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94 1 UPPER GASTROINTESTINAL CANCER
A
10
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Figure 7 Survival stratified by ypT, ypN, and ypM categories for ESCC.
2
ypM1
468 10
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Figure 8 Postneoadjuvant pathologic stage groups (ypTNM): adenocarcinoma and squamous cell carcinoma.
noncurative ER. While additional esophagectomy is recommended when postoperative histopathological factors indicate
a high risk of nodal involvement and/or incomplete resection,
accurate patient selection for additional surgery is needed since
the majority of additional surgical resections for ESCC were
tumor-free compared to adenocarcinoma (Liu 2021).
Another adjuvant therapy for high risk tumors after ER is
chemoradiotherapy. The JCOG0508 evaluated the efficacy of
CRT after noncurative ER. Three-year progression free survival
was 73–88%. Minashi etal. reported that ESD combined with
selective adjuvant CRT for cT1bN0M0 ESCC could achieve
oncologic results non-inferior to esophagectomy (Minashi
2019). In conclusion, ER is a valuable treatment for superficial
ESCC, under the precondition that early stage EC can be accurately diagnosed (Kato 2021).
Ablation
Unlike adenocarcinoma, where several indications for ablation
of Barrett’s epithelium exist, the role of ablative therapies for
ESCC has still to be determined. Endoscopic radiofrequency
ablation (RFA) does not allow histological examination and the
risk of lymph node metastasis is thus undetermined. RFA is to
be combined with other modalities but its’ role in the treatment
armamentarium for ESCC is still unknown (Noordzij 2019).
Esophagectomy
Radical therapy offers the best chance of control and cure for
ESCC and surgical resection still remains the cornerstone of
curative treatment.
i Preoperative Selection
Eligibility of a patient for surgical resection strongly depends
on the extent of the disease, as well as on the general condition
of the patient. Preoperative selection should be carried out
carefully. A multidisciplinary team is then necessary for
choosing the appropriate treatment for each patient individually, not only on the basis of the TNM-classification system
tumor stage, but also depending on tumor location, histological subtype, comorbidities, and age. Patients with T1-2
ESCC without nodal disease are recommended to undergo
immediate surgery in Asian practices, but they could also be
candidates for preoperative treatment (Ajani 2019). Patients
with T3 or N-positive disease are candidates for preoperative
chemotherapy and/or radiotherapy followed by elective surgery, while patients with T4a or N3 disease are candidates for
definitive chemoradiotherapy followed by salvage surgery.
In contrast to adenocarcinoma, ESCC are more proximally
located tumors and proximal tumors are usually poor candidates for surgery because of limitations in surgical techniques (e.g., confined working space and poor overview).
Furthermore, due to its anatomical proximity to the hypopharynx, surgery includes a combined pharyngo-laryngoesophagectomy in some cases, resulting in permanent
tracheostomy and affecting the quality of life of these patients
enormously. These patients frequently depend on definitive
chemoradiotherapy, with encouraging three-year outcomes
and acceptable toxicity (Borggreve 2018).
As for comorbidities, a large population-based study
showed that 65% of the patients have an American Society
of Anesthesiologists (ASA) score of 3. Anastomotic leakage
is known to be associated with pre-existent cardiovascular
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disease such as arterial calcifications, making those patients at
risk of developing anastomotic leakage due to esophageal conduit necrosis. Preoperative pulmonary function is also related
to the incidence of pulmonary complications, but could be
reduced by dedicated preoperative physical therapy to increase
cardiorespiratory function (Lagarde 2008). Age has historically been a selection criterion for treatment and management
in cancer patients, but old age should not be the only reason to
exclude patients from receiving survival improving treatments
such as surgical resection. The association of age with severity
of complications after esophagectomy is demonstrated by an
adjusted odds ratio of 1.02 per year increase in age, but no
specific limitation of age has been demonstrated as a contraindication for surgery (Nienhueser 2015).
ii Surgical Techniques
Principles of Resection: Tumor Resection
Esophageal tumors tend to spread longitudinally within the
submucosa of the esophageal wall. A radical resection without
microscopically positive margins (R0 resection) is of great
concern for surgeons since it defeats the primary objective of
surgery. The definition of a positive radial margin depends on
the pathologic reporting system used. The Royal College of
Pathologists defines an R1 (microscopically positive) margin
as cancer within 1 mm of the margin; the College of American
Pathologists defines R1 as microscopic involvement of the
margin. Ten percent of esophagectomy patients had positive
resection margins and survival is markedly diminished in
patients with incompletely resected tumors (Rice 2017).
In Japan, a three-field LN dissection is recommended, but this
is not yet part of the routine surgical practice, especially not in
the West due to higher risk on serious postoperative complications. As part of a three-field lymphadenectomy, dissection
along the recurrent laryngeal nerve (RLN) could induce RLN
palsy and induce aspiration pneumonia, potentially resulting
in postoperative deaths (Matsuda 2017).
The Japanese classification of LN is based on the spread of LN
rather than the count, which can give additional information on
the extent of lymphadenectomy but is more complex to define.
(See Section 4: clinical staging) Furthermore, the Japanese
classification defines the concepts of D1–D3 dissection, which
indicates extent of lymphadenectomy. Using these definitions,
a surgeon can plan for extent of dissection based on the location of primary lesions.
1 DX Extent of lymph node dissection cannot be assessed.
2
D0 No or incomplete dissection of Group-1 lymph nodes.
D1 Complete dissection of Group-1 lymph nodes, but no or
3
incomplete dissection of Group-2 lymph nodes.
4 D2 Complete dissection of Group-1 and Group-2 lymph
nodes, but no or incomplete dissection of Group-3 lymph nodes.
D3 Complete dissection of Group-1, Group-2 and Group-3
5
lymph nodes.
Lymphadenectomy should be based on regional lymph node maps.
However, a higher lymph node yield has been associated with
improved survival in several international studies but it should be
noted that these findings have to be interpreted with caution, and
the debate on the benefit of extensive lymphadenectomy has not yet
been settled. Lymphadenectomy sufficient to determine pN is different from that necessary for optimal survival; at surgery, a balance
of these goals is necessary (Esposito 2020; Visser 2019).
Principles of Resection: Lymphadenectomy
The lymphatics in the squamous esophagus are located in an
extensive, highly interconnected submucosal plexus. They
drain through the muscularis propria to a paraesophageal
plexus and a group of lymph nodes (LN) situated on the outer
wall, then to the periesophageal nodes close by, and finally to
lateral esophageal nodes. Sequential drainage may not occur
with connections direct from the periesophageal nodes to lateral LN. The Japanese Society published the original and
detailed lymph node maps allowing classification and defining
radical surgical excision (Akiyama 1994).
A one-field resection would only encompass the para- and
periesophageal nodes, a standard two-field resection will
include these nodes together with the thoracic duct, the left
and right pulmonary hilar nodes, and the paratracheal and
tracheal bifurcation nodes. A radical three-field dissection
includes the nodes around the right and left recurrent laryngeal nerve, the deep lateral and external cervical chain, and
those around the brachiocephalic vein. Lymph node metastasis occurred in 33% of patients with upper thoracic ESCC
and 28% in ESCC located in the middle third (Udagawa 2012).
Surgical Approaches
A transthoracic approach is generally considered for esophagectomy to be optimal in oncological terms, as it allows for twofield lymphadenectomy with upper mediastinal dissection. The
alternative, transhiatal esophagectomy, was designed to reduce
postoperative morbidity and mortality by avoiding thoracotomy
and is therefore often reserved for patients with considerable
comorbidity and high risk of complications following a potential
thoracotomy (Barreto 2010). However, ESCC are mostly located
in the upper and middle part of the esophagus, thus operation
via the transthoracic route is mostly performed and associated
with lower pneumonias, anastomotic leaks, wound infections,
strictures, and an improvement in nodal harvest. Survival was
also significantly improved in patients who underwent transthoracic esophagectomy (Takahashi 2021).
Anastomotic Techniques
After esophagectomy for cancer removal, gastrointestinal
continuity is most commonly restored by gastric tube reconstruction with an esophagogastric anastomosis, but colon- or
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jejunum-interposition can also be used as alternatives. Several
anastomotic techniques are available to construct an esophagogastrostomy. When the lowest part of the thoracic esophagus is
resected, an intrathoracic esophagogastric anastomosis high in
the chest is performed (Ivor Lewis procedure) (Lewis 1946). If
a subtotal esophagectomy is performed, a cervical esophagogastric anastomosis is created (McKeown procedure) (D’Amico
2014). Intrathoracic anastomoses are associated with lower
anastomotic leak rates and shorter hospital stay. Reported
factors that may explain include less tissue ischemia due to the
shorter distance the blood supply must travel and less risk of
tension on the anastomosis and further. Some surgeons still
prefer a cervical anastomosis, however, because the sequelae
of cervical anastomotic leakage are claimed to be less severe.
The ICAN trial showed that intrathoracic anastomosis resulted
in better outcome for patients treated with transthoracic minimally invasive esophagectomy for mid to distal EC, but no
upper EC were included in this trial (Van Workum 2021).
Minimally Invasive Surgery
Open esophagectomy (OE) is traditionally performed but associated with considerable morbidity due to its highly invasive
approach. Minimally invasive alternatives using thoracoscopy
and laparoscopy have been increasingly adopted for esophageal
surgery to reduce the physiological stress response to trauma
and postoperative pain to promote recovery. Minimally invasive esophagectomy (MIE) describes an esophagectomy
procedure that avoids the invasiveness of thoracotomy and laparotomy by performing thoracoscopy and laparoscopy instead.
MIE is associated with fewer postoperative pulmonary infections, less blood loss, shorter hospitalization, lower pain scores,
and better quality of life on short terms (Mariette 2019). As no
differences were found in three-year overall and disease-free
survival it suggests that MIE provides short-term advantages
while maintaining oncological standards (Biere 2012).
As the worldwide implementation of MIE has reached an
advanced stage, MIE is a complex procedure with a learning
curve that only reaches a plateau after more than 100 cases. The
thoracoscopic part of MIE is particularly difficult to master,
thus hybrid procedures (either laparoscopy or thoracoscopy)
have been introduced. For surgeons in low-volume centers who
would face challenges in completing their thoracoscopic/laparoscopic learning phase owing to insufficient caseload, this
could be a viable alternative (Mariette 2019).
1 Morbidity and Mortality Outcomes
Outcome reporting after esophageal cancer surgery is heterogeneous. As mentioned earlier, different surgical/anastomotic
techniques have differences in postoperative morbidity and
mortality. The overall incidence of postoperative complications varies widely between 40–65% and includes systemic
complications as well as complications specific to the surgical
procedure (e.g. anastomotic leaks, recurrent laryngeal nerve
injury). Pulmonary complications are the most common
postoperative complications, occurring in 16–40% of patients,
but anastomotic leak is the most dreaded, occurring in 5–30%
of the patients. In Table 5, the outcomes of cornerstone trials
in comparing new surgical techniques versus OE are summarized (Biere 2012; Mariette 2019; Van der Sluis 2019).
A standardized list of complications was only created in
2015, to provide a template for recording individual complications associated with esophagectomy. These quality
parameters were documentation on mortality, comorbidities, completeness of data collection, blood transfusion,
grading of complication severity, changes in level of care,
discharge location, and readmission rates (Low 2015).
Summary
1 For intramucosal ESCC, endoscopic resection (ER) is the standard
treatment. Adjuvant therapy is indicated in tumors with unfavorable pathological characteristics (lymphovascular invasion, poor
differentiation grade) and for incomplete endoscopic resections.
2
Patients with cT1-2 ESCC without nodal involvement qualify for sur-
gery in Asian practice; in the Western world, neoadjuvant treatment
followed by surgery is indicated for T2 or higher and/or N1 cancers.
3
A three-field lymph node dissection is often performed in Asia, but
is not outside Asia given the increased risk of postoperative complications. A transthoracic esophagectomy with two-field nodal dissection is standard treatment in the West.
An intrathoracic anastomosis results in better outcomes compared
4
to a cervical anastomosis for mid to distal esophageal cancer.
5 A standardized list of complications and its definitions was created in
2015. Before that, outcomes were heterogeneous and lacks methodological rigor.
Section 7 Curative Treatment Part II
Worldwide, there are different paradigms in the curative
treatment of ESCC. In general, multimodality treatment offers
the best chance for cure. The European Society for Medical
Oncology (ESMO) and Nation Comprehensive Cancer Network
(NCCN) guidelines recommends neoadjuvant chemoradiotherapy (nCRT) over neoadjuvant chemotherapy (nCT) as
curative therapy for esophageal cancer, as this results in better
local tumor control through high radical resection rates and
better survival (Lordick 2016) (Ajani 2019). In addition to
nCRT, definitive chemoradiation (dCRT) is also a potentially
curative treatment option according to The American Society
of Clinical Oncology (ASCO) (Shah 2020). This is in line with
the recommendation of the Nation Comprehensive Cancer
Network (NCCN) which also prefers neoadjuvant chemoradiotherapy for curable locally advanced esophageal tumors.
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Table 5 An overview of neoadjuvant and adjuvant therapies.
First author
Accural
period
Stages
enrolled Chemotherapy
Radiotherapy Surgery No. of patients Survival P-value
Neoadjuvant chemoradiotherapy vs. surgery alone
Cao (Cao 2009) 1991–
2000
II, III, IV Mitomycin (10 mg/m2)
Cisplatin (20 mg/m
5-FU (500 mg/m
2
2
) x 5
) x 5
40 Gy TTE 116 87 3y-OS:
× 2 cycles
2
)
Bosset (Bosset
1997)
Yang (Yang
2018)
1989–1995 I, II Cisplatin (80 mg/m
x 2 cycles
2007–2014 IIB, III Cisplatin (75 mg/m
Vinorelbin (25 mg/m
37 Gy TTE 143 139 MST: 18.6 moMST: 18.6 mo0.78
2
)
40 Gy TTE 185 227 MST: 100.1 moMST: 66.5 mo0.025
2 × 2
)
x 2 cycles
Hagen (Van
Hagen 2012)
2004–2008 I, II, III Carboplatin (AUC 2 mg/
ml)
Paclitaxel (50 mg/m
2
)
41.4 Gy TTE and
THE
168 186 MST: 49.4 moMST: 24
x 5 cycles
2
Lee (Lee 2004) 1999–2002 II, III Cisplatin (60 mg/m
5-FU (1000 mg/m
)
45.6 Gy TTE 35 48 MST: 28.2 moMST: 27.3 mo0.69 study
2
)
x 2 cycles
Neoadjuvant chemoradiotherapy vs. neoadjuvant chemotherapy
Wang (Wang
2021)
2017–2018 I, II, III Cisplatin (25 mg/m
Paclitaxel (50 mg/m
40 Gy TTE and
2
)
114 108 1y-OS:
THE
2
)
x 2 cycles
Neoadjuvant doublet chemotherapy vs. triplet chemotherapy
2
Kato (Ken 2022) 2012–2018 IB, II, III Cisplatin (80 mg/m
5-FU (800 mg/m
or
Cisplatin (75 mg/m
5-FU (750 mg/m
Docetaxel (70 mg/m
)
2
2
- - 199 202 3y-OS:
)
2
)
)
2
)
Neoadjuvant chemotherapy vs. adjuvant chemotherapy
Ando (Ando
2012)
2000–2006 II, III Cisplatin (80 mg/m2)
5-FU (800 mg/m
2
)
- TTE Pre-op
149
Post-op
157
Pre-op
5y-OS:
x 2 cycles
Adjuvant chemotherapy vs. surgery alone
Zhang (Zhang
1995–2012 II, III, IV Different regimens - THE 887 1160 Not stated Not stated 0.25
2014)
TTE: transthoracic esophagectomy; THE: transthoracic esophagectomy; MST: median survival time; OS: overall survival.
73.3%
87.1%
72.1%
55%
3y-OS:
53.4%
mo
1y-OS:
82.6%
62.6% 0.006
Post-op
5y-OS:
43%
< 0.005
0.003
stopped
0.30
0.004
Whereas the preoperative treatment in the West preferably
consists of a combination of chemotherapy and radiotherapy,
the Asian guideline edited by the Japan Esophageal Society prefers chemotherapy alone followed by radical resection, based
on concerns about higher postoperative complication rates
(Kitagawa 2019).
Neoadjuvant Therapy
i Neoadjuvant Chemoradiotherapy
The neoadjuvant combination of chemotherapy and radiotherapy aims to achieve improved local and systemic disease
control, while exploiting the potent radiosensitizing properties
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of several chemotherapeutic agents (Wilson 2006). Numerous
studies comparing nCRT followed by surgery with surgery
alone in patients with ESCC have been reported.
A Chinese study investigated the effect of neoadjuvant
chemotherapy (mitomycin, cisplatin and 5-FU), neoadjuvant radiotherapy (40 Gy), nCRT (using the same cytostatics with concurrent 40 Gy irradiation) or surgery
alone on survival in patients with locally advanced ESCC
(Cao 2009). This study showed a significantly higher
three-year survival both in patients treated with radiotherapy (69%) and in those treated with chemoradiotherapy (74%) before surgery, compared to chemotherapy
(57%) and surgery alone (53%). However, one-year and
five-year survival rates did not differ between these four
groups. The suboptimal power of the study complicates
correct interpretation and implementation of these data.
Notwithstanding these inconclusive study results, there
have been many studies which investigated survival in patients
treated with neoadjuvant chemoradiotherapy followed by
surgery compared to surgery alone. In 1997, a French study
group conducted a multicenter, randomized trial comparing
nCRT (cisplatin with concurrent 37 Gy irradiation) plus
surgery with surgery alone in patients with stage I-II ESCC
(Bosset 1997). This study showed a prolonged disease-free
survival (DFS) and longer interval free of local disease (RR =
0.6, 95% CI 0.4–0.9, p = 0.003), but overall survival (OS)
was not improved. Postoperative mortality was higher in
the nCRT group compared to surgery alone (12% vs. 3.6%),
mostly due to respiratory insufficiency and mediastinal infection or sepsis. Another study group performed a randomized
trial comparing a different nCRT regimen (vinorelbine and
cisplatin with concurrent 40 Gy irradiation) plus surgery with
surgery alone (Yang 2018). The primary endpoint OS was significantly improved in patients treated with nCRT and surgery
over surgery alone (median 100.1 vs. 66.5 months). Also DFS
was longer in patients treated with neoadjuvant chemoradiotherapy (median 100.1 vs. 41.7 months). Contrary to the
French trial, postoperative mortality did not differ between
both treatment arms. The CROSS study from a research group
from the Netherlands randomly assigned patients with resectable esophageal cancer to receive surgery alone or weekly
administration of carboplatin (AUC 2mg/ml) and paclitaxel
(50 mg/m2) for 5 weeks with concurrent 41.4 Gy radiotherapy
(in 23 fractions, 5 days per week), followed by surgery (Van
Hagen 2012). The updated results after reaching 10-year follow-up data showed better OS in ESCC patients treated with
nCRT plus surgery (46%) compared to surgery alone (23%)
(p = 0.061) (Eyck etal. 2021b). Despite the positive effect of
chemoradiotherapy on synchronous locoregional plus distant
relapse (13% vs. 22%), isolated distant relapse was comparable
between both treatment groups (27% vs. 28%). Of 178 patients
in the chemoradiotherapy plus surgery arm, 8 patients died
related to treatment and of 188 patients in the surgery arm, 7
patients died related to treatment.
Contradictory to these results, a Korean study in patients
with stage II-III ESCC showed an excessive locoregional
failure rate in patients treated with neoadjuvant chemoradiotherapy (cisplatin, 5-FU with concurrent 45.6 Gy irradiation
compared to surgery alone (22% vs. 12%, p = 0.31)) (Lee
2004). Therefore, the authors conclude that neoadjuvant
chemoradiotherapy provided no survival benefit for resectable ESCC. Remarkably, the majority of patients in this study
did not undergo surgery, resulting in an unexpectedly high
drop-out rate for surgery of 31%. This may be an explanation
for these unexpected findings which are opposite to other
neoadjuvant chemoradiotherapy trials where approximately
80% of patients underwent surgery after chemoradiation.
A multicenter randomized clinical trial performed between 2017 and 2018 in China compared safety and efficacy of nCRT with neoadjuvant chemotherapy followed
by minimally invasive esophagectomy (MIE) in patients
with potentially curable ESCC (Wang 2021). The chemotherapy, based on paclitaxel (50 mg/m2) and cisplatin (25
mg/m2), was administered to both groups, while 40 Gy
of concurrent radiotherapy was added for the neoadjuvant chemoradiotherapy group. One-year overall survival
was 87.1% in the neoadjuvant chemoradiotherapy group
and 82.6% in the neoadjuvant chemotherapy group
(p =0.30). Postoperative morbidity, mortality and complications did not significantly differ between both groups.
In summary, several studies with all different chemotherapy and radiotherapy regimens have shown the positive
effect of nCRT plus surgery on survival in ESCC patients as
compared to surgery alone. The various nCRT regimens have
not been compared head-to-head, and the fact that the Dutch
CROSS regimen is favored in large parts of the Western world
is mostly explained by its low toxicity rates and the absence of
a negative effect on postoperative mortality.
ii Chemotherapy with Concurrent Proton-based
Radiation
Over the past decades, multiple studies focused on protonbased radiation in combination with chemotherapy for esophageal cancer. Proton-based radiotherapy provides dosimetric
sparing of vital structures and organs surrounding the tumor
which could potentially result in less radiation-related toxicities and postoperative complications. A recent randomized
phase-II trial compared total toxicity burden and PFS between
proton beam therapy (PBT) and intensity-modulated radiation (IMRT) in patients with esophageal cancer (Lin 2020).
Patients were randomly assigned to PBT or IMRT (50.4 Gy).
Total toxicity burden (TTB) consisted of the cumulative
adverse events severity experienced by patients. Patients
receiving IMRT experienced an average TTB score that was
2.3 times higher than PBT (39.9 vs. 17.4). The mean postoperative complication score was 7.6 times higher for patients
treated with IMRT compared to PBT (19.1 vs. 2.5). No statistically differences were seen in PFS, OS or quality of life (based
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on EQ-5D). This study support treatment toxicity benefit of
PBT compared to IMRT. However, further validation of these
results is required within a phase-III trial to see whether OS
after treatment with PBT is non-inferior to IMRT.
iii Neoadjuvant Chemotherapy
In Japan, (neo)adjuvant chemotherapy (nCT) is considered
to be standard of care for esophageal cancer patients, in part
explained by concerns about postoperative mortality following nCRT. Followed by a three-field lymphadenectomy,
patients treated with nCT have non-inferior oncological outcomes compared to treatment strategies including irradiation. The JCOG1109 trial compared doublet and triplet
chemotherapy and chemoradiotherapy in patients with
ESCC stage IB-III, including overall survival as primary endpoint (Ken 2022). Patients were randomly assigned to neoadjuvant doublet chemotherapy (cisplatin 80 mg/m
1, 5-FU 800 mg/m
motherapy (docetaxel 70 mg/m
2
m
on day 1 and 5-FU 750 mg/m2 on day 1–5 Q3W/3 course)
or chemoradiotherapy (cisplatin 75 mg/m
1000 mg/m
2
on day 1–5 Q3W/2 course), triplet che-
2
on day 1–4 Q4W/2 course with concurrent 41.4
2
on day 1, cisplatin 70 mg/
2
2
on day
on day 1, 5-FU
Gy radiation). The three-year overall survival was significantly increased in patients treated with triplet chemotherapy compared to doublet chemotherapy (72.1% vs.
62.6%, HR 0.68; 95% CI 0.50–0.92, p = 0.006) with no
significant difference in toxicity. As a result of this trial,
triplet chemotherapy could be considered as potential neoadjuvant regimen for patients with locally advanced ESCC.
While neoadjuvant chemoradiation treatment predominates in Western countries, the place for nCT remains uncertain. Efforts have been made to establish whether neoadjuvant
chemotherapy should be preferred over adjuvant chemotherapy. Theoretically, because of the adverse effect of esophagectomy on patient’s condition, more patients may be able
to complete a neoadjuvant treatment compared to an adjuvant one. Moreover, administering chemotherapy while the
primary tumor is still in situ enables response evaluation and
assessment of pathological tumor regression, which can be
helpful in treatment decisions moving forward. The Japanese
study group of Ando etal. initiated a randomized controlled
trial to evaluate the optimal timing for perioperative chemotherapy, that is, before or after surgery (Ando 2012). Patients
with ESCC clinical stage II/III, excluding cT4, were
randomized to undergo surgery followed by adjuvant chemotherapy or neoadjuvant chemotherapy followed by surgical resection. Chemotherapy consisted of two courses of
cisplatin (80 mg/m
2
) on day one and 5-FU (800 mg/m2 per
continuous infusion) over days 1–5×2 courses with a threeweek interval. Primary endpoint was progression-free
survival (PFS), measured from the date of randomization to
the date of first evidence of relapse or death due to any cause.
The primary endpoint did not reach statistical significance,
but the five-year OS in patients treated with nCT was
superior to that with adjuvant chemotherapy (55% vs. 42%,
HR 0.73, 95% CI 0.54–0.99, p = 0.04). No difference was
described in postoperative morbidity between the two
groups. There are several possible reasons to explain the
better OS in patients treated with neoadjuvant chemotherapy. First, neoadjuvant chemotherapy can lead to tumor
down-staging as shown by the equivalent amount of patients
with clinical stage II ESCC at baseline compared to higher
proportion of pathological stage II ESCC or lower in this
group. In addition, R0 resection was slightly more frequent
in the group of patients treated with neoadjuvant chemotherapy. Third, completion of the full chemotherapy regimen
was much better in the neoadjuvant chemotherapy group
(85.4% vs. 75%, p = 0.04). Hence, optimal timing of treatment
with chemotherapy seems to be before surgical resection.
However, a letter to the authors rightly noted that in the
adjuvant treatment arm, only node-positive patients were
treated with chemotherapy, while in the neoadjuvant
treatment arm both node-positive and node-negative
patients were treated (Ajani and Swisher 2012). Because of
this imbalance in treatment arms, drawing a conclusion
about the timing of chemotherapy remains challenging.
Adjuvant Therapy
Very few meta-analyses or reviews have been published on the
value of adjuvant CT for ESCC, a strategy which is more commonly used in the East than in the West. Not only are Westernoriented guidelines more reluctant to make a recommendation
about adjuvant chemotherapy in esophageal cancer (ESMO,
NCCN, ASCO), the evidence in Asian guidelines are only showing recommendations based on weak evidence (Ajani 2019;
Kitagawa 2019; Lordick 2016; Shah 2020).
An Asian study group performed a meta-analysis of randomized
controlled trials and non-randomized studies in 2014, including
2047 patients (Zhang 2014). All studies compared surgery plus
adjuvant chemotherapy with surgery alone in patients with
resectable ESCC. The regimen of cisplatin plus 5-FU was predominantly used with cisplatin dose ranging from 70 mg/m2 to
120 mg/m2, in varying but mostly three-weekly schedules. The
studies were also heterogeneous in their predominant surgical
technique, as both two-field and three-field lymphadenectomies
were performed. There was no statistically significant benefit in
three-year OS for adjuvant chemotherapy (RR = 0.89, 95% CI
0.72–1.09; p = 0.25); an effect was seen on 1-year DFS (RR = 0.68,
95% CI 0.51–0.89; p= 0.006) but not on three-year DFS (RR =
0.97, 95% CI 0.73–1.29; p = 0.84). This may be explained by the
fact that the effect of chemotherapy can extinguish over time.
The benefit of adjuvant immunotherapy has been proven in
the randomized controlled CheckMate 577 trial (Kelly 2021).
Patients with resected (R0) stage II or III esophageal or gastroesophageal junction cancer who had received nCRT and had
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residual pathological disease were given nivolumab (at a dose
of 240 mg every 2 weeks for 16 weeks, followed by nivolumab at
a dose of 480 mg every 4 weeks) or placebo. The median disease-free survival was significantly longer in patients who
received nivolumab (22.4 months versus 11.0 months; p<0.001).
This treatment strategy is already available in many regions
even before the long-term results has been published.
Denitive Chemoradiotherapy
Definitive chemoradiation (dCRT) has been the mainstay for the
non-operative management of localized esophageal cancer after
several RCTs revealed its superiority to radiation alone, and it
represents a standard of care in both Europe and the US. Patients
may be considered unfit for surgical resection due to overall
frailty or cardiopulmonary comorbidities, since surgery is associated with substantial perioperative complications. Furthermore,
dCRT constitutes the treatment of choice for tumors (usually
SCC) of the cervical esophagus, where radical surgery requires
concomitant removal of the larynx and is associated with a
chronically elevated risk of aspiration and severe impact on
quality of life (Allum 2011). dCRT is also used in the management
of advanced locoregional disease, including potentially resectable (T4a) and unresectable (T4b) primary disease (Jeene 2018).
According to the ESMO guideline, dCRT consisting of
cisplatin/5-FU combined with radiation doses of 50.4 Gy in
fractions of 1.8 Gy is regarded as standard, while alternatively
six cycles of FOLFOX can be given (Lordick 2016). The NCCN
panel prefers the combination of paclitaxel and carboplatin for
dCRT, as well as the combination of FOLFOX and 5-FU plus
cisplatin, although FOLFOX alone is associated with less treatment-related adverse events (Ajani 2019). The ASCO and the
Asian guidelines both do not favor any treatment regimen for
dCRT (Kitagawa 2019; Shah 2020).
dCRT has not been directly compared to nCRT or chemotherapy plus surgery in patients with resectable tumors. Therefore,
in patients with a potentially resectable tumor but concerns about
the feasibility of major surgery given a frail condition or significant
comorbidities, the optimal choice of therapy should be weighed
on an individual patient basis (Table 6).
The RTOG 85–01 trial randomly assigned 123 patients (88%
with squamous histology) with T1-3N0-1M0 tumors to receive
either dCRT or radiotherapy alone (Cooper 1999). CRT consisted of cisplatin at a dose of 75 mg/m2 on day one and infusional 5-FU at a dose of 1000 mg/m2/24h on days 1–4 repeated
in weeks 1, 5, 8, 11 (four courses) with radiation therapy commencing on day one and consisting of a total dose of 50 Gy in
25 fractions (5 fractions per week, 2 Gy per fraction). The
radiotherapy control arm consisted of a high total dose of 64
Gy, delivered in doses of 2 Gy per fraction. Randomization was
suspended after inclusion of 90 patients, given the results of the
interim analysis which showed statistically different survival
rates in favor of the combined modality therapy arm. A statistically significant five-year OS benefit was seen in favor of CRT
Table 6 An overview of definitive chemoradiotherapy.
Regimen 1 Regimen 2
First
author
Definitive chemoradiotherapy vs. radiotherapy alone
Cooper
(Cooper
1999)
Definitive chemoradiotherapy
Minsky
(Minsky
2002)
Hulshof
(Hulshof
2021)
MST: median survival time; OS: overall survival; PFS: progression-free survival; CT: chemotherapy.
Accural
period
1985–
1990
1995–
1999
2012–
2018
Stages
enrolled Chemotherapy
I, II, III Cisplatin (75 mg/
I, II, III Cisplatin (75 mg/
I, II, III, IV Carboplatin (AUC
2
)
m
5-FU (1000 mg/
2
)
m
x 4 cycles
2
)
m
5-FU (1000 mg/
2
)
m
2 mg/ml)
Paclitaxel (50 mg/
2
)
m
x 6 cycles
Radiotherapy Chemotherapy
50 Gy - 64 Gy 36 58 5y-OS:
64.8 Gy Cisplatin (75 mg/
50.4 Gy Carboplatin (AUC
2
)
m
5-FU (1000 mg/
2
)
m
2 mg/ml)
Paclitaxel (50 mg/
2
)
m
x 6 cycles
Radiotherapie
50.4 Gy 109 109 MST: 13 moMST:
61.6 Gy 130 130 3y-PFS:
No. of
patients
Survival P-value
5y-OS: 0%Not
26%
75%
18.1
mo
3y-PFS:
79%
stated
Not
stated
0.11
102 1 UPPER GASTROINTESTINAL CANCER
https://t.me/medicina_free
(26% vs. 0%). The authors concluded that a combination of
CRT increases the survival compared with radiotherapy alone.
However, the dose of radiation and the choice of chemotherapeutic agents remain a matter of debate, and the guidelines
are not unequivocal about this. Several randomized trials have
attempted to determine the optimal CRT regime for patients
undergoing dCRT. The INT 0123 trial included 236 patients
with cT1-4N0-1M0 esophageal cancer who were treated with
combined-modality therapy, consisting of four-monthly cycles
of 5-FU (1000 mg/m2/24h) and cisplatin (75 mg/m2 bolus day
1) with concurrent 64.8 Gy radiotherapy versus the same chemotherapy regimen with a lower dose of concurrent 50.4 Gy
radiotherapy (Minsky 2002). This study showed no significant
difference in median survival (13.0 vs. 18.1 months), two-year
survival (31% vs. 40%) or locoregional recurrence (56% vs. 52%)
between normal-dose or high-dose therapies. Therefore, the
authors concluded that 50.4 Gy radiotherapy should be considered as standard radiation dose for patients treated with dCRT.
The ARTDECO study investigated the effect of radiation
dose escalation on local tumor control in dCRT for patients
with inoperable and/or unresectable esophageal carcinoma
(Hulshof 2021). Patients were randomly assigned between
standard dose of radiotherapy (50.4 Gy in 1.8 Gy fractions) or
high dose radiotherapy (61.6 Gy in 2.2 Gy fractions) to the primary tumor. The chemotherapy regimen consisted of carboplatin (AUC 2) and paclitaxel (50 mg/m2) in both treatment arms.
The primary endpoint, three-year local PFS, did not statistically differ between both treatment arms in ESCC (75% in the
standard dose arm vs. 79% in the high dose treatment arm).
The absence of a dose effect indicates that the current radiation
dose of 50.4 Gy does not require modification.
Summary
1 Whereas preoperative treatment in the West preferably consists of
chemoradiotherapy, Eastern countries still prefer chemotherapy.
2 Adjuvant therapy is more commonly used in the East than in the
West, but little is known about the true benefit.
3 Definitive chemoradiotherapy is the mainstay for non-operative
management of ESCC, but guidelines are not unequivocal on the
dose of radiation and choice of chemotherapeutic agents.
Section 8 Palliative Treatment
Palliative Treatment
A Chemotherapy
While the benefit of systemic chemotherapy is limited compared to treatment of other malignancies of the digestive
tract, chemotherapy can be a valid option for patients with a
good performance status and metastatic ESCC. The aim is to
prolong survival, improve and maintain quality of life, and
ameliorate disease-related symptoms. Most commonly, a
platinum compound (oxaliplatin, carboplatin, or cisplatin) is
combined with 5-fluorouracil (5-FU), capecitabine or a taxane (Janmaat 2017). This section focuses on established regimens as well as current trends in the use of chemotherapy
for patients with unresectable or metastatic ESCC (Table 7).
i First-line Therapy
Combination of Chemotherapeutic Agents
The most widely studied chemotherapeutic agent is cisplatin, which has been in use since the early 1980s and
forms the basis of many of the combination regimens
used in this disease. The effectivity of cisplatin and
5-fluorouracil (5-FU) has mostly been investigated as
neoadjuvant treatment, but data are also available on
their role in the palliative setting. Studies showed that
the treatment combination of 5-FU with cisplatin
improve response rates compared to cisplatin alone, but
no survival benefit was seen. A randomized phase-II
study in patients with locally advanced or metastatic
ESCC treated with combined cisplatin (100mg/m
day 1) and 5-FU (1000mg/m
2
day 1–5) or cisplatin
2
on
alone was performed in 1997 (Bleiberg 1997). Response
to therapy was determined using radiological and endoscopic diagnostic modalities, the latter of which is not a
standard method to determine response to systemic
therapy in advanced disease. Of 88 included patients,
35% responded to the combination therapy whereas
19% responded to cisplatin alone. The one-year and
two-year survival in the combination therapy arm was
numerically higher (34% and 18%) compared to
patients treated with cisplatin alone (27% and 9%),
respectively. Toxicity was more frequent and more
treatment-related deaths were observed after combined
therapy. Based on the toxicity of the regime, the authors
conclude that combined therapy with cisplatin and
5-FU is not recommended. This is in line with the
results of a randomized phase-II French study, comparing 5-FU (1000mg/m
dose of 100mg/m
2
2
day 1–5) and cisplatin (single
or 20 mg/m2/day spread over 3 hours
for 5 days) with no chemotherapy as palliative therapy
for ESCC (Levard 1998). This study included patients in
the curative setting, who received the chemotherapy
after oncologic primary tumor resection, as well as
patients with unresectable or metastatic tumors. In the
36 patients who did not undergo surgical resection
because of advanced or metastatic disease, median
overall survival was not significantly longer in patients
treated with chemotherapy compared to the control
group (both 12 months). However, significantly more
patients experienced hematological and renal adverse
Table 7 An overview of palliative therapeutic regimens.
https://t.me/medicina_free
5 ESOPHAGEAL SQUAMOUS CELL CARCINOMA 103
Accural
First author
period Therapy Regimen 1 Regimen 2
Dual chemotherapy vs. single chemotherapy
Bleiberg
(Bleiberg
1985–
1989
First-line Cisplatin (100 mg/m
5-FU (1000 mg/m
1997)
Chemotherapy alone
Levard
(Levard
1987–
1992
First-line Cisplatin (100 mg/m
5-FU (1000 mg/m
1998)
Polee (Polee
2004)
Not stated First-line Cisplatin (60 mg/m
Paclitaxel (180 mg/m
PD-1 inhibitors
Sun (Sun
2021)
2017–
2019
First-line Cisplatin (80 mg/m
5-FU (800 mg/m
Pembrolizumab (200 mg)
Rui-hua
(Rui-Hua
2021)
Shen (Shen
2021)
2018–
2020
First-line Cisplatin (75 mg/m
Paclitaxel (175 mg/m
Camrelizumab 200 mg
Not stated First-line Cisplatin (75 mg/m
Paclitaxel (175 mg/m
Sintilimab (200 mg)
Immunotherapeutic agents
Doki (Doki
2022)
2017–
2019
First-line Cisplatin (80 mg/m
5-FU (800 mg/m
Nivolumab (240 mg)
First-line Nivolumab (240 mg)
Ipilimumab (1mg/kg)
EGFR inhibitors
Lorenzen
(Lorenzen
2009)
Moehler
(Moehler
2020)
2004–
2006
2012–
2015
First-line Cisplatin (100 mg/m
5-FU (1000 mg/m
Cetuximab (400 mg/m
First-line Cisplatin (100 mg/m
5-FU (1000 mg/m
Panitumumab (9mg/kg)
Second-line regimens
Dutton
(Dutton
2009–
2011
Second-lineGefitinib (500 mg) Placebo 224 225 MST: 3.73 mo MST:
2014)
Kato (Kato
2019)
Kojima
(Kojima
2016–
2017
2015–
2017
Second-lineNivolumab (240 mg) Paclitaxel (100 mg/m
Second-linePembrolizumab (200 mg) Paclitaxel (80–100 mg/m
2020)
No. of
patients Survival P-value
2
Cisplatin (100 mg/m
)
2
)
2
No chemotherapy 72 84 MST: 20 mo MST: 20 moNot stated
)
2
)
2
- 51 - MST: 9 mo
)
2
)
2
)
2
)
Cisplatin (80 mg/m
5-FU (800 mg/m
2
) 44 44 2y-OS: 27% 2y-OS: 9%Not stated
- N/A
1y-OS: 43%
2
)
2
)
373 376 MST: 13.9 mo MST: 8.8 mo< 0.0001
Placebo
2
)
Cisplatin (75 mg/m
2
)
Paclitaxel (175 mg/m
Placebo
2
)
Cisplatin (75 mg/m
2
)
Paclitaxel (175 mg/m
Placebo
2
)
2
)
Cisplatin (80 mg/m
5-FU (800 mg/m
Cisplatin (80 mg/m
5-FU (800 mg/m
2
)
)
2
)
2
)
)
Cisplatin (100 mg/m
5-FU (1000 mg/m
Cisplatin (100 mg/m
5-FU (1000 mg/m
2
2
2
)
298 297 MST: 15.3 mo MST:
2
)
12.0
0.0010
mo
2
)
327 332 MST: 16.7 mo MST:
2
)
12.5
< 0.0001
mo
2
2
)
2
2
)
2
)
2
)
321 324 MST: 15.4 mo MST: 9.1 mo< 0.0001
)
325 324 MST: 13.7 mo MST: 9.1 mo0.0010
)
2
32 30 MST: 9.5 mo MST: 5.5 mo0.32
)
2
73 73 MST: 9.4 mo MST:
)
0.43
10.2
mo
0.29
3.67
mo
2
210 209 MST: 10.9 mo MST: 8.4 mo0.019
) or
2
Docetaxel (75 mg/m
or Docetaxel (75 mg/m
or Irinotecan (180 mg/m
)
2
)
314 314 MST: 8.2 mo MST: 7.1 mo0.0095
2
)
2
)
(Continued)
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