Introduction
Purpose of the guidelines
The primary objective of these guidelines was to provide general clinicians with information
that would guide them to make informed choices from the available diagnosis/treatment
strategies for esophageal cancer (intended only for malignant esophageal tumors of
epithelial origin, and not for any other non-epithelial malignant tumors of the esophagus
or metastatic malignant esophageal tumors). Furthermore, these guidelines are also
intended as an aid for healthcare professionals other than physicians, and also for
patients and their family members, to help them understand the fundamental principles
of the diagnosis and treatment of esophageal cancer. These guidelines are intended
to allow physicians to share the information contained therein and promote mutual
understanding among healthcare professionals, patients, and the patients’ family members.
Target users
The main target users of the guidelines are general clinicians and physicians specializing
in the diagnosis and treatment of esophageal cancer. The guidelines also provide useful
information to healthcare professionals other than physicians involved in the diagnosis
and treatment of esophageal cancer, and also to the patients and their family members.
Target patients
The guidelines are intended for adult patients with esophageal cancer and/or Barrett’s
esophagus. While the mean age of patients diagnosed as having esophageal cancer is
increasing with the ageing of the population, users should exercise caution when applying
the guidelines to elderly patients aged 76 years or older, as many of the clinical
studies from which evidence was drawn while formulating the guidelines involved patients
who were 75 years or younger.
Precautions for use
The guidelines are intended for standard diagnosis and treatment covered by the national
health insurance system in Japan. Emphasis has been placed on evidence obtained from
patients with esophageal squamous cell carcinoma, which is the most common histological
type in East Asian countries, including Japan, while attention was also paid to the
background and indications for treatment of esophageal carcinoma in Europe and the
United States, where the main histological type is esophageal adenocarcinoma.
The guidelines are intended to guide physicians to provide standard diagnosis and
treatment and not to force them to provide specific diagnosis and treatment. Since
treatment of esophageal cancer is highly invasive and often requires treatment equipment
(e.g., endoscopic treatment equipment, surgical treatment equipment, radiotherapy
equipment, and intensive care unit) and human resources (multidisciplinary treatment
team), individual diagnosis/treatment strategies should be determined according to
the patient’s condition and the circumstances of the institution. Therefore, the person(s)
directly in charge of diagnosis and treatment, and not the community or individuals
involved in the development of the guidelines, will be responsible for the results
of the diagnosis and treatment.
Method of development of the esophageal cancer practice guideline
Scope formulation
The present revision of the guidelines was carried out based on the following:
Basic principles adopted for the preparation of the guidelines
The basic principles for developing this 5th edition were deliberated upon at the
meeting of the 1st Committee on Guidelines for Diagnosis and Treatment of Esophageal
Cancer in April 2018. The present Edition continues to adopt the algorithm that provides
a bird’s eye view of the entire flow of diagnosis and treatment of esophageal cancer
and the detailed algorithms for each stage of the disease, which were newly introduced
in the previous version of the guidelines. The committee agreed that Clinical Questions
(CQs) related to debatable points in the algorithm that would require the physicians’
judgment in the clinical practice setting were to be extracted.
Major changes in the guidelines resulting from this revision
Representatives of cooperative bodies including professionals other than physicians,
and representatives of patients with esophageal cancer, were included as members of
the Guideline Preparation Committee, and their multifaceted views were incorporated
in the guidelines.
A nationwide questionnaire survey was conducted, based on the results of which Quality
Indicator (QI) studies would be conducted to determine the prevalence of usage of
the guidelines and CQs would be created.
In collaboration with the Japanese Gastric Cancer Association, the Japan Esophageal
Society developed CQs relating to carcinoma of the esophagogastric junction and laid
down the following ecommendations.
A chemotherapy regimen for cStage IVB esophageal cancer recommended by the algorithm
is shown.
Systematic reviewers were transparently recruited.
On the methodology of preparation of the guidelines
The guidelines were prepared by referring to the Minds Manual for Guideline Development
2017 and 2020, issued by the Information Division of the Medical Information Network
Distribution Service EBM (Minds), the Japan Council for Quality Health Care.
Preparation of CQs and search of the literature
The 41 CQs contained in the 4th edition of the guidelines were reexamined to exclude
those related to treatments that had already become standard treatments from the 5th
edition and are described in the text of the guidelines. New CQs, 39 in total, pertaining
to clinically important problems, were prepared and included in the 5th edition of
the guidelines. The Japan Medical Library Association was entrusted with a systematic
search of the literature published on the treatment of esophageal carcinoma between
January 2000 and August 2020, using keywords extracted from the CQs. The PubMed and
Cochrane Library databases were used to search for articles in the English language,
and the ICHUSHI-Web to search for articles published in Japanese.
Of the 39 CQs, 15 related to debatable points in the algorithm were adopted in the
English version of the guidelines.
Moreover, a manual search was also conducted for articles/papers that had escaped
retrieval by the systematic search and for those published after September 2020, as
needed, based on information provided by the systematic review (SR) team and Guideline
Preparation Committee members.
