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Esophageal Cancer
10
DiMartinoNatale andMonacoLuigi
10.1 Introduction
Over recent decades, the percentage of elderly people in the world’s population has
progressively increased, and while representing percentages in the order of 5% in
countries with high population growth, such as Brazil and China, it reaches percentages of approximately 20% in countries such as Germany, Japan, and Italy as well.
For many patients, in particular for esophageal cancer, surgery is still the main
treatment. Esophagectomy is the major surgical procedure although burdened by a
high incidence of morbidity and mortality.
However, the effect of age on the outcome of these patients is still controversial.
In the early 1990s, Fentiman (1990) published an interesting review in the Lancet
analyzing the treatment of older oncological patients showing that these patients
received treatments, both medical and surgical, that were considered suboptimal.
That observation, according to the author, was secondary to the fact that these
patients presented a reduced long-term survival and that the procedures to which
they were subjected had a high postoperative mortality and morbidity [1, 2].
Over the last decades, however, this trend has been signicantly reversed, and at
the root of these changes, there is evidence that not all elderly patients have the
same surgical risk. The wider clinical heterogeneity of over 65-year-old subjects, in
fact, even with an equal chronological age, requires that eligibility for a particular
type of antineoplastic treatment should not rely solely on the registry data.
D.M. Natale (*)
Division of General and Gastroenterologic surgery, University of Campania “Luigi
Vanvitelli”, Naples, Italy
e-mail: natale.dimartino@unina2.it
M. Luigi
General and Laparoscopic Surgery, Nursing Home Villa Esther Avellino, Avellino, Italy
© Springer International Publishing AG, part of Springer Nature 2018
A. Crucitti (ed.), Surgical Management of Elderly Patients,
https://doi.org/10.1007/978-3-319-60861-7_10
161
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D.M. Natale and M. Luigi
These considerations have allowed recruitment of a greater number of t for
surgery older patients demonstrating, in recent years, a morbidity and postoperative
mortality comparable to those of young patients [3–5].
10.2 Epidemiology andRisk Factor
Over the last decades, esophageal tumors have shown a signicant increase in incidence around the world, and the demographical increase in elderly patients, also in
relation to higher life expectancies, has led to an increase of over 65-year-old
patients coming to the observation suffering with cancer.
In the 1960s the incidence of esophageal adenocarcinoma (EAC) began to
increase, and in the 1990s esophageal cancer was predominant in the USA, but,
worldwide, the squamous cell carcinoma (SCC) is still predominant [5, 6]. These
differences in incidence are to be related to different ethnic groups, different geographical areas, genetic factors, and lifestyles that all seem to play a fundamental
role in the development of the EAC or SCC [7–9].
In particular, SCC is predominant in East Asia, Eastern and Southern Africa, and
Southern Europe.
Tobacco is the major cause of SCC, and the risk of SCC is higher in current
smokers and those who smoked >30packs/year [10].
Other important risk factors are alcohol consumption, and it has been
observed that more than 170g of alcohol intake per week increases the risk of
SCC [11].
Gastroesophageal reux disease (GERD) is not clearly associated with SCC nor
body mass index (BMI), but BMI is associated with high blood pressure, and this
correlates to an increased risk of SCC [12].
EAC is predominant in Northwestern Europe and North America and shows a
high incidence in the UK, France, Ireland, and the Netherlands [13].
Several risk factors participate in the development of EAC but rst of all
GERD.Symptoms of GERD that occur weekly increase the risk of EAC by approximately vefold. GERD is associated to EAC through a cascade of events that lead
from erosive esophagitis to Barrett’s esophagus [
Barrett patients develop EAC probably because this evolution occurred in predisposed subjects [16, 17].
BMI is associated with an increased risk of EAC, and the risk increases proportionally to BMI probably because obesity increases hiatal hernia, GERD, and the
incidence of Barrett’s esophagus [18].
Smoking is a risk factor for the development of both Barrett’s esophagus and
EAC, and continuing to smoke increases the risk of EAC by about twofold [19].
All correlations between risk factors and esophageal cancer are summarized in
Table10.1.
14, 15], but not all the cohort of
10 Esophageal Cancer
163
Table 10.1 Risk factor
related to squammous cell
carcinoma (SCC) and
adenocarcinoma of the
esophagus
Tobacco +++ ++
Alcohol +++ – – –
Barrett’s esophagus – – – ++++
Weekly reux – – – +++
Obesity – – – ++
Achalasia +++ – – –
Caustic lesions ++++ – – –
Plummer-vinson syndrom ++++ – – –
Head and neck cancer ++++ – – –
RT For breast cancer +++ +++
Hot drink + – – –
Poor life condition ++ – – –
SCC
ADC
10.3 Symptoms
In the early stage, unfortunately esophageal cancer is poorly symptomatic, and
when symptoms occur, the cancer is in an advanced stage. In any case, the typical
symptom of esophageal cancer is dysphagia, and initially it is experienced when
ingesting solid food but eventually progresses to include liquids. This symptom is
typically localized in the neck only when the cancer is cephalic, but when the cancer
occurs in the distal esophagus, the patient is not usually able to localize the site
describing difculty in a point as far cephalic as the sternal notch.
Besides dysphagia, esophageal cancer may present unexpected weight loss
which represents the second most common symptom and occurs in more than 50%
of patients.
Bleeding, epigastric or retrosternal pain, hoarseness caused by invasion of
the laryngeal nerve, and a persistent cough represent other symptoms of esophageal cancer, and they are correlated with advanced disease. In fact, less than
25% of patients with esophageal cancer have localized disease at the time of
presentation [20].
10.4 Preoperative Assessment
The management of esophageal cancer is mainly based on exhaustive preoperative
assessment, and in particular in elderly patients, the accuracy of diagnosis and staging is as important as the evaluation of the performance status of the patients.
In fact, there were no signicant differences in tumor location and size, histological type, and differentiation between the elderly and younger patients [21], but
the differences in postoperative morbidity and mortality were related to the performance status of patients and the presence of many comorbidities [22].
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D.M. Natale and M. Luigi
The procedure for identication of elderly people at higher risk is not yet standardized. The impairment of the muscular and nervous systems resulting in impaired
motor function of the lower limbs appears to be a determining factor. The events
triggering disability can be varied and include a reduction in lean body mass, poor
nutrition, cognitive impairment, lack of social support, immobilization, acute diseases, and aggressive treatments [4].
In geriatric oncology there is an operational denition of frailty given by Balducci
that can be obtained when one or more of the following parameters are present: the
presence of at least one geriatric syndrome and/or dependence in at least one ADL
and/or >3 comorbidities and/or age>85years.
The evaluation of the performance status of the elderly patient (Karnofsky score,
ECOG score, EHO score, Lansky score) must also be associated to a series of
parameters such as cognition, emotional condition, geriatric syndromes, nutrition,
the use of drugs, socioeconomic conditions, and nally, but no less important, the
evaluation of lung, kidney, and heart function and the presence of any additional
comorbidities. Still today, though, conventionally and widely used in the literature,
the elderly are dened as patients over the age of 70years, and yet there are few
trials that evaluate the elderly not in relation to the anagraphical age but to the biological age that helps to classify these patients as fragile and non-fragile, the latter
with a signicantly higher life expectancy than those classied as fragile [23].
Both in elderly and younger patients, a proper diagnosis and staging is mandatory for the planning of the most suitable therapeutic strategy, and it appears to be
the main key to decreased morbidity and improved long-term survival.
The endoscopy with biopsy is the gold standard for diagnosis. In particular, it is
able to show localized tumors and to detect the tumor’s location and the proximal
and distal extents of the mass and their relationship to the cardias. In fact, according
to the Siewert classication, type 1 and 2 tumors are treated as esophageal tumors
and type 3 as gastric tumors.
EUS is more accurate than cross-sectional imaging techniques (CT or PET) to
assess the depth of invasion (T status), but for supercial cancer (T1a or T1b), EUS
can over-stage the lesion, and for T1b tumors, where endoscopic treatment should
be indicated, the endoscopic mucosal resection (EMR) should be included in the
staging [
24]. EUS associated to ne needle biopsy is the best modality for assessing
involvement of loco-regional lymph nodes [25]. EUS shows limits in the assessment of tumors with strictures that prevent passage and in the posttreatment (CRT)
assessment due to brosis.
