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Table 7 (Continued)
Accural
First author
Third-line regimens
Kato (Ken
2021)
Shah (Shah
2019)
MST: median survival time; OS: overall survival; ORR: objective response rat
period Therapy Regimen 1 Regimen 2
2014 Third-line Nivolumab (3mg/kg) - 65 - MST: 10.8 mo
2016–
2017
Third-line Pembrolizumab (200 mg) - 121 - ORR: 14.3% - N/A
events as well as polyneuropathy with chemotherapy.
Thus, in this small study, combined 5-FU and cisplatin
did not have benefit over best supportive care. Of note,
both in the 1997 and the French study the cisplatin dose
was higher than what is nowadays commonly used in
palliative chemotherapy combinations. Furthermore,
DPYD (deleterious polymorphisms in the gene encoding dihydropyrimidine dehydrogenase) genotyping to
identify patients at increased risk of 5-FU toxicity was
not implemented in clinical practice. Both these factors
will have affected the rate of adverse events in these
studies.
A phase-II study performed in the Netherlands
in 2002 investigated the efficacy of a bi-weekly
combination of paclitaxel (180 mg/m
(60 mg/m
2
) in patients with metastatic or unresect-
2
) and cisplatin
able adenocarcinoma, undifferentiated- or SCC of
the esophagus or junction (Polee 2002). Patients were
evaluated after three and six cycles and responding patients received a maximum of eight cycles. All
included patients received at least three cycles of chemotherapy. The median survival was 9 months (range
2–29 months), with a one-year survival rate of 43%.
Sensory neurotoxicity was the predominant toxicity;
grade 2 neurotoxicity was seen in 20% of patients. This
study shows that the combination of paclitaxel and cisplatin is relatively well tolerated and has promising efficacy (Polee 2004). A slightly adapted regime of weekly
carboplatin (AUC 4) and paclitaxel (100 mg/m
2
) was
investigated in a phase-I trial, with better tolerance and
equally promising activity. These treatment regimens
were never investigated in a phase-III randomized trial.
Overall, data on palliative chemotherapy for ESCC
are scarce, do not show unequivocal proof for survival
benefit and come from smaller and older trials.
Therefore, best supportive care alone or treatment in a
clinical trial should also be considered as valid treatment
options in the absence of other treatment options such
as immunotherapy.
No. of
patients Survival P-value
- N/A
5y-OS: 6.3%
Chemotherapy Plus PD-1 Inhibitors
As discussed earlier, chemotherapy alone is of limited
effect, and based on its paradigm-changing efficacy in
other solid tumors, the value of immune checkpoint
inhibitors when added to palliative chemotherapy has
been investigated in several large clinical trials. Immune
checkpoint inhibitors, in the form of PD-(L)1 or CTLA4inhibitors, is effective through activation of an antitumor response by the patient’s own immune system.
One of the pivotal trials is the KEYNOTE-590 trial,
which is a randomized phase-III study investigating firstline chemotherapy with or without pembrolizumab for
advanced unresectable or metastatic esophageal cancer
(Sun 2021). This study included 749 patients, of whom
almost 75% had ESCC. All patients were treated with
pembrolizumab (200 mg) or placebo, plus 5-fluorouracil
(800 mg/m
2
day 1–5) and cisplatin (80 mg/m2 day 1 every
3 weeks), once every 3 weeks for up to 35 cycles. The dual
primary endpoints of this study were OS and PFS, which
were tested according to seven primary hypotheses in all
included patients; those with PD-L1 combined positive
score (CPS) ≥ 10 and ESCC patients OS was superior for
pembrolizumab plus chemotherapy in patients with
PD-L1 CPS ≥ 10 with a median OS of respectively 13.9 vs.
8.8 months (HR 0.57, 95% CI 0.43–0.75). In the other
patient subgroups such as those with adenocarcinomas or
ESCC and PD-L1 CPS < 10, median PFS was increased
but no OS benefit was seen. Addition of pembrolizumab
seems to be particularly effective in the (in this trial) 30%
of patients with ESCC who had a CPS score ≥ 10.
The phase-III ESCORT-1st study investigated the efficacy and safety of camrelizumab plus chemotherapy vs.
chemotherapy alone in patients with untreated advanced
or metastatic ESCC (Rui-Hua 2021). Patients were
randomized to receive camrelizumab 200 mg or placebo,
both combined with 6 cycles of paclitaxel (175 mg/m2)
and cisplatin (75 mg/m2). Primary endpoints were OS
and PFS. With a median follow-up of 10.8 months, camrelizumab plus chemotherapy significantly improved
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OS compared with placebo plus chemotherapy (median
15.3 months vs. 12 months, HR 0.70, 95% CI 0.56–0.88).
Camrelizumab plus chemotherapy showed also superior
PFS compared to placebo plus chemotherapy (median
6.9 months vs. 5.6 months, HR 0.56, 95% CI 0.46–0.68).
Treatment-related adverse events were comparable between both treatment arms. As result of this study, FDA
approval was requested from the China National Medical
Products Administration for camrelizumab plus chemotherapy in untreated advanced or metastatic ESCC.