Inclusion criteria
Randomized controlled studies and observational researches among studies conducted
in adult patients with esophageal cancer were adopted, in principle. Studies on accumulated
cases, nevertheless, were also actively adopted, depending on the outcomes determined.
Only papers written in Japanese or English were adopted.
Contents of other documents, such as expert reviews and guidelines from other countries,
were also reviewed in detail as reference data, although none of these was used as
evidence.
(2)
Exclusion criteria
Genetic studies and experimental studies in laboratory animals were excluded.
Systematic review procedure
For each of the CQs, the outcomes in terms of the balance between the benefits and
risks were extracted and the level of importance thereof is presented. Each retrieved
article was subjected to a primary and secondary screening, summarized, and then assessed
for bias, besides classification of the study design. For each outcome in terms of
the benefits and risks, individual papers were summed up and evaluated as a whole
body of evidence, and the strength (certainty) of evidence was determined according
to the Minds Manual for Guideline Development 2017 and 2020 (Table 1).
Table 1
Strength (certainty) of the whole body of evidence
A
Strong
We have strong confidence that the estimated effect adequately supports the recommendation
B
Moderate
We have moderate confidence that the estimated effect adequately supports the recommendation
C
Weak
We have limited confidence that the estimated effect adequately supports the recommendation
D
Very weak
We have very little confidence that the estimated effect adequately supports the recommendation
Determination of the strength of recommendations
The members of the Guideline Preparation Committee prepared drafts of the recommendation
statements based on the results of a systematic review, and a consensus conference
(online conference, because of the COVID-19 pandemic) was held to examine the strength
of the recommendations. The strength of each recommendation was examined on the ground
of the certainty of evidence, patient preferences, benefits and risks, and cost evaluation.
As for the method of arriving at a consensus, a secret ballot was held with independent
voting using a Google form, in accordance with the GRADE grid method; the strength
of the recommendation was determined based on a ≥ 70% consensus. When a ≥ 70% consensus
was not achieved in the first vote, a second vote was planned after the consultation;
however, a ≥ 70% consensus was achieved in the first vote itself for all the CQs included
in this 5th edition. When the Committee considered it difficult to determine the strength
of recommendation for the CQ, a ballot was held in which “unable to determine the
strength of the recommendation at present” was included in the choices, and a decision
was made based on a ≥ 70% consensus.
The strength of recommendation was expressed in two directions × 2 steps as follows:
Conduct or non-conduct is “strongly recommended.”
Conduct or non-conduct is “weakly recommended.”
Public hearing and external review
In May 2022, a draft of the guidelines was published on the website of the Japan Esophageal
Society, inviting public comments from clinicians, other healthcare professionals,
and patients.
The Guideline Preparation Committee examined the public comments, conducted a systematic
review of important items, and revised the guidelines, as needed. In addition, The
Guideline Review Committee independent from The Guideline Preparation Committee has
been established to conduct external reviews.
Revision
After publication of the guidelines, the Committee on Guidelines for Diagnosis and
Treatment of Esophageal Cancer of the Japan Esophageal Society has taken the initiative
to continue to review the contents of the guidelines and conduct public relations
and dissemination/utilization activities. A revision of the guidelines is planned
for approximately 5 years after publication of this guideline. In addition, a prompt
report will be made when the results of a clinical study(ies) are published or in
accordance with changes in the medical circumstances, such as revision of the health
insurance coverage.
Efforts related to public relations/dissemination (including plans)
Improvement of the method of guideline development
Improvement of flow charts, description of voter turnout, etc.
Improvement of convenience for users
Publication as a book and publication on the internet, free of charge (websites of
the Japan Esophageal Society, Minds, Japan Society of Clinical Oncology, etc.), public
lectures, public relations at meetings of scientific societies/study groups, etc.
Conflict of Interest (COI) and Economic Independence
Conflict of interest (COI) reporting
Members of the Guideline Review Committee and Guideline Steering Committee personally
reported their conflicts of interests in conformity with the regulations of the Japan
Esophageal Society. The Board of Directors and the Ethics Committee of the Japan Esophageal
Society confirmed the personally reported conflict-of-interest situations.
Restrictions at the recommendation decision conference based on COI
In case that any member who personally reports a COI (1) was an author of a paper
that served as evidence for preparation of these guidelines (academic COI) or (2)
has a COI concerning an enterprise or competing enterprise that manufactured and/or
marketed a related drug(s) or medical device(s) (economical COI), the member will
not be allowed to participate in the voting at the consensus conference, by self-declaration.
Efforts to prevent academic bias unique to the society
Efforts were made to avoid academic COI of any single academic organization, by constructing
a cooperative system with a plurality of related academic bodies.
Economic independence
The Japan Esophageal Society met the entire expenditure for the preparation and publication
of these guidelines and did not receive funding from any enterprises.
Epidemiology, present status, and risk factors
Summary
As for the dynamic trends of esophageal carcinoma in Japan, the incidence rate of
this cancer has been constant or decreasing in men, while remaining constant or very
gradually rising in women. The mortality rate has been decreasing in both men and
women.