In the assessment of esophageal tumors, there are numerous imaging techniques,
and their role is to study and to stage distant metastasis. In particular, CT scan is
used to study thoracic and abdominal metastasis and associated to positron emission
tomography (PET) can detect more accurately the distant metastasis, but this technique shows less sensitivity to study low-depth invasion (T1a or T1b) compared to
EUS [26]. PET is also used to evaluate posttreatment reassessment and to appraise
the response to neoadjuvant therapy [27].
To detect brain metastasis, MRI should be considered because PET/CT is not
effective for studying tissue with high glucose uptake.
10 Esophageal Cancer
165
In the study of patients with esophageal cancer, diagnostic laparoscopy has a role
in directing patients with subcarinal tumors to chemotherapy [28], particularly those
with liver subcapsular metastases and/or peritoneal carcinomatosis [29].
For retrocarenal neoplasms, the tracheobronchoscopy allows patients to be excluded
from surgery in which radical resection (R0) would be scarcely attainable and admits a
signicant number of patients to be directed to neoadjuvant therapy [30].
10.5 Staging
Staging is an essential prerequisite for the long-term success of the therapy and in
particular of surgical therapy, and proper staging is intended to exclude patients
with metastatic disease from surgery and identify subgroups for adjuvant or neoadjuvant therapy, ensuring comparability of case studies and quality controls for
clinical trials.
Proper staging is the most important factor in improving long-term survival in
patients with esophageal cancer because the treatment options are mainly driven by
the stage of the disease. In fact, if intramucosal tumors (T1a) have a small percentage of or no lymph node invasion, this percentage increases signicantly for tumors
that invade the deeper layers (T1b).
From the anatomical, topographical, and endoscopic point of view, the esophagus is divided into cervical esophagus, thoracic esophagus (upper-middle-lower),
and gastroesophageal junction (crossing point between squamous epithelium and
glandular epithelium).
The latter, from the anatomical and topographical point of view, according to the
classication of Siewert, is divided into three types [31]:
• Type 1: the center of the tumor is located at 1–5cm above the cardias.
• Type 2: the center of the tumor is located between 1cm above and 2cm below
the cardias.
• Type 3: the center of the tumor is localized to 2–5cm below the cardias.
Siewert type 1 and type 2 should be classied and staged as esophageal tumors,
and type 3 should be classied and staged as gastric cancers.
The esophageal wall is composed of successive layers, the mucosa, consisting in
turn of epithelium, lamina propria, and muscularis mucosae; the submucosa, which
is separated from the mucosa by a layer called the basal membrane; the muscularis
propria; and, more externally, the adventitia.
The EAC and SCC are staged according to the AJCC (American Joint Committee
on Cancer). This staging system, updated in 2010 (seventh edition), for the rst time
stages esophageal adenocarcinoma and squamous cell carcinoma separately [32]
(Table10.2a, b).
Neoplasms affecting mucosal layers are dened as intramucose and represent the
T1a, and those invading the submucosa represent T1b. Invasion reaching the deeper
layers is classied into T2 when they invade the muscularis propria and in T3 when
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Table 10.2 AJCC classication of squamous cell carcinoma (a) and adenocarcinoma of the
esophagus (b) according to 7th edition 2010
(a) Squamous cell carcinoma (b) Adenocarcinoma
Stage T N M Grade
0 Tis (HGD) N0 M0 1 Any 0 Tis (HGD) N0 M0 1
IA T1 N0 M0 1 IA T1 N0 M0 1–2
IB T1 N0 M0 2–3 Any IB T1 N0 M0 3
T2-3 N0 M0 1 Lower T2 N0 M0 1–2
IIA T2-3 N0 M0 1 Upper,
T2-3 N0 M0 2–3 Lower IIB T3 N0 M0 Any
IIB T2-3 N0 M0 2–3 Upper,
T1-2 N1 M0 Any Any IIIA T1-2 N2 M0 Any
IIIA T1-2 N2 M0 Any Any T3 N1 M0 Any
T3 N1 M0 Any Any T4a N0 M0 Any
T4a N0 M0 Any Any IIIB T3 N2 M0 Any
IIIB T3 N2 M0 Any Any IIIC T4a N1-2 M0 Any
IIIC T4a N1-2 M0 Any Any T4b Any M0 Any
T4b Any M0 Any Any Any N3 M0 Any
Any N3 M0 Any Any IV Any Any M1 Any
IV Any Any M1 Any Any
Tumor
location Stage T N M Grade
IIA T2 N0 M0 3
middle
middle
T1-2 N1 M0 Any
they exceed the adventitia. As for the tumors classied as T4, i.e., malignancies that
invade organs or periesophageal structures, they should be divided into T4a when
they invade structures such as the pleura, pericardium, or diaphragm; despite the
invasion of adjacent structures, they can still be regarded as potentially resectable
and divided into T4b, i.e., neoplasms that affect structures, such as the aorta, vertebral bodies, or trachea, which therefore are not resectable.
10.6 Treatment Option
Although in the last few decades, there has been an increase in long-term survival
for cancer of the esophagus, for patients treated, altogether it still stands at around
20% at 5years, and, unfortunately, more than 50% of the patients who come to
observation present with locally advanced or non-resectable tumors [33]. The aging
of the population and a longer life expectancy have led to a signicant increase in
elderly patients being referred for treatment.
For these reasons the multimodality therapy has become the foundation for treatment of the majority of patients with cancer of the esophagus and cardias. The treatment approach depends on several factors and requires a team of specialists
including gastroenterologists, pathologists, radiologists, surgeons, oncologists,
radiotherapists, and also nutritionists and support staff. The right treatment strategy,
therefore, must be guided by the stage of disease and the patient’s condition, and as
previously highlighted, the treatment options can range from endoscopic treatment
for early-stage cancer, multimodal treatment for locally advanced or metastatic, up
10 Esophageal Cancer
167
to salvage therapies for relapsing tumors or, nally, purely palliative for nonresectable tumors or for patients unt for surgery or unt for CT and/or RT.
10.6.1 Chemotherapy andRadiotherapy
Studies of analysis of the results of chemotherapy and radiotherapy in esophageal
cancer are often characterized by difculties in interpretation dependent on heterogeneity of the histological types in the different case studies, such as patient selection,
difculty to attribute the primitiveness (esophageal or gastric) to adenocarcinomas of
the junction, different surgical techniques adopted, response criteria, different radiotherapy schedules (doses and fractionation), and different chemotherapy regimens.
Numerous studies, recent guidelines and in particular clinical trials, show that
the sole use of chemotherapy or, worse still, radiation therapy alone has little or no
success in the treatment of esophageal cancer compared to surgery alone [34, 35].
On the contrary, many reviews on clinical trials published over the last 20years
have shown that unlike the sequential use, the combined use of chemotherapy and
radiotherapy before surgical treatment (neoadjuvant trimodality therapy) indicated
that this protocol is important to understage disease and optimize surgery [36], and
it also leads to the optimization of benets of each treatment reducing the cancer
burden, removing persistent microscopic disease after chemoradiation, and increasing pathologic complete resection rate with negative circumferential margins, and it
has an adjuvant effect on micrometastatic disease with pathological complete
response (pCR) ranging from 20 up to 40% (Table10.3); in fact, it is the latter that
is the most important prognostic factor. Obtaining a complete pathologic response is,
Table 10.3 Summary of the most important articles comparing CRT and surgery vs surgery alone
Survival
Authors Treatment Pts (N) RT (Gy)
Walsh Cisplatin/5-FU 58 40 NS 25 16 3-Y 32%
Surgery 55 11 3-Y 6%
Urba Cisplatin/5-FU/Vnb 50 HFX, 45 45 24 16,9 3-Y 30%
Surgery 40 45 17,6 3-Y 6%
Bosset Cisplatin 143 SC, 37 26 18,6
Surgery 139 18,6
Burmeister Cisplatin/5-FU 128 35 80 16 22,2 NS
Surgery 128 59 27,3 NS
Lee Cisplatin/5-FU 51 HFX,
45,6
Surgery 50 84 27 2-Y 57%
Tepper Cisplatin/5-FU 30 50,4 NS 40 54 5-Y 39%
Surgery 26 21,6 3-Y 16%
van Hagen Carboplatin/Ptx 175 41,4 92 29 49 3-Y 59%
Surgery 188 69 24 3-Y 48%
Modied from Orditura etal. [36]
5-FU Fluoruracil, Vnb Vinorebine, Ptx Paclitaxel, SC Short Course, HFX Hyperfractionated
R0 rate
(%)
68 43 28,2 2-Y 49%
Median
pCR
(mo) Overall
(%)
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D.M. Natale and M. Luigi
in fact, the main goal of neoadjuvant therapy and is the prerequisite for control of
the disease over time.
In the study CROSS, published in 2012, which used a scheme with carboplatin and
weekly paclitaxel combined with RT 41.4Gy, survival was superior to that with surgery
alone. More specically, in patients with unresectable carcinoma (T2-3N0-1M0) of the
esophagus and gastroesophageal junction (75% AC, 23% SCC), the preoperative
chemoradiotherapy branch showed statistically signicant benets compared to surgery
alone with a survival average (49 vs. 24months), short- and medium-term survival (47
vs. 34% at 5years), and surgical radical R0 resection (92 vs. 69%). The complete pathologic response was greater for patients with squamous cell carcinoma compared to that
obtained in adenocarcinomas (49 vs 23% p=0.008), but the histological type was not a
prognostic factor for survival. Although combined chemoradiotherapy treatment was
generally well tolerated (toxicity gr. 3–4 23%), it should be pointed out that the average
age of the patients corresponded to 69years (range 36–79years), and also not having
been conducted a specic sub-analysis by age group, it is therefore complex to generalize the efcacy, results, and tolerability in the elderly population [37].
Patients with good performance status with adenocarcinoma of the esophagus
and gastroesophageal junction may be referred to a three-drug chemotherapy treatment, adding epirubicin or a taxane to a brace cisplatin (oxaliplatin) and uorouracil
(oral uoropyrimidine).
The most used protocols (level of evidence 1 ++) are represented by cisplatin
75–100mg/m2, uorouracil+750–1000 mg/m2 continuous infusion×96 h every
28days concomitant with radiotherapy 50–50.4Gy (1.8Gy/die−2Gy/day) [36], or
carboplatin AUC 2 + paclitaxel 50 mg/m2 weekly × 5 weeks concomitant with
radiotherapy 41.4Gy (1.8Gy/day) [37].
Finally, there are many new chemotherapeutic agents that might play a role in the
control of micrometastases including paclitaxel, irinotecan, and gemcitabine that
are also potent radiation sensitizers.
10.6.2 Target Therapy
At present, new medical treatment modes are being evaluated to improve long-term
survival through the use of monoclonal antibodies. In particular, encouraging results
have been reported from the use of antibodies to the VEGF ligand, Anti-HER2, and
TK1s [38].
10.6.3 Esophagectomy
Surgery is the main option to get local control of the disease, and the esophagectomy represents the best chance for treatment in localized and locally advanced
tumors [47] although it appears to be still one of the more difcult operations and
still burdened by signicant postoperative mortality.
Progress in pre-, intra-, and postoperative managing has signicantly improved
results in terms of morbidity and mortality. The improvement of anesthetic
10 Esophageal Cancer
169
techniques, adequate preparatory and intraoperative assessment, and better postoperative pain control have certainly increased the number of patients, especially the
elderly, eligible for surgical therapy. Though, in relation to younger patients, the
number of t-for-surgery elderly patients is still signicantly lower, this is related
to the fact that eligibility for esophagectomy must consider several parameters, in
particular the presence of comorbidities that are signicantly greater in elderly
patients.
Although the role of surgery appears to be clear, there is still debate on what is
the most appropriate surgical treatment, particularly for elderly patients, and, for
esophageal resection, several approaches have been described.
The surgical procedures for esophagectomy are represented by:
– Transhiatal esophagectomy which requires abdominal access and a neck inci-
sion. The esophagus is mobilized and prepared, abdominally through the esopha-
geal hiatus the medial and lower portion of the esophagus and the upper portion
of the neck. An anastomosis is performed in the neck. This procedure has the
disadvantage of not allowing a perfect exposition of the medial esophageal can-
cer and does not guarantee a complete lymph node dissection in the chest.
– Tri-incisional esophagectomy provides in addition to the transhiatal esophagec-
tomy a thoracic access to adequately prepare the medial esophagus and a large
thoracic lymphadenectomy.
– Abdominothoracic esophagectomy (Ivor-Lewis procedures) implies an abdomi-
nal phase to prepare the esophagus and a left thoracotomy for preparation of the
thoracic esophagus to the superior segment where the anastomosis is performed.
Thanks to this procedure is possible to have a good mediastinal lymphadenec-
tomy, a good exposure of the tumor, and provides intrathoracic anastomosis.
Minimally invasive esophagectomy (MIE) has recently been proposed requiring
an Ivor-Lewis procedure to be performed with laparoscopic access for abdomi-
nal phase and a thoracoscopic access to the thoracic phase.
Which approach is chosen depends on tumor location and the surgeon’s ability to
obtain a curative R0 resection and adequate lymphadenectomy. In fact, some authors
propose transhiatal esophagectomy as the treatment of choice for older patients
because it ensures lower morbidity and better short-term results; others, on the contrary, prefer to extend esophagectomy with a two-eld lymphadenectomy in all
patients with cancer of the esophagus in order to achieve maximum cancer control
and reduce the risk of local recurrence, although there is no level 1 evidence that any
of these different approaches increases survival time [39].
Many studies, homogeneous in terms of patients analyzed, showed that the
elderly (i.e., patients aged >70year) have a higher morbidity and mortality than
younger patients (Table 10.4) but, adjusted for comorbidities, the outcomes are
similar across the group with no signicant differences in morbidity and in mortality rate [5].
Another topic that was discussed and is still discussed is how much the lymphadenectomy (i.e., two- and three-eld lymphadenectomy) should be extended. The
CROSS trial [37] showed that patients treated with surgery alone had a better
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Table 10.4 Results of Esophagectomy in the elderly and Young patients: Summary of some of the
most important articles
30-day
Age
Author
Ellis >70 147 37.5 4.5 5.3 24.1
Alexiou >70–86 186 34.4 – 6.4 21.2
Poon >70 167 >39.5 7.2 18.0 26.0
Joungon >70 89 24.7 – 7.5 13.3
Thomas >70 56 50.0 8.9 10.7 17.0
Naunheim >70 38 68 – 18 13
Fang >70 79 65.8 3.3 8.9 40.9
Morita >80 16 25 0 0 9
Moskovitz >80 31 >32 – 6 16.8 mo
Ruol >70 165 49.1 1.9 1.9 35.4
Alibakhshi >70 165 23.5 3
Modied from Alibakhshi etal. [57]
(years)
<70 358 32.3 1.25 2.4 22.4
<70 337 24.7 – 4.7 25.1
<70 570 >28.1 3.0 14.4 35.0
<70 451 26.8 – 5.3 20.7
<70 330 57.3 7.9 11.2 18.9
<70 362 61.6 0.3 3.8 48.1
70–79 158 42 8 2 28
<70 494 32 7 3 39
70–79 207 >22 – 15 29.1 mo
<70 599 48.6 1.9 2.7 33.6
<70 315 22.1 2.8
No. of
patients Morbidity (%)
mortality
rate (%)
In-hospital
mortality
rate (%)
Overall
survival
rate (%)
long- term survival when a more extensive lymph node dissection was carried out,
but as evidenced by Noordmann and Van Lanshot, advantage was annulled in
patients treated with neoadjuvant therapy. At present, according to the most recent
guidelines, adequate lymph node dissection should include at least 18 negative
nodes with a total number of lymph nodes removed >25 [40].
10.7 Treatment Decision
Proper treatment planning for cancer of the esophagus is inuenced by numerous
factors represented in the rst instance by the stage, grading, and location of the
tumor and, in the case of elderly patients, the patient’s general condition and the
presence of comorbidities taking a role of primary importance to the operability of
the patient and postoperative outcome.
The most appropriate treatment protocol must rst of all take into account the
involvement of the wall which appears to be strongly associated with the presence
of lymph node involvement and distant metastases in order to plan the most appropriate therapeutic approach which would guarantee the best results in terms of morbidity and survival in relation to the patient’s performance status (Figs.10.1, 10.2,
and 10.3).
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