, it is not typically reversed by optimization of nutritional status through the provision of additional nutritional support. The
causes underlying the development of cancer cachexia are multifactorial and remain
to be fully elucidated. However, it appears to be the product of a negative protein and
energy balance, thought to result from a combination of decreased nutrient ingestion
and altered metabolism. Cancer cachexia can be described as a spectrum ranging
from precachexia classified as <5% weight loss to cachexia with weight loss >5% or
BMI <2 0 and weight loss >2% and finally refractory cachexia whereby the degree
of cachexia is variable but cancer not responsive to treatment with <3-month
expected survival. Patients may present at diagnosis with some manifestations of
cancer cachexia, depending on how advanced the disease process is. It may also
feature in the postoperative management in the context of early cancer recurrence
with incomplete resection.
9.5 Change in Dietary Intake
The standard reconstruction during an esophagectomy is to use a tabularized segment of the stomach as a “pull-up” into the mediastinum from the abdomen. The
ideal gastric conduit has a width of no more than 3–4 cm, promoting antegrade
drainage of gastric content (Fig. 1). Although there is a variety of physiological
elements involved in postoperative weight loss, there are direct mechanical effects
that should be recognized, and reduced stomach volume may contribute to postoperative weight loss. Further mechanical changes attributed to the loss of the lower
esophageal sphincter following esophagectomy may contribute to the nearly 75% of
patients who report ongoing and worsening reflux symptoms in the postoperative
period (Wainwright et al. 2007). In addition to having a deleterious effect on the
quality of life, it is thought to be a possible contributory factor in affecting food
intake.
Conduit function in the postoperative esophagectomy patient is poorly understood. In a proportion of patients, the gastric conduit fails to empty normally leading
to conduit dysfunction, which can have deleterious metabolic and nutritional effects
(Donington 2006 ). Changes in the pattern of dietary intake to small, frequent meals
and increased intake of soft food are frequently advised. However, there is little
evidence showing such changes make any difference to long-term weight loss
(Soriano et al. 2018). Gastric conduit dysfunction represents a spectrum of changes,
which include delayed gastr ic conduit emptying, characterized by dysphagia, nausea, vomiting, early satiety, regurgitation, and inability to meet caloric needs orally
(Konradsson et al. 2020). The understanding of this phenomenon is poor, and there
is a paucity of research on the mechanisms involved. Although limited, evidence
suggests that the incidence is higher with minimally invasive techniques; this is of
concern with the increasing adoption of these approaches. It is unclear why there
may be an increased risk of gastric conduit dysfunction with minimally invasive
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Fig. 1 Tubularization of the
mobilized stomach to fashion
a gastric conduit used to
replace the affected segment
of the esophagus
approaches. However, it has been proposed that the omission of a pyloroplasty to
improve drainage may play a role (Konradsson and Nilsson 2019).
9.6 Dumping Syndrome
Patients undergoing upper GI surgery, including esophagectomy and bariatric surgery, may be affected by dumping syndrome, thought to be the result of altered
anatomy leadi ng to the rapid d elivery of undigested food to the small intestine. The
syndrome can be further subdivided into early and late dumping syndrome according
to timing. Early dumping syndrome is characterized by abdominal pain, bloating,
and vasomotor symptoms, which may be mediated by osmotic effects as well as
vagal response (Tack et al. 2009). Late dumping syndrome is associated with
symptoms of hypoglycemia and, in the context of esophagectomy, is related to the
observed exaggerated GLP-1 response mediating increased insulin secretion and
sensitivity (Elliott et al. 2019a). Up to 50% of patients may experience dumping
syndrome following esophagectomy, frequently resulting in food avoidance and
subsequent weight loss (Arts et al. 2009). A 2020 international consensus
recommended dietary adjustment as the first-line treatment for dumping syndrome,
with acarbose specifically for late dumping syndrome and somatostatin analogs for
those who do not respond to initial treatment (Scarpellini et al. 2020). Given the role
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