Among patients with this malignancy, the percentage of males is higher, as is the
percentage of patients in their 60–70 s. The carcinoma is most frequently located
in the middle thoracic esophagus, and squamous cell carcinoma is the overwhelmingly
predominant histologic type. Esophageal cancer is known to be frequently associated
with synchronous or metachronous multiple carcinomas.
The risk factors cited for esophageal squamous cell carcinoma include smoking and
habitual alcohol consumption. On the other hand, a factor cited as protecting against
development of this cancer is intake of vegetables and fruits. In regard to the risk
factors for adenocarcinoma, Barrett’s epithelium arising from persistent inflammation
of the lower esophagus due to gastroesophageal reflux disease (GERD) has been reported
to serve as a risk factor for the development of esophageal carcinoma in Europe and
the United States. In Japan, however, the risk of development of esophageal carcinoma
associated with Barrett’s esophagus remains unclear because of the scarcity of documented
cases.
General remarks
Incidence and mortality
According to the statistics released by the Center for Cancer Control and Information
Services, National Cancer Center, based on the cancer incidence (morbidity incidence
rate) data derived from the Population-Based Cancer Registry, the estimated incidence
rate of esophageal carcinoma (crude incidence rate) in 2015 was 31.2 persons per 100,000
population in men and 5.9 persons per 100,000 population in women. The age-adjusted
incidence rate has been constant or decreasing in men recently, while remaining constant
or very gradually increasing in women.
The vital statistics compiled by the Ministry of Health, Labour and Welfare showed
that there were 11 619 deaths from esophageal carcinoma in 2019 (crude mortality rate:
9.4 persons per 100,000 population), accounting for 3.1% of all deaths from malignant
neoplasms. The crude mortality rate associated with esophageal carcinoma in men was
15.9 persons per 100,000 population, ranking below the rates for cancers of the lung,
stomach, colorectum, pancreas, liver and prostate, and the rate in women was 3.2 persons
(per 100,000 population), ranking below the tenth place (http://ganjoho.jp/reg_stat/index.html).
The age-adjusted mortality rate of esophageal carcinoma has been showing a downward
trend in both men and women.
Cancer mortality data derived from vital statistics and from various graphs constructed
based on those data are available at the Center for Cancer Control and Information
Services, National Cancer Center (http://ganjoho.jp/reg_stat/index.html).
Present status of esophageal carcinoma in Japan
As for the present status of esophageal carcinoma in Japan, according to a nationwide
survey conducted by the Japan Esophageal Society (8019 patients who were treated in
2013 and analyzed in 2019) [1], male patients outnumber female patients, with a male–female
ratio of about 5.4:1, and most patients are in their 60 s or 70 s, these age groups
accounting for about 70% of the patients overall. The carcinoma is predominantly located
in the middle thoracic esophagus (in approximately 47% of cases), followed, in order
of frequency, by the lower thoracic esophagus (in approximately 28% of cases), upper
thoracic esophagus (in approximately 12% of cases), abdominal esophagus (in approximately
8% of cases), and cervical esophagus (in approximately 5% of cases). Squamous cell
carcinoma is the overwhelmingly predominant histologic type, accounting for about
86% of all cases, followed in frequency by adenocarcinoma, including Barrett’s esophageal
cancer, which accounts for about 7% of all cases. As for the treatment modalities,
endoscopic treatment is performed in about 18% of cases, esophagectomy in about 61%
of the cases, and chemotherapy/radiotherapy/chemoradiotherapy in about 51% of the
cases.
Risk factors
The most frequent risk factors for esophageal carcinoma identified in Japan are the
smoking habit and habitual alcohol consumption. These are the most important risk
factors for squamous cell carcinoma, being identified as risk factors in about 90%
of all diagnosed cases of esophageal carcinoma in Japan. Concomitant use of tobacco
and alcohol has been shown to be associated with a multiplied risk for the development
of esophageal carcinoma [2–6]. In regard to the smoking habit in apparently healthy
individuals, a systematic review was carried out to respond to “CQ1-1: Is smoking
cessation recommended for healthy individuals from the perspective of preventing the
development of esophageal carcinoma?”, and based on the systematic review, the recommendation
statement was formulated and included in the previous edition of the guidelines: “There
is strong evidence to recommend smoking cessation to apparently healthy individuals
from the perspective of preventing the development of esophageal carcinoma”. No new
evidence to contradict that recommendation has been reported since, and this CQ is
not included in the present edition. In addition, for “CQ2: Is continued smoking and
alcohol cessation recommended for patients cured of esophageal carcinoma?”, the following
recommendation statement was formulated and included in the previous edition of the
guidelines: “There is strong evidence to recommend continued smoking and alcohol cessation
for patients cured of esophageal carcinoma”; therefore, this CQ was also excluded
from the present edition of the guidelines.