More recent, the first results of the ORIENT-15 were
published (Shen 2021). This study randomized patients
with unresectable locally advanced, recurrent of metastatic ESCC either to sintilimab (200 mg) or placebo, both
combined with chemotherapy (paclitaxel 175 mg/m2 and
cisplatin 75 mg/m
2
). The primary endpoint was OS in
patients with PD-L1 CPS ≥ 10 and all patients. Secondary
endpoints include PFS and ORR. Sintilimab plus chemotherapy was superior for OS compared to placebo plus
chemotherapy in all patients (median 16.7 months vs. 12.5
months, HR 0.628, 95% CI 0.508–0.777) and patients with
CPS ≥ 10 (median 17.2 months vs. 13.6 months, HR 0.638,
95% CI 0.480–0.848). ORR was 75.5% vs. 56.9% in all
patients and PFS was also superior in patients treated with
sintilimab plus chemotherapy (median 7.2 months vs.
5.7 months, HR 0.558, 95% CI 0.461–0.676, p < 0.0001).
Treatment-related adverse events were similar between
both groups. The results of this trial are promising for firstline treatment with sintilimab plus chemotherapy.
Combination of Immunotherapeutic Agents
Recently, the results of the Checkmate 648 study were
reported. This randomized, open-label phase-III study
was performed in patients with unresectable advanced,
recurrent or metastatic ESCC (Doki 2022). Primary endpoints were OS and PFS in subjects with PD-L1 expressing tumors (≥ 1%). Patients were randomly assigned to
either cisplatin (80 mg/m
2
) and 5-FU (800 mg/m2) in a
4-weekly schedule or to cisplatin, 5-FU plus nivolumab
(240 mg 2qw) or nivolumab (same dose) plus ipilimumab (a CTLA-4 inhibitor, at 1mg/kg q6w). Superior OS
was seen in patients with tumor cell PD-L1 ≥ 1% treated
with chemotherapy plus nivolumab (median 15.4
months) compared to CT alone (median 9.1 months)
(HR 0.54, 99.5% CI 0.37–0.80). Patients with tumor cell
PD- L1 ≥ 1% treated with nivolumab and ipilimumab
had significant improved OS as well compared to CT
alone (median 13.7 months vs. 9.1 months respectively,
HR 0.64, 98.6% CI 0.46–0.90). The efficacy of the
combined immunotherapy regimen versus the CT plus
immunotherapy regimen was not compared directly. The
incidence of grade ¾ treatment-related adverse events
was highest in patients treated with CT plus nivolumab,
and numerically lowest in patients treated with dual
immunotherapy, while treatment-related serious adverse
events were numerically more common in the dual
immunotherapy arm. Depending on patient characteristics and assuming positive decisions by the regulatory
agencies, both combinations represent a new potential
standard of care.
Chemotherapy Plus Target Epidermal Growth
Factor Receptor (EGFR)
Recently, studies focused on therapeutic agents that
enhances the antitumor effect of chemotherapy are gaining interest. Agents targeting the EGFR have been successfully implemented in clinical practice for colorectal and
lung cancer. The efficacy of EGFR inhibitors is precluded
to those patients whose tumor is KRAS wild type, as
tumors with a gain-of-function KRAS mutations have a
constitutively active pathway downstream of EGFR. In
2009, the additional effect of cetuximab on tumor response
was assessed in a randomized phase-II trial in patients
with advanced KRAS wild type ESCC who were treated
with either triple therapy (cisplatin, 5-FU and cetuximab)
or dual therapy (cisplatin and 5-FU) (Lorenzen 2009).
Patients received cisplatin (100 mg/m
2
mg/m
at days 1–5) and in case of triple therapy also cetux-
imab 400 mg/m
2
initial dose followed by 250 mg/m2
2
day 1), 5-FU (1000
weekly thereafter. Primary endpoint was tumor response.
Overall response rates were 34% in patients treated with
additional cetuximab and 30% in cisplatin and 5-FU alone,
which is in line with the results of the study of Bleiberg
etal. (Bleiberg 1997). This did not translate into a statistically significant increase in median PFS and OS (respectively 5.9 vs. 3.6 months, p = 0.21 and 9.5 vs. 5.5 months,
p = 0.32). In conclusion, cetuximab may increase the
response rate of treatment with cisplatin and 5-FU chemotherapy, but based on this phase-II study, no definitive
conclusions could be drawn on the effect on survival.
Another German study group investigated the effect of
panitumumab on survival in patients with ESCC that was
neither curatively resectable nor qualified for definitive
chemoradiotherapy (Moehler 2020). Remarkably, KRAS
mutation status was assessed nor used as an inclusion criterion. Patients were randomly assigned to cisplatin (100
2
mg/m
day 1) and 5-FU (1000 mg/m2 per day at days
1–4 of every 3-week cycle) or treatment with combined
cisplatin, 5-FU and panitumumab (9mg/kg on day 1 of
3-week cycle prior to chemotherapy). The trial was terminated prematurely because of high early mortality
rate (within 30 days after randomization) as well as an
increased frequency of therapy-related serious adverse
events in the panitumumab therapy arm and the interim
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analysis that showed significantly higher median overall
survival in favor of the standard therapy arm over panitumumab (HR 1.77, 95% CI 1.06–2.98, p = 0.028). In
the final analysis, median OS was 10.2 versus 9.4 months
for cisplatin/5-FU versus cisplatin/50FU plus panitumumab, respectively (HR 1.17, 95% CI 0.79–1.75; p =
0.43). Serious adverse events grade 5 were seen in 23.6%
of patients treated with panitumumab compared to 4.3%
in patients treated with combined chemotherapy only. In
conclusion, while the addition of cetuximab may increase
response rates, the developments in the anti-EGFR field
for esophageal cancer have largely stopped, owing to its
lack of impact on survival and substantial toxicity.
ii Second-line Therapy
In 2014, a phase-III randomized placebo-controlled trial was
performed among patients with progressive junctional type
I/II Siewert tumors after chemotherapy (Dutton 2014). Both
esophageal adenocarcinomas and squamous cell carcinomas
were included, and no tumor biomarkers were used to select
patient subgroups. Patients were randomly assigned to gefitinib (500 mg), an EGFR-inhibitor, or matching placebo and
treatment continued till disease progression or unacceptable
toxicity occurred. The primary outcome overall survival did
not differ between both groups with a median OS of 3.7
months in both groups (HR 0.90, 95% CI 0.74–1.09, p =
0.29). In a post-hoc analysis, patients with EGFR copy
number gain as determined by FISH or EGFR amplification
did benefit from gefitinib (HR for death 0.59; 95% CI 0.35–
1.00, p = 0.05) (Petty 2017). Unfortunately, no prospective
trial has been published confirming the benefit of gefitinib
in this patient subgroup, and gefitinib has thus not made its
way into clinical practice for esophageal cancer.
In 2019, the efficacy of nivolumab was investigated in the
ATTRACTION-3 trial (Kato 2019). This multicenter, international phase-III trial included patients’ refractory to
previous chemotherapy from both eastern and western
countries. Patients were randomly assigned to either
nivolumab (240 mg for 30 minutes every 2 weeks) or investigator’s choice of chemotherapy (paclitaxel 100 mg/m
2
once per week for 6 weeks then 1 week off; or docetaxel
75mg/m
2
every 3 weeks). In total 48% of patients had PD-L1
expression of whom 30% had a CPS score ≥ 10. A slight
improvement in median overall survival of 2.5 months was
observed in patients who received nivolumab, in comparison
with patients who received chemotherapy (HR 0.77 [95%
CI 0.62–0.96]; p= 0.019). Progression-free survival was not
significantly different between the two treatment arms, and
also PD-L1 expression did not identify patients with greater
benefit. Fewer grade 3 or 4 treatment-related adverse events
were reported in the nivolumab group (18% vs. 63%) which
implicates that treatment with nivolumab is safe and may be
better tolerated than chemotherapy.
Another study in patients with advanced/metastatic
esophageal cancer who had progressed on or after firstline therapy is the KEYNOTE-181 trial (Kojima 2020).
This Asian study group conducted an open-label, phaseIII study in which patients were randomly assigned to
pembrolizumab 200 mg every 3 weeks for up to 2 years or
chemotherapy of investigator’s choice (paclitaxel, docetaxel
or irinotecan). Primary endpoints were OS in patients
with PD-L1 combined positive score (CPS) ≥ 10, in
patients with squamous cell carcinoma, and in all patients.
In patients with PD-L1 CPS ≥ 10, OS was significantly
prolonged with pembrolizumab versus chemotherapy
(median 9.3 vs 6.7 months; HR 0.69, 95% CI 0.52–0.93; p
= 0.0074). In patients with ESCC (64%), the primary endpoint median OS was slightly in favor of treatment with
pembrolizumab (8.2 vs. 7.1 months, HR 0.78, 95% CI
0.63–0.96, p = 0.0095). However, in all patients, the median
OS was not statistically different between the pembrolizumab group and chemotherapy group, both 7.1 months
(HR 0.89, 95% CI 0.75–1.05; p = 0.0560). In conclusion,
pembrolizumab showed survival benefit versus chemotherapy as second-line therapy for advanced esophageal
cancer in patients with PD-L1 CPS ≥ 10.
iii Third-line Therapy
The ATTRACTION-1 multicenter phase-II trial conducted in Japan evaluated the activity and safety of
nivolumab in patients with advanced ESCC refractory or
intolerant to fluoropyrimidine-, platinum- and taxanebased chemotherapy (Ken 2021). Patients were treated
with 3mg/kg nivolumab every 2 weeks in 6-week cycles
until disease progression or toxicity. The primary endpoint was ORR and the secondary endpoint included OS.
After a minimum follow-up of 5 years, 11 out of 64 patients
had an objective response (17.2%, 95% CI 9.9–28.2). The
median OS was 10.8 months (95% CI 7.4–13.9) and the
estimated 5-year OS was 6.3% (95% CI 2.0–14.0). PFS at
5-years was 6.8% (95% CI 2.2–15.1). Diarrhea and rash
occur with a frequency of > 10%. This study shows
nivolumab as potential third-line treatment option.
Another phase-II study, the KEYNOTE-180, enrolled
patients with advanced, metastatic esophageal cancer that
progressed after two or more lines of therapy (Shah 2019).
Patients were treated with pembrolizumab 200 mg every 3
weeks until disease progression or unacceptable toxic
effects, for up to 2 years. Primary endpoint was ORR.
Median duration of follow-up was 5.8 months. The ORR
was 9.9% (95% CI 5.2–16.7) in all patients and 14.3% (95%
CI 6.7–25.4) among patients with ESCC. Only 12.4% of
patients had treatment-related adverse events grade 3–5.
This study shows the durable antitumor effect of pembrolizumab with manageable safety in pretreated patients
with esophageal cancer.
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Radiotherapy
Radiotherapy alone has a modest role in the radical management
of locally advanced ESCC and is usually reserved for patients who
are not considered good candidates for surgery or chemotherapy.
If curative treatment is no longer an option due to the extent of
the disease, palliative radiotherapy can be useful to relief symptoms (dysphagia and pain) and to improve patients’ quality of life.
External-beam Therapy
The use of external-beam radiotherapy is established in the
setting of inoperable disease where, at doses of 20 Gy in 5 fractions or 30 Gy in 10 fractions, it can effectively palliate dysphagia
and pain. Fractionated external-beam radiotherapy often causes
swelling first with increase of dysphagia as a result, followed by
sustained relief of dysphagia when swelling decreases.
Although fractioned external-beam radiotherapy is widely
used, data on its efficacy is scarce. In 2012, a retrospective
review was performed in patients with esophageal cancer
unsuitable for radical treatment who underwent external beam
radiotherapy (Murray 2012). In total 93% of patients complained of dysphagia prior to radiotherapy. Almost all patients
were treated with 20 Gy external-beam radiotherapy in 5 fractions. Improvement in dysphagia was seen in 75% of patients
and 31% of patients received additional therapy for palliation.
External-beam radiotherapy was well tolerated with 2 patients
(1%) failing to complete the full regimen and hospitalization in
only 5 patients (3%) with no treatment-related death. The
POLDER study group investigated the effect of short-course
external beam radiotherapy compared to intraluminal brachytherapy for palliation of dysphagia (Jeene 2020). Improvement
of dysphagia was observed in 83% after external beam therapy
versus 64% after brachytherapy (p = 0.048) and severe toxicity
occurred in 3% and 13%, respectively. The authors therefore
conclude that external beam therapy is at least as effective as
brachytherapy in the palliation of dysphagia.
Another study from Australia randomly assigned patients with
advanced or metastatic esophageal cancer to either palliative chemoradiotherapy or radiotherapy alone for treatment of malignant dysphagia (Penniment 2018). Primary endpoint was dysphagia relief at
nine weeks and maintenance four weeks later. Complete dysphagia
relief was obtained in 26 (24%) of patients treated with radiotherapy
alone compared to 32 (29%) of patients treated with chemoradiotherapy (p = 0.44). Grade 3–4 toxicity occurred less frequent in
patients treated with radiotherapy (16%) compared to chemoradiotherapy (36%) (p = 0.0017). Therefore, the authors conclude that
radiotherapy alone should be considered a safe and well tolerated
treatment option for patients with malignant dysphagia.
In conclusion, external-beam should be considered as safe
and well tolerated palliative treatment option for patients with
malignant dysphagia. In the same context, endoluminal brachytherapy constitutes an acceptable alternative.
Brachytherapy
Brachytherapy involves endoscopic placement of a radioactive applicator into the esophagus. During endoscopy, the
upper and lower tumor borders are marked and dilatation
of the malignant stricture could be performed with caution
to perforation. This allows treatment with a high radiation
dose to a localized area of the esophagus, sparing surrounding structures as much as possible. The European Society for
Medical Oncology (ESMO) guideline recommends singledose brachytherapy after external radiotherapy since it provides better long-term relief of dysphagia (Lordick 2016). The
Asian guideline edited by the Japan Esophageal Society concludes that brachytherapy is scarcely performed in Japan and
therefore results of several studies have no direct implication
for clinical practice (Kitagawa 2019).
In 2017, an Italian study group performed a systematic
review to determine the efficacy and safety of brachytherapy in
patients with malignant dysphagia (Fuccio 2017). Results of
623 patients were analyzed regarding dysphagia-free survival
and adverse event rates. The authors conclude that brachytherapy was highly effective, resulting in six months dysphagia-free
survival of 47.4% (95% CI 38.5–56.5). Despite the severe
adverse event rate of 22.6% with the main reported adverse
events brachytherapy-related stenosis (12.2%) and fistula
development (8.3%), it appears to be a relatively safe treatment
option which is currently underused. Most applied radiation
doses range from 12 Gy up to 21 Gy, however, the best radiation
dose to palliate dysphagia remains uncertain. In addition, a
randomized trial from the Netherlands compared stent
placement or single-dose (12 Gy) radiotherapy in inoperable
esophageal cancer patients with dysphagia (Homs 2004). This
study showed rapidly improved dysphagia after stent placement
compared to brachytherapy, however, long-term relief of dysphagia was better after brachytherapy and also was associated
with less complications (33% vs. 21%; p = 0.02). No difference
was seen in persistent or recurrence dysphagia or median
survival between both groups. The authors therefore conclude
that brachytherapy should be considered as primary treatment
for palliation of dysphagia in patients with an expected survival
of more than three months. Despite the benefits of brachytherapy, there are pitfalls too including the risk of esophagitis, stricture and fistula as well as patients’ commitment to multiple
treatments. In the future, results from a large multicenter prospective study comparing external-beam and intraluminal
radiotherapy are expected.
Best Supportive Care
The decision to offer palliative therapy or best supportive care
could depend on the patient’s performance status according to
the Eastern Cooperative Oncology Group Performance Status
Scale (ECOG PS) or the Karnofsky Performance Status Scale
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(KPS). Best supportive care is focused on preventing or
relieving symptoms instead of trying to cure esophageal cancer or to prolong life. In case of pain or physical discomfort,
analgesics could be used. If food passage through the esophagus is no longer possible due to progressive disease in patients
with short life expectancy, food intake could be restored by
placement of an esophageal stent. For palliation of malignant
dysphagia fully or partially covered expandable metal stents
made of nitinol are recommended and can be placed across
the length of the tumor using endoscopy. Although its fast
improvement of dysphagia symptoms, it can also lead to symptoms such as reflux and chest pain.
Summary
1 The aim of palliative chemotherapy is to prolong survival and main-
tain quality of life, but its benefit is limited.
2 First-line, second-line and third-line therapy could consist of
combined chemotherapeutic agents, chemotherapy plus PD-1 inhibitors/epidermal growth factor receptor or combined immunotherapeutic agents.
3
Palliative radiotherapy alone could be considered in patients not fit for
surgery and can be useful to relief symptoms as dysphagia and pain.
4 Best supportive care, including esophageal stenting or analgesics
are used to prevent or relieve symptoms instead of cure esophageal
cancer or prolong life.
Section 9 Targeted Therapy and
Immunotherapy
Targeted Therapy
With the identification of new biomarkers for esophageal cancers (EC), targeted therapies are gaining interest. Potentially targetable pathways in EC includes human epidermal growth factor
receptor 2 (HER2, Neu, ErbB2), the epidermal growth factor
receptor (EGFR, Her1, ErbB1), the vascular endothelial growth
factor (VEGF) and the mesenchymal-epithelial transition (MET)
factor (Table 8).
HER2
HER2 is a tyrosine kinase that localizes to the cell membrane
and conducts extracellular-intracellular signaling to regulate
cell growth and differentiation, as well as the development of
cancer. For adenocarcinoma, trastuzumab is the primary
therapeutic drug targeting HER2 and part of the standard firstline treatment for HER2-positive gastroesophageal junction
(GEJ). In the phase III JACOB trial, another HER2 targeted
agent pertuzumab was added to trastuzumab plus chemotherapy for the treatment of metastatic HER2-postive adenocarcinoma of the GEJ or stomach and in a Chinese and Japanese
subpopulation analysis of this trial, overall survival was
Table 8 Clinical trials of targeted therapies for ESCC.
First author Type of study Study population Targeted therapy In combination with Results
HER
Guo (Guo 2018) Lapatinib / Preclinical Paclitaxel Synergistic antitumor
activity
EGFR
Zhang (Zhang 2019) Nimotuzumab Metastatic ESCC (Fist line) Phase II Paclitaxel and Cisplatin Median PFS 6.6–18.1mo
MST 11.5–26.2mo
Xu (Xu 2016) Gefitinib ESCC (Second line) Phase II None Median PFS 2.2 mo
MST 6.1 mo
Huang (Huang 2016) Icotinib ESCC Phase II / Median PFS 52 days
MST 153 days
VEGF/VEGFR
Chang (Chang 2013) Endostar / Preclinical Paclitaxel +
Cisplatin
Li (Li 2019) Apatinib ESCC Phase II Docetaxel Median PFS 175 days
Huang (Huang 2021) Anlotinib ESCC (second line) Phase II None Median PFS 3.02 mo
Abbreviations: ESCC: Esophageal squamous cell carcinoma; PFS: Progression free survival; MST: Median survival time.
Inhibitory effect on
ESCC
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numerically but not statistical significantly improved by
addition of pertuzumab. The same evidence for ESCC, however,
has not been established. Lapatinib on the other hand, a smallmolecule inhibitor of EGFR and HER2, was proven to have
highly synergistic effect on inhibiting cell proliferation in vitro
and significantly reduced the invasion and migration of ESCC
cells in combination with paclitaxel (Guo 2018). The clinical
evidence of HER2’s role in patients with ESCC is yet to be
explored.
EGFR
EGFR (Her1, ErbB1) is a receptor tyrosine kinase that belongs
to the ErbB family which includes three other members (ErbB2/
HER2/Neu, ErbB3/HER3, and ErbB4/HER4). Activation of
EGFR leads to phosphorylation of the receptor which then
activates several downstream effectors, such as the RAS-RAFMEK-ERK-MAPK and the PI3K- AKT-mTOR pathways. In EC,
the efficacy of EGFR inhibitors is precluded to those patients
whose tumor is KRAS wild type, as tumors with a gain-offunction KRAS mutations have a constitutively active pathway
downstream of EGFR. An FDA approved anti-EGFR agent is
cetuximab, used to treat patients with advanced metastatic colorectal cancer. Several studies suggested that adding cetuximab
to other treatments (such as radiotherapy or chemotherapy) can
improve survival outcomes in ESCC. (For details see previous
Section First-line treatment.) Nimotuzumab, on the other
hand, is a fully recombinant, humanized monoclonal antibody
against EGFR. It is the first monoclonal antibody in China used
to treat malignant tumors, such as head and neck cancers. In
comparison with conventional chemotherapy, nimotuzumab
achieved significant anticancer effect with tolerable toxicity for
metastatic ESCC (Zhang 2019). The same limited evidence of
potential treatments for ESCC has been found for gefitinib and
icotinib, both showed promising results in phase II trials (Xu
2016) (Huang 2016). Although EGFR inhibitors could develop
into a vital candidate for treating ESCC, further research on the
clinical implications are needed.
cisplatin or other chemotherapy drugs to treat small cell lung
cancer, but effects on ESCC have only been studied in animal
models (Chang 2013). Apatinib and anlotinib, both with VEGFR
inhibition effects, have undergone phase II trials showing beneficial effects on progression free survival. Anlotinib monotherapy was included in the 2019 version of the Chinese Society of
Clinical Oncology (CSCO) – EC guidelines as a second-line and
beyond treatment for ESCC (Li 2019) (Huang 2021).
MET
The tyrosine protein kinase MET is a receptor for the hepatocyte growth factor (HGF) and interaction between those two
leads to tumor cell growth, invasion and metastasis. Agents
such as AMG102, AMG331 and Onartuzumab failed to demonstrate any survival benefits in EC patients, but further
research is required to better elucidate which patient populations may potentially benefit from this therapy.
Immunotherapy
Diagnosis of ESCC typically occurs in patients with locally
advanced unresectable or metastatic disease, when palliative chemotherapy is the primary treatment option, but five-year survival
rates can be as low as 5%. Better systemic therapies are an urgent
call in the treatment landscape of ESCC. Immunotherapy is a
strategy to enhance the efficacy and specificity of the immune
cells to suppress cancer progression (Figure 9). In the treatment
of EC, immune checkpoint inhibitors which can bind to protein receptors on the surface of T cells or tumor cells to prevent
tumor cells from immune escape, is a hot research area. The
programmed cell death protein 1 (PD-1) pathway is considered
one such important inhibitory mechanism and programmed cell
death-ligand 1 (PD-L1) inhibitors are considered effective drugs
to address cancer cell evasion of T cells.
Camrelizumab (See First Line Therapy in
Section 8)
VEGF
As regulators of angiogenesis, VEGFs play an important role in
the proliferation and angiogenesis of vascular endothelial cells.
The evidence of the efficacy of well-known VEGF inhibiting
agents such as bevacizumab and ramucirumab are limited to
patients with EAC or GEJ. Targeting ESCC, Chinese scientists
developed a novel recombinant human endostatin Endostar,
which has found effective in suppressing angiogenesis and
tumor growth. Endostar has been approved by the China Food
and Drug Administration (CFDA) for use with
Camrelizumab is a humanized anti-PD-1 monoclonal antibody
independently developed in China. One of the pivotal trials is
the KEYNOTE-590 trial, which is a randomized phase-III
study investigating first-line chemotherapy with or without
pembrolizumab for advanced unresectable or metastatic
esophageal cancer. The phase-III ESCORT-1st study investigated the efficacy and safety of camrelizumab plus chemotherapy vs. chemotherapy alone in patients with untreated
advanced or metastatic ESCC. The survival benefit was revealed
across all strata, irrespective of programmed cell death ligand 1
(PD-L1) expression.
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Advanced/metastatic
Second lin
ESCORT-1st
Camrelizumab + CT
CheckMate
648
Nivo + CT
ESCC
Figure 9 Summary of immunotherapy treatment trials for ESCC. Abbreviation: Nivo=Nivolumab; CT=Chemotherapy; IPI=Ipilimumab; Mono=
Monotherapy; Sinti=Sintilimab; Pembro=Pembrolizumab.
Nivo + IPI
KEYNOTE-590 ATTRACTION-3
Pembro + CT
ORIENT-15
Sinti + CT
Nivo mono
KEYNOTE-181
PEMBRO mono
ATTRACTION-1
Nivo mono
hird lineFirst line
KEYNOTE-180
Pembro mono
Pembrolizumab (See Second Line Therapy in
Section 8)
Pembrolizumab is approved by the FDA for the treatment as a
second line option for PD-L1 positive ESCC, based on the
KEYNOTE-180 phase II and KEYNOTE-181 phase III trials.
In the first-line setting, the addition of pembrolizumab to chemotherapy was investigated in the KEYNOTE-590 trial, in
which 73% of the patients had ESCC. This trial demonstrated
that the addition of pembrolizumab to chemotherapy in this
group prolonged overall survival in all subgroups, but this was
most pronounced in the PD-L1 CPS >10 group (from 8.8 to
13.9 months). In Europe, the EMA has registered pembrolizumab for this PD-L1 high subgroup only.
Nivolumab (See Palliative Treatment in
Section 8 and Adjuvant Therapy in Section 7)
Nivolumab has been approved for a variety of metastatic or locally
advanced tumors, including ESCC. In the phase III CheckMate
648 trial focused on ESCC, the overall survival advantage with
nivolumab plus chemotherapy vs chemotherapy alone was 15.4
vs. 9.1 months in patients with tumor-cell PD-L1 expression of
1 or greater. In all randomized patients, the beneficial effect of
nivolumab was less pronounced (13.2 vs 10.7 months). A third
group receiving only nivolumab plus ipilimumab (dual checkpoint inhibition) had likewise favorable results, but was not
directly compared to the chemotherapy plus nivolumab arm. In
patients with a specific contra-indication for chemotherapy but
overall good performance, this does give the option of a chemotherapy-free treatment. Moreover, nivolumab administered as
adjuvant treatment following neoadjuvant chemoradiation and
complete surgical resection in patients with esophageal or GE
junction cancer without pathological complete response, demonstrated statistically significant improvement in disease-free
survival (DFS) in the phase III CheckMate-577 trial with a doubling of DFS from 11 to 22 months.
Immune checkpoint inhibitors (in combination with chemotherapy), and even dual checkpoint inhibition, will become a feasible option for many patients with ESCC worldwide. Nevertheless,
besides the challenge of selecting the patients most likely to
benefit from immunotherapy approaches, it will be paramount to
tackle issues of access, especially in low-resource settings.
Summary
1 The evidence for targeted therapies in treating ESCC is limited to
results from phase II trials.
2 Immune checkpoint inhibitors will likely become a feasible option for
many patients with ESCC worldwide.
Section 10 Recent and Future
Developments
Neoadjuvant Immunotherapy
The benefit of neoadjuvant immunotherapy is that this may
induce tumor shrinkage and facilitate a radical resection of
the tumor. Shen etal. administered 28 patients with resectable
locally advanced ESCC to evaluate the feasibility and safety of
a neoadjuvant treatment protocol of PD-1 inhibitors (pembrolizumab: 2 mg/kg, nivolumab: 3 mg, camrelizumab: 200 mg)
5 ESOPHAGEAL SQUAMOUS CELL CARCINOMA 111
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combined with nCT (albumin paclitaxel + carboplatin). This
regimen produced an unprecedentedly high R0 resection and
pathologically complete response rates (pCR). (Shen 2021). The
Palace-1 study included 20 resectable ESCC patients to receive
preoperative pembrolizumab with concurrent carboplatin, paclitaxel, and radiotherapy. Grade III and higher adverse events
were observed in 65% of the patients and the pCR rate was
55.6%. Despite these positive findings, it is still uncertain what
the optimum number of neoadjuvant therapy cycles is and no
phase-3 trial has been completed yet (Shen 2021).
Robot-assisted Minimally Invasive
Esophagectomy (RAMIE)
The introduction of RAMIE is one of the most important
developments on surgical techniques in the past 10 years.
Robotic assistance allows for more natural hand movements
and provides an enhanced three-dimensional vision of the surgical field. The evidence of superiority of RAMIE over other
techniques is limited yet. However, a reduction in pulmonary
complications is seen over open approach as has been reported
for other minimally invasive approaches. Tumor RAMIE is safe
and an alternative to open esophagectomy (van der Sluis etal.
2012). The long term results and the possible benefits over
minimally invasive techniques still are unclear (Tagkalos 2021).
Since metastases to upper mediastinal nodes are commonly
seen in ESCC, lymph node dissection along the bilateral recurrent laryngeal nerve (RLN) may become easier with RAMIE and
reduce post-procedural morbidity. A multicenter randomized
trial randomized trial – termed REVATE – is currently ongoing
with the aim of comparing the rates of successful RLN nodal
dissection during RAMIE versus MIE.
Surgery as Needed
The CROSS trial showed a pathologically complete response
(pCR) in the resection specimen in 49% of patients with
squamous cell carcinoma after neoadjuvant chemoradiotherapy
(Van Hagen 2012). This high pCR rate raises the question if surgical resection is of benefit to these patients or if patients already
were cured locoregionally by neoadjuvant treatment alone.
Theoretically, an organ sparing approach might be feasible as
esophagectomy in patients with no residual disease likely does
not change the outcome. Surgery is associated with considerable
perioperative morbidity and reduces quality of life in the short
and long term. Therefore, if one could identify patients with a
clinically complete response after neoadjuvant chemoradiotherapy, applying active surveillance in these patients may be a realistic option. The preSANO trial revealed that the combination of
endoscopic bite-on-bite biopsies, endoscopic ultrasound (EUS)
with fine-needle aspiration (FNA) of suspected lymph nodes and
18F-FDG PET-CT had a sensitivity of 90% to detect TRG3-4
residual tumors (>10% residual tumor cells) (Noordman etal.
2018a). This combination of diagnostic modalities is now being
used in a phase-III randomized controlled trial (SANO-trial).
The SANO-trial investigates whether an active surveillance
strategy is non-inferior to standard surgery after neoadjuvant
chemoradiotherapy (Eyck etal. 2021a; Noordman etal. 2018b).
The first results of this trial are expected in late-2023. A recent
meta-analysis of seven cohort studies showed that overall
survival between patients undergoing standard surgery or active
surveillance after neoadjuvant chemoradiotherapy is comparable
(Van der Wilk 2022). This may support offering active surveillance as an alternative treatment strategy, but this study has several shortcomings. The study included predominantly
retrospective studies with small sample sizes and patients
included in active surveillance from these studies are likely
highly selected and as such may represent a subgroup with a
more favorable prognosis.
Based on the diagnostic modalities used in the preSANO
trial, a prospective multicenter study (preSINO trial) is recruiting patients with esophageal squamous cell carcinoma in order
to assess the accuracy of response evaluation after neoadjuvant
chemoradiotherapy in the eastern population (Zhang 2020). In
France also, a current study on active surveillance is performed
(Esostrate trial) which enrolls both esophageal SCC and adenocarcinoma. A lot of research is being done into organ-sparing
treatment for esophageal cancer whose results are still awaited.
Key Take Home Messages
• Advanced endoscopic imaging has shown promising results in
the detection of early cancerous lesions. Existing screening pro-
grams are however limited to high-risk Chinese populations.
• Routine clinical staging of esophageal cancer includes upper
endoscopy with biopsies, endoscopic ultrasonography with
fine-needle aspiration and
tion bronchoscopy EBUS, MRI-scan or diagnostic laparos-
copy/thoracoscopy.
• The precursor of ESCC is squamous dysplasia and is com-
monly divided into low- and high- grade dysplasia. ESCC is
divided into well, moderately and poorly differentiated.
• The 8th edition of UICC/AJCC TNM and the Japanese
classification system JES are used for pathological staging of
ESCC. The Japanese classification differs in lymph node
mapping as this is based on location of lymph nodes
according to tumor location.
• Endoscopic resection is the standard treatment for intramu-
cosal ESCC. Adjuvant therapy may be needed in tumors with
unfavorable pathological characteristics and for incomplete
resections.
• Patients with cT1-2 ESCC without lymph node metastases
qualify for immediate surgery according to Asian guidelines.
18
F-FDG PET/CT and on indica-
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A transthoracic esophagectomy with two- or three field
nodal dissection is standard treatment.
• Preoperative treatment for SCC in the West preferably con-
sists of chemoradiotherapy, while Eastern countries may
prefer chemotherapy or adjuvant therapy.
• Definitive chemoradiation is an alternative treatment for
SCC and treatment of choice for irresectable (T4b) SCC or
for patients unfit for surgery.
• There has been a shift in the treatment of adjuvant or meta-
static esophageal cancer toward chemotherapy combined
with immunotherapy, including PD-1 inhibitors, epidermal
growth factor receptor and targeted therapies.
Knowledge Gaps
• Cytology and serum blood-markers appear as a promising
non-invasive test for (early) disease detection for ESCC, but
further investigations are required to assess clinical
applicability.
• Indications for adjuvant systematic therapy or resection after
endoscopic resection for ESCC are inconsistent.
• The extent of lymph node dissection during esophagectomy
differs in Eastern and Western practices and its therapeutic
benefit is still debated.
• Guidelines are not unequivocal about the use, optimal dose of
radiation and choice of chemotherapeutic agents for definitive chemoradiotherapy. This needs to be further examined.
• Proton-based radiation (in combination with chemotherapy)
is promising, but more research need to be done to evaluate
its benefit compared to standard photon-based radiation.
• The role of neoadjuvant immunotherapy is promising but no
phase-3 trial has been completed yet.
• In patients with a locoregional complete clinical response to
neoadjuvant treatment may undergo active surveillance (i.e.
surgery as needed) could be of benefit. However, results of
prospective trials (SANO trial, Esostrate) should be awaited
before waiving standard esophagectomy after neoadjuvant
therapy can be discussed.
(Inter)national Evidence-based Websites
• National Cancer Institute
https://www.cancer.gov/types/esophageal
• The Japan Esophageal society
https://www.esophagus.jp/global
• National Comprehensive Cancer Network
https://www.nccn.org/home
• European Society for Medical Oncology
https://www.esmo.org/guidelines/guidelines-by-topic/
gastrointestinal-cancers/oesophageal-cancer
• UpToDate
https://www.uptodate.com/contents/clinical-manifestationsdiagnosis-and-staging-of-esophageal-cancer
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