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Challenges of Onco-therapeutics in Early-Onset Colorectal Cancer 297
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(Mols et al. 2014; Seretny et al. 2014). Oxaliplatin can cause acute and chroni c
peripheral neuropathies, with acute neuropathic syndrome occurring in 90% of
patients (Simard et al. 2019). There has been a focus on reducing the duration of
treatment to reduce the risk of peripheral neuropathy, with cumulative dose the most
important risk factor in platinum-based drugs (André et al. 2013; Buccafusca et al.
2019). Neuropathy can impact occupational performance and can delay return to
work, with added financial impacts (Lim et al. 2021).
Chemotherapy-induced ovarian failure is an essential consideration for women of
childbearing age, yet to complete their family unit. Distress from failure to fulfil
reproductive goals can persist for several years (Kort et al. 2014). Discussion, even
brief, on the impact of treatment on ovarian function and fertility improves patients’
perception of their care (Partridge et al. 2004). Discussion of fertility preservation is
imperative with all patients. Unfortunately, there is low use of fertility preservation
in early-onset cancer, and this can be even less in patients with EOCRC than other
cancer types (Selter et al. 2019).
5 The Growing Use of Cancer Immunotherapy
Increasing understanding of the immunobiology of colorectal cancer has enabled the
development of molecularly directed and individualised treatment (Kanani et al.
2021). Immune microenvironment is of crucial importance in disease progression,
therapy response, and overall survival in colorectal cancer (Ganesh et al. 2019).
Immunotherapy has emerged as an alternative in cancer treatment, with promising
results observed in clinical trials (Zaborowski et al. 2021b; Eng et al. 2022). Most
early trials focused on metastatic CRC; however, recent data from the phase I/II
(NICHE-1) study suggest an upfront role for immunotherapy in operable stages I–III
disease.
Microsatellite status has important therapeutic implication in CRC as it appears to
predict response to immunotherapy with checkpoint blockade (Zaborowski et al.
2021b). Clinical efficacy is predominantly limited to tumours with microsatellite
instability, while microsatellite stable tumours are largely refractory (Le et al. 2017).
The molecular profile and immune microenvironment of EOCRC remains largely
undefined; however, it has been shown that younger patients more frequently have
tumours displaying microsatellite instability (Zaborowski et al. 2020). Two recent
studies have reported rates of MSI in 26% of early-onset colonic tumours and 12.5%
of rectal tumours (REACCT Collaborative 2022a, b, c). Based on this evidence,
there is a restricted number of young patients who would achieve a durable response
from current immunotherapeutic strategies. Therefore, the critical challenges with
immunotherapy in colorectal cancer are whether MSS tumours can be triggered to
respond to immune modulation and establish mechanisms to overcome immunotherapy resistance in these subtypes.
Radiation and chemotherapy have non-specific effects on tissue and exert cytotoxic effects on normal cells, with immunotherapy overcoming the issue of
298 K. Doogan et al.
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specificity (Johdi and Sukor 2020). However, with the increasing implementation of
immune-based therapies into clinical practice, the potential damaging collateral
effects on the immune system have come to greater attention (Ramos-Casals et al.
2020; Nappi et al. 2018). Immune-related toxicities are of concern to those who
would be eligible to receive immunotherapy agents and are known as immunerelated adverse events (irAEs). Two-thirds of cancer immunotherapy-related
complications are related to immune checkpoint inhibitors, with ipilimumab,
pembrolizumab, and nivolumab responsible for approximately 60% of cases
(Ramos-Casals et al. 2020). Combination therapy with anti-CTLA-4 and anti-PD-1
carries the highest rates of adverse events (Kanani et al. 2021). Dermatological,
gastrointestinal, hepatic, and endocrine effects occur most commonly, but irAEs can
involve virtually any organ system, with pulmonary, pancreatic, renal, cardiac,
neurological, haematological, and rheumatological adverse effects also documented
(Ganesh et al. 2019). Typically these adverse events have delayed onset and can
have prolonged duration (Ramos-Casals et al. 2020). They are frequently low grade
and reversible and, however, can lead to more permanent morbidity, with overall
irAE-associated mortality estimated to be in the region of 0.6% (Ramos-Casals et al.
2020). Initial concerns regarding immunotherapy-induced colitis leading to delay in
subsequent surgery appear unwarranted (Kanani et al. 2021). Although generally
considered less toxic than chemotherapy, due consideration must still be given to the
significant unanticipated side effects (Jannin et al. 2019).
While the main challenge is to elucidate the mechanisms to provide the benefits of
immunotherapy to metastatic colorectal cancer patients that are mismatch repair
proficient or microsatellite stable or have low microsat ellite instability, other
questions remain to be an swered. Other key challenges that remain to be addressed
include optimal duration of therapy, the benefits of a combination of ICIs and
chemotherapy and/or radiotherapy, and how to best monitor response to immunotherapy. Additional challenges of accessibility to these treatments, treatment cost,
and reimbursement must be considered.
6 Conclusion
As patients with EOCRC are more likely to present with advanced disease with
requirements for multimodal treatment, it appears that they face higher risks for
long-term treatment toxicity. Furthermore, following cessation of therapy, patients
may not actively seek help for symptoms, as they can believe they no longer have
access to healthcare services and support. Striking a balance between treating cancer
while preserving bowel, bladder, sexual function, and fertility is imperative. As
treatment options expand, quality of life in survivorship is of increasing importance.
The impact of an early-age colorectal cancer diagnosis and treatment on the personal
life of individuals affected must be acknowledged. Multidisciplinary collaboration is
needed to overcome the challenges of treatment in EOCRC.
Challenges of Onco-therapeutics in Early-Onset Colorectal Cancer 299
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Unintentional Weight Loss
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and Malnutrition After Esophageal
Cancer and Treatment
Alexis Sudlow, Annelie Shaw, Clare Corish, and Carel W. le Roux
Abstract
Patients with esophageal cancer present a management challenge from a
nutritional standpoint. Among patients with esophageal cancer, weight loss and
nutritional deficiencies are common with nearly 80% experiencing clinically
significant (>10%) weight loss at the time of diagnosis. Nutritional complications
arise not only as a result of the underlying disease process itself but also due to
subsequent medical and surgical treatment. The implications of malnutrition in
this patient population should not be underestimated as it has been identified as an
independent risk factor in predicting survival and, in some, may either delay or
entirely preclude undertaking surgery with curative intent. In patients who do
undergo esophagectomy, nutritional compromise is common with approximately
a quarter of patients being unable to meet caloric intake targets 1 year postopera-
tively and nearly one-third losing 15% of their baseline weight by 3 years. The
primary causes of weight loss are often attributed to early satiety, dumping,
reflux, and dysphagia; however, the underlying pathophysiology is incompletely
characterized. Mechanistic studies looking at other operations which induce
profound and sustained weight loss including bariatric surgery have provided
critical insights into some of the potential mediators involved in weight loss
including changes in gut hormones which modulate satiety and appetite via the
hypothalamic gut-brain axis. In addition to physiological changes, there are
important considerations with regard to alterations in eating behaviors and
Alexis Sudlow and Annelie Shaw are joint first authors.
A. Sudlow · A. Shaw · C. Corish · C. W. le Roux (✉)
Diabetes Complications Research Centre, Conway Institute, University College Dublin,
Dublin, Ireland
e-mail: carel.leroux@ucd.ie
#
The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
Interdisciplinary Cancer Research, https://doi.org/10.1007/16833_2023_142
Published online: 2 March 2023
305
306 A. Sudlow et al.
https://t.me/med1917
anatomy. A more complete understanding of the complex interaction between the
physiological, psychological, and anatomica l changes related to esophageal cancer and treatment may contribute to the development of a patient-centered
approach in the management of weight loss and nutritional compromise in both
the pre- and postoperative period, including the development of novel pharmaceutical agents to mitigate these changes.
Keywords
Esophageal cancer · Esophagectomy · Weight loss
1 Introduction
The management of patients with esophageal cancer (EC) is challenging from a
nutritional standpoint. The disease process itself, as well as subsequent treatment,
has a substanti al impact on nutritional status and may have important implications
for outcomes. In patients with severe nutritional compromise, this may limit further
treatment options, including chemotherapy.
There are more than 20 defined histological subtypes of esophageal cancer
recognized according to the World Health Organization (WHO) classification
system. These are broadly classified according to their origin (epithelial or
non-epithelial) and whether they are benign or malignant. Adenocarcinoma
(AC) is predominant in North America and Europe (Table 1), attributed in part to
specific risk factors contributing to its development, namely, the increasing prevalence of obesity, gastroesophageal reflux disease (GERD), and Barrett’s esophagus
(Malhotra et al. 2017), while squamous cell carcinoma (SCC) remains the most
common histological subtype within most of Asia.
Table 1 Risk factors for adenocarcinoma and squamous cell carcinoma (Domper Arnal et al. 2015;
Wheeler and Reed 2012)
Risk factor AC SCC
Geographical area Australian, North America
Race/ethnicity White > black Black > white
Gender Males > females Males > females
Alcohol consumption - ++++
Tobacco ++ ++++
Obesity +++ GERD ++++ Poor intake of fruit and
vegetables
Socioeconomic factors - ++
Genetic characteristics + ++
GERD gastroesophageal reflux disease
+: Associated risk
-: No associated risk
(United States), Western Europe
+++
Asia Iran, Southeastern Africa,
South America
Unintentional Weight Loss and Malnutrition After Esophageal Cancer and Treatment 307
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2 Diagnosis and Staging
Patients presenting with symptoms suggestive of EC, highlighted in Table 2, should
undergo urgent upper gastrointestinal (GI) endoscopy. Those who have visible
changes on direct endoscopic observation (i.e., macroscopic findings), alongside
common presenting symptoms, should have an urgent referral to a tertiary specialist
center that has experience in managing EC (Allum et al. 2018).
Both direct observation at endoscopy and histological confirmation are used to
diagnose the primary tumor. Following endoscopy demonstrating the presence of a
suspicious lesion, urgent investigations, including computerized tomography (CT),
should be arranged to facilitate prompt staging and allow for multidisciplinary team
(MDT) discussion. The TNM staging system is a universal system to classify the
anatomical extent and spread of cancers. In the absence of metastatic disease, the
MDT may then request further investigations such as PET +/- endoscopic ultrasound (EUS) to determine resectability.
Staging is paramount in developing a treatment pathway for an individual
diagnosed with EC. Due to the risk associated with esophageal resection, in addition
to the compromised quality of life postoperat ively, it is vital to select candidates
suitable for surgi cal intervention to avoid and minimize futile surgery in those with
incurable diseases (Shemmeri and Fabian 2021). Consideration of the significant
impact undergoing esophagectomy has on quality of life is an important factor that
should be discussed with each patient. Although a multifactorial process, changes in
appetite and body weight are important components (Wainwright et al. 2007 ). The
centralization of care has been recognized as a critical factor influencing postoperative outcomes, with better outcomes observed in high-volume centers, where surgical experi ence is significant and a strong MDT is established (Wouters et al. 2009).
3 Treatment and Management of Esophageal Cancer
Immediate, essential MDT planning is vital to the clinical and disease stage-specific
management of EC, taking consideration of comorbidities, and is recommended in
the European guidelines for the management of EC (Rice et al. 2017). Generally
speaking, the management approach for AC and SCC is comparable, with subtle
differences in the choice of chemotherapy and/or surgery (Lordick et al. 2016).
Table 2 Presenting symptoms of esophageal cancer (EC) (2020)
Common presenting symptoms
of esophageal cancer
Progressive dysphagia Hoarseness
Weight loss Cough
Heartburn (unresponsive to medical treatment) Pneumonia
Signs of blood loss/anemia
Uncommon presenting symptoms
of esophageal cancer
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