As for habitual alcohol consumption, in October 2009, a working group of the World
Health Organization specified that the acetaldehyde formed after consumption of alcoholic
beverages is a Group 1 carcinogen [5]. In addition, genetic factors related to the
capacity to metabolize alcohol or acetaldehyde were also reported to modify the risk
of cancer associated with habitual alcohol consumption [7]. Since the strength of
the recommendation regarding alcohol consumption for healthy individuals could not
be established in the previous edition, CQ2 was formulated and included again in this
edition to examine alcohol consumption in Asian heavy alcohol consumers.
In relation to dietary factors, poor nutritional status and vitamin deficiencies due
to inadequate intake of fruits and vegetables have also been reported as risk factors
for esophageal carcinoma. Since the intake of green and yellow vegetables and fruits
has been suggested as a protective factor [8–10], a new CQ1 about the intake of vegetables
and fruits was formulated.
Whilst adenocarcinoma accounts for only a small percentage of esophageal carcinoma
patients in Japan, the percentage of esophageal carcinoma patients with this histological
subtype is increasing in Europe and North America, and currently accounts for about
more than half of all the cases of esophageal carcinoma in these regions. Barrett’s
epithelium, caused by persistent inflammation of the lower esophagus due to GERD,
is known as a predisposing lesion for the development of esophageal adenocarcinoma,
and there are also reports of the contribution of GERD, high body mass index (BMI)
(which is a risk factor for GERD), and smoking to the development of esophageal adenocarcinoma
[11–14]. In Japan, however, no clear evidence has been established yet, because of
the scarcity of cases of esophageal adenocarcinoma.
Treatment algorithms for esophageal cancer and treatment policies based on the algorithm
Japanese classification of esophageal cancer and tumor, node, metastasis (TNM) (Union
for International Cancer Control [UICC]) classification
It should be noted that there exists some discordance on the subject of disease staging
in this edition of the guidelines, as the disease staging was conducted in accordance
with the Japanese Classification of Esophageal Cancer and the edition of the TNM (UICC)
Classification prevailing at that time.
However, a by-histologic type classification system is adopted in the 8th Edition
of TNM (UICC), in consideration of the difference in the prognosis between squamous
cell carcinoma and adenocarcinoma, inferred largely from the therapeutic outcomes
reported from Europe and the United States. In the present guidelines, the by-stage
treatment algorithm is based on the 12th Edition of the Japan Esophageal Society’s
Japanese Classification of Esophageal Cancer.
Treatment algorithm for cStage 0 to I esophageal cancer (Fig. 1)
Fig. 1
Treatment Algorithm for cStage 0 to I Esophageal Cancer
Summary
To determine the treatment strategy for cStage 0 or I carcinoma of the esophagus,
the clinical stage of the disease should first be confirmed by modalities such as
upper gastrointestinal endoscopy, computed tomography (CT) of the neck, chest and
abdomen, and positron-emission tomography (PET). Then, it is important to assess the
depth of tumor invasion to select the most appropriate treatment from among the options
of endoscopic resection (ER), surgery, and chemoradiotherapy. The treatment algorithm
for cStage 0/cStage I carcinoma of the esophagus is described in such a way as to
make it consistent with the ESD/EMR guidelines for esophageal cancer.
Minimally invasive ER could be considered where the physician wavers in his/her assessment
of the depth of tumor invasion and in patients who cannot tolerate surgery due to
poor general condition. Assessment of the circumferential extent of the lesion should
be undertaken in patients with clinical (c)Stage 0 disease (cT1a; cT1b-submucosal
1 [SM1] should be managed similarly to cT1a-muscularis mucosae [MM], when these cannot
be differentiated from each other) scheduled to undergo ER to determine the risk of
development of post-ER stenosis. When the post-resection ulcer is expected to involve ≥ 3/4th
of the esophageal circumference, a preventive measures against stenosis should be
considered, as such lesions are associated with a high risk of stenosis after ER.
In patients with cStage I (T1b) disease, the selection between surgery and chemoradiotherapy
should be made after assessing the patient’s surgical tolerability.
Post-ER pathological assessment is of vital importance to determine if any additional
treatment might be required to ensure radical cure. In patients classified as having
pathological (p)T1a-epithelium (EP)/lamina propria mucosae (LPM) disease, follow-up
may be scheduled; on the other hand, in patients diagnosed as having pT1a-MM/pT1b-SM
disease, additional treatment (surgery or chemoradiotherapy) should be considered.
CQ4: What would be the recommendation for preventing postoperative stenosis following
endoscopic resection of superficial cancer of the esophagus?
Recommendation statement
There is evidence to strongly recommend oral prednisolone treatment, submucosal triamcinolone
injection, or concurrent oral prednisolone treatment + submucosal triamcinolone injection
for preventing stenosis after endoscopic resection. (Consensus rate: 85.2% [23/27],
strength of evidence: C).
Explanatory note
A search of the literature in relation to this CQ yielded 255 PubMed articles, 52
Cochrane articles, and 107 ICHUSHI articles. Along with one additional article identified
by a manual search, the 415 articles, in total, were subjected to a primary screening.
From the primary screening, we extracted 42 articles referring to the following stenosis
prevention measures used in clinical practice: “oral prednisolone treatment,” “submucosal
triamcinolone injection,” “oral prednisolone treatment + submucosal triamcinolone
injection,” “prophylactic balloon dilatation,” “triamcinolone acetonide-filling method,”
“shielding with a polyglycolic acid sheet,” and “esophageal stenting (not approved
in Japan)”. These articles were subjected to a secondary screening, and finally, 21
articles (3 randomized controlled studies, 3 non-randomized studies, and 15 observational
studies) were selected for qualitative systematic reviews.
In the systematic reviews, non-circumferential resection and whole circumferential
resection cases were examined separately, because the outcomes such as the “incidence
of stenosis” and “number of dilatation sessions” differed greatly between the two
procedures.
Table 2 shows the incidence of stenosis and the number of dilatation sessions in cases
of post-ER ulcers involving ≥ 3/4th of the esophageal circumference, but not the entire
esophageal circumference. The incidence of stenosis was 8.6–23.1% in patients treated
with oral prednisolone [15–18], 9.2–36.2% in patients treated with submucosal triamcinolone
injection [17–21], 10.0–13.3% in patients treated with oral prednisolone + submucosal
triamcinolone injection [18, 19], and 50.0–80.0% in patients in whom no prophylactic
measures were adopted [15–17, 19, 21]. Thus, adoption of preventive measures was associated
with a reduced incidence of stenosis and lower number of dilatation sessions as compared
with no adoption of preventive measures.
Table 2
Outcomes of prophylactic measures undertaken in cases of non-circumferential resection
Prophylactic measure
Circumferential extent
Incidence of stenosis
No. of dilatation sessions
Reference number
PSL
> 3/4a
23.1% (3/13)
3.0b
[15]
PSL
> 3/4
14.3% (2/14)
6.0b
[16]
PSL
> 3/4
20.0% (5/25)
–
[17]
PSL
> 3/4a
8.6% (6/70)
0c
[18]
TA
> 3/4a
33.3% (2/6)
–
[17]
TA
> 3/4
9.2% (8/87)
0c
[18]
TA
> 3/4
36.2% (17/47)
6.0c,d
[19]
TA
> 3/4
11.3% (13/115)
7.0c
[20]
TA
> 3/4
19.1% (4/21)
8.9b
[21]
PSL + TA
> 3/4
10% (1/10)
–
[18]
PSL + TA
> 3/4
13.3% (2/15)
5.5c,d
[19]
Control
> 3/4a
80.0% (8/10)
16.9b
[15]
Control
> 3/4
64.3% (9/14)
7.5b
[16]
Control
> 3/4a
50.0% (11/22)
–
[17]
Control
> 3/4
75.0% (15/20)
8.8b
[21]
Control
> 3/4
60.7% (17/28)
12.5c
[19]
PSL Oral prednisolone treatment, TA submucosal triamcinolone injection
aIncluding some cases of whole circumferential resection, baverage, cmedian, donly
cases of post-resection ulcer involving ≥ 7/8th of the esophageal circumference
Table 3 shows the incidence of stenosis and number of dilatation sessions in cases
of post-ER ulcers involving the entire esophageal circumference. The incidence of
stenosis was 33.3–100% in patients treated with oral prednisolone [2, 4, 8, 16, 16,
22], 100% in patients treated with submucosal triamcinolone injection [18, 19, 23],
18.8–91.7% in patients treated with oral prednisolone + submucosal triamcinolone injection
[18–20], and 100% in whom no prophylactic measures were adopted [16, 19, 22, 23].
In patients with whole-circumferential post-ER ulcers, submucosal triamcinolone injection
alone was not effective for preventing stenosis, but the other prophylactic measures
lowered the incidence of stenosis and decreased the number of dilatation sessions
required as compared with the group in which no preventive measures were adopted.
Table 3
Outcomes of prophylactic measures undertaken in cases of whole circumferential resection
Prophylactic measure
Incidence of stenosis
No. of dilatation sessions
Reference number
PSL
33.3% (1/3)
2.0a
[16]
PSL
33.3% (8/24)
–
[18]
PSL
100% (10/10)
13.8a
[22]
TA
100% (4/4)
–
[18]
TA
100% (5/5)
10.4a
[23]
TA
100% (6/6)
–
[19]
PSL + TA
18.8% (3/16)
–
[18]
PSL + TA
71.4% (10/14)
–
[19]
PSL + TA
91.7% (11/12)
13.0b
[20]
Control
100% (2/2)
11.0a
[16]
Control
100% (5/5)
22.2a
[23]
Control
100% (5/5)
–
[19]
Control
100% (13/13)
33.5a
[22]
PSL Oral prednisolone treatment, TA submucosal triamcinolone injection
aAverage, bmedian
As for adverse events, 0.7% of patients treated with oral prednisolone (one of 134
patients) developed cytomegalovirus enterocolitis [18]. Perforation during balloon
dilatation was observed in 1.9% of patients treated with submucosal triamcinolone
injection (6 of 308 patients), which was only slightly higher than the incidence of
1.5% in the control group (in which no prophylactic measures were adopted; 1 of 69
patients) [19, 20, 23].
Thus, oral prednisolone treatment, submucosal triamcinolone injection, and concurrent
oral prednisolone treatment + submucosal triamcinolone injection decreased the incidence
of stenosis and number of dilatation sessions required as compared with no adoption
of prophylactic measures, and were also associated with a very low incidence of adverse
events. As for the burden on the patients, oral prednisolone treatment places some
burden on the patients, because it takes 6–18 weeks, while submucosal triamcinolone
injection places little burden on patients, because it is often performed only at
the end of the ESD procedure. In regard to the costs, prednisolone costs about 10
yen per 5-mg tablet and the total cost for the usual treatment duration of 6–18 weeks
is about 1500–4500 yen. Submucosal triamcinolone injection is inexpensive: each 50 mg/5 mL
vial costs about 200 yen, and 1–3 vials (about 200–600 yen) are usually used. In addition,
balloon dilatation used for the treatment of stenosis is expensive, corresponding
to 12,480 medical remuneration points (37,440 yen for patients who pay 30% of the
medical fees). The above-described data indicate that the number of dilatation sessions
and total treatment cost can be reduced by using oral prednisolone treatment and/or
submucosal triamcinolone injection. We concluded that oral prednisolone treatment,
submucosal triamcinolone injection, or concurrent oral prednisolone treatment + submucosal
triamcinolone injection can be recommended, because each of these was associated with
a reduced incidence of stenosis and number of dilatation sessions required after endoscopic
treatment of esophageal cancer, and also little risk. No comparison was made between
oral prednisolone treatment and submucosal triamcinolone injection, because there
were no informative articles.
In patients in whom prophylactic balloon dilatation was performed/not performed for
the prevention of post-ER stenosis when they had no symptoms of stenosis, the incidence
of stenosis was 58.6%/91.7%, and surprisingly, the number of dilatation sessions required
for treatment was 8/4.5 [24]. There were no adverse events associated with prophylactic
balloon dilatation. Prophylactic balloon dilatation decreased the incidence of stenosis
[24], but it was less effective than oral prednisolone treatment and submucosal triamcinolone
injection. In addition, the number of balloon dilatation sessions required for treatment
was greater in patients who had received prophylactic balloon dilatation than in those
who had not received any prophylactic measures, and prophylactic balloon dilatation
increased the burden on the patients as well as the costs; therefore, we concluded
that there is no evidence to recommend prophylactic balloon dilatation prior to the
onset of symptoms of stenosis.
There were two reports identified on the triamcinolone acetonide-filling method. Although
this procedure requires endoscopic examination every 2 weeks and additional triamcinolone
acetonide filling, as needed, until epithelialization of the ulcer, it has been reported
to be highly effective: the incidence of stenosis requiring balloon dilatation was
only 4.5–5.0% and the number of dilatation sessions required for the treatment of
stenosis was 2–3 [25, 26]. Although this method is promising, we concluded that currently,
there is insufficient evidence to recommend it, because the two studies involved only
a small number of patients (22 and 20 patients) and most of them were from single-institute.
Three articles were extracted on shielding with a polyglycolic acid sheet [27–29].
One of the articles reported the usefulness of combined use of a polyglycolic acid
sheet with stenting, which is not approved in Japan. The other two studies compared
shielding with a polyglycolic acid sheet and submucosal triamcinolone injection [28]
and no prophylactic measures [29], and found no significant difference in the incidence
of stenosis. Although shielding with a polyglycolic acid sheet was not associated
with adverse events, it is expensive: the sheet costs about 8000 yen and the physiological
tissue adhesive that fixes the sheet to the ulcer floor costs about 54,000 yen. We
concluded that there is no evidence to recommend shielding with a polyglycolic acid
sheet, because of the inferior risk–benefit balance as compared to oral prednisolone
treatment or submucosal triamcinolone injection.
Three overseas studies have reported the use of esophageal stents, which are not yet
approved in Japan, to prevent benign stenosis [30–32]. All these studies used a covered
metal stent, which was inserted into the ulcer soon after endoscopic treatment and
removed 2–8 weeks later. The incidence of stenosis was 18.2% (2 of 11 cases) in cases
of post-resection ulcers involving ≥ 3/4th of the esophageal circumference [32], and
the outcomes of esophageal stenting were comparable to those of oral prednisolone
treatment or submucosal triamcinolone injection as prophylactic measures against the
development of stenosis. On the other hand, rather promising outcomes were reported
in cases of post-resection ulcers involving the entire esophageal circumference: the
incidence of stenosis was 17.4% (4 of 23 cases) in one study [30] and 50% (6 of 12
cases) in another. However, it should be noted that the incidence of adverse events
was also higher (15.2%, 7 of 46 cases; stent migration in 5 cases, bronchial fistula
in 1 case, and pain in 1 case) as compared with that associated with other prophylactic
modalities, and some of the adverse events were serious.
All of the aforementioned studies, except one of oral prednisolone treatment versus
submucosal triamcinolone injection, were non-randomized studies. We concluded that
the strength (certainty) of the overall evidence for all outcomes is C, because use
of oral prednisolone treatment or submucosal triamcinolone injection was highly effective
as compared with no adoption of prophylactic measures, although the risk of bias is
high. However, we concluded that oral prednisolone treatment or submucosal triamcinolone
injection is strongly recommended, because all other factors, such as the risk–benefit
balance, patient preferences, and costs support to adoption of oral prednisolone treatment
or submucosal triamcinolone injection as a prophylactic measure to prevent stenosis
after ER.
CQ5: Which is recommended, esophagectomy or definitive chemoradiotherapy, in patients
with cStage I (T1bN0M0) thoracic esophageal cancer?
Recommendation statement
There is weak evidence to recommend esophagectomy in patients with cStage I (T1bN0M0)
thoracic esophageal cancer, and there is also weak evidence to recommend definitive
chemoradiotherapy with adequate follow-up and salvage therapy in patients with cStage
I who desire for esophageal preservation. (Rate of consensus: 92.3% [24/26], strength
of evidence: C).
Explanatory note
A search of the literature conducted to respond to this CQ yielded 347 PubMed articles,
64 Cochrane articles, and 192 ICHUSHI articles. These articles, together with 1 article
published in 2021 and 1 article on the results of the JCOG0502 Study presented at
the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancer Symposium
(GI), were subjected to primary and secondary screenings, and 1 report of a meta-analysis
[33], 3 reports of retrospective studies [34–36], and 1 report of a prospective study
(JCOG0502) [37] were extracted. Of the references cited for data on cStage I esophageal
cancer in the meta-analysis, 1 report of a study with a short follow-up period [38]
was excluded, and the remaining 4 articles [39–42] were added, and a total of 8 articles
were subjected to a qualitative systematic review. There was no published randomized
controlled study directly comparing the outcomes of surgery and definitive chemoradiotherapy
for cStage I cases.
The qualitative systematic review showed that the 5-year overall survival rate (odds
ratio [OR], 0.68; 95% confidence interval [CI], 0.49–0.95; p = 0.02) and 5-year progression-free
survival rate (OR 0.53; 95% CI 0.30–0.95; p = 0.03) were significantly higher in patients
treated by surgery. However, the level of evidence is low, because none of the studies
was a randomized controlled study; therefore, the background factors of the patients
differed among many studies.
According to the only report of a prospective study, JCOG0502, patients treated by
surgery showed a 5-years progression-free survival rate of 81.7% (95% CI 75.7–86.3),
and a 5-year overall survival rate of 86.5% (95% CI 81.0–90.5), while patients treated
by definitive chemoradiotherapy showed a complete response rate of 87.3% (95% CI 81.1–92.1),
a 5-year progression-free survival rate of 71.6% (95% CI 63.9–78.0), a 5-year overall
survival rate of 85.5% (95% CI 78.9–90.1), and a 5-year esophagus preservation rate
of 80.4% (95% CI 73.3–85.8). Although surgery significantly prolonged the progression-free
survival (hazard ratio [HR]: 1.478 [95% CI 1.01–2.16]), there was no significant difference
in the overall survival between the two treatment modalities (HR 1.05 [95% CI 0.67–1.64]).
In regard to the toxicity (according to the Common Terminology Criteria for Adverse
Events [CTCAE]), the acute toxicities in the patients receiving definitive chemoradiotherapy
in the JCOG0502 Study were esophagitis (Grade 3–4; 10%), leukopenia (Grade 3–4; 11%),
and febrile neutropenia (Grade 3–4; 1.9%), and the late toxicities were esophagitis
(Grade 3–4; 0.6%), radiation pneumonitis (Grade 3–4; 1.9%), and pleural effusion (Grade
3–4; 2.5%). No deaths were reported during or within 30 days of completion of the
protocol treatment. On the other hand, the postoperative complications reported in
the patients who were treated by surgery were pneumonia (Grade ≥ 2; 13%), recurrent
laryngeal nerve paralysis (Grade ≥ 2; 15%), and anastomotic leakage (Grade ≥ 2; 15%);
in addition, two cases of treatment-related death were reported. Although patients
treated by chemoradiotherapy showed a shorter progression-free survival than those
treated by surgery, patients who received chemoradiotherapy followed by appropriate
aftertreatment showed a comparable overall survival to those who were treated by surgery,
with a 5-year esophagus preservation rate of 80.4%. Accordingly, chemoradiotherapy
is a valid treatment option for patients who wish for their esophagus to be preserved.
On the basis of the systematic review of the extracted articles, we determined that
surgery can be weakly recommended based on the survival rates; however, taking into
account the risk–benefit balance and patient preferences, we concluded that “there
is weak evidence to recommend esophagectomy in patients with cStage I (T1bN0M0) thoracic
esophageal cancer, and there is also weak evidence to recommend chemoradiotherapy
with adequate follow-up and salvage therapy in patients who wish to have their esophagus
preserved”.
CQ6: Which is recommended as an additional treatment—esophagectomy or chemoradiotherapy—in
cases with a pT1a-MM lesion showing positive vascular invasion or a pT1b-SM lesion
following endoscopic treatment for superficial esophageal cancer?
Recommendation statement
There is evidence to recommend esophagectomy or chemoradiotherapy as an additional
treatment in patients identified as having a pT1a-MM lesion with positive vascular
invasion or a pT1b-SM lesion after endoscopic treatment for superficial esophageal
cancer; however, currently there is insufficient evidence to definitively recommend
one over the other. (Rate of consensus: 89.3% [25/28]; strength of evidence: C).
Explanatory note
A search of the literature conducted to respond to this CQ yielded 23 PubMed articles,
2 Cochrane articles, and 8 ICHUSHI articles through a primary screening, and secondary
screening of these articles led to the retrieval of 14 articles, which were subjected
to a qualitative systematic review.
All of the 14 articles were reports of retrospective studies, including three studies
of only cases treated by surgery as an additional treatment after endoscopic resection,
four studies of only cases treated by chemoradiotherapy, and seven studies comparing
surgery and chemoradiotherapy as an additional treatment. There was a bias in the
patient characteristics, such as a preferential selection of chemoradiotherapy for
elderly patients and for patients who could not tolerate surgery, and differences
in the radiation dose according to the depth of invasion and the presence/absence
of vascular invasion among the studies [43–54].
In patients who were treated by surgery and chemoradiotherapy, the 5-year overall
survival rates were 79–100% and 60–100%, respectively, and the 5-year disease-free
(recurrence-free) survival rates were 89.5–100% and 55–100%, respectively. The reported
risk factors for recurrence include SM invasion, positive vascular invasion, and tumor
diameter ≥ 40 mm. In the pT1a-MM and pT1b-SM cases overall, the overall survival and
disease-free (recurrence-free) survival rates tended to be higher in patients who
were treated by surgery, although the difference was not significant. Three studies
compared surgery and chemoradiotherapy in cases with SM or deeper invasion, and all
three reported a significantly worse prognosis in patients who were treated by chemoradiotherapy
as compared with that in patients treated by surgery. In the JCOG0508 Study, cT1bN0
esophageal cancer with a limited depth of invasion, which was considered endoscopically
resectable, was treated endoscopically, and patients with pathologically confirmed
complete resection who had pT1a with positive vascular invasion or pT1b received additional
chemoradiotherapy. With such treatment, these patients showed a 3-year survival rate
of 90.7%, suggesting the usefulness of the strategy [55]. On the other hand, of the
15 patients who had positive vertical resection margins after endoscopic treatment
and received definitive chemoradiotherapy, 4 had metastatic recurrence and 3 (20%)
died of the disease. Further investigation is needed to determine the most suitable
additional treatment(s) for cases in which complete resection fails to be accomplished
by endoscopic treatment.
As for the toxicity of surgery and chemoradiotherapy, there are few systematic reviews
of postoperative complications following additional surgery after endoscopic resection
or adverse events associated with chemoradiotherapy as additional treatment. Therefore,
we investigated the toxicity of surgery and chemoradiotherapy by referring to reports
of initial surgery for cT1 esophageal cancer and additional chemoradiotherapy after
endoscopic resection, regardless of the histopathological results. The treatment-related
mortality due to surgical complications in T1 cases has been reported to be 0.2–3.6%.
The reported causes of treatment-related death after additional chemoradiotherapy
were radiation pneumonitis, sudden death, and myocardial infarction. In addition,
esophageal fistula (3.2%), esophagostenosis (3.2%), Grade 3 cardiac ischemia (1%),
and respiratory failure (2.8%) were reported as late complications.
In summary, although there are no randomized controlled studies or prospective studies
directly comparing surgery and chemoradiotherapy as additional treatments after endoscopic
resection, the therapeutic responses (in terms of the overall survival) to surgery
and chemoradiotherapy appear to be comparable in pT1a-MM and pT1b cases. However,
even in pT1b (particularly SM2-3), pT1a-MM, or pT1b-SM1 cases, patients with positive
vascular invasion have been reported to show a tendency towards a worse prognosis
after chemoradiotherapy than after surgery, suggesting that surgery may be the optimal
additional treatment option in these high-risk patients.
Thus, it was rather difficult to provide a clear and definitive response to this CQ
on the ground of the evidence obtained from this systematic review. Any treatment
is associated with some risk of postoperative complications and adverse events, and
treatment-related deaths have also been reported. Therefore, treatment should be carefully
tailored to individual cases, after taking into consideration the risk–benefit balances
and patient preferences.
Treatment algorithm for cStage II to Stage III esophageal cancer (Fig. 2)
Fig. 2
Treatment Algorithm for cStage II to III Esophageal Cancer
Summary
To select the appropriate treatment strategy for cStage II and III esophageal carcinoma,
the patient’s tolerability to surgical intervention should first be confirmed through
evaluation of the patient’s general condition after accurate diagnosis of the clinical
stage by upper gastrointestinal endoscopy, CT, and PET. When no problem is identified
with respect to the surgical tolerability, preoperative chemotherapy followed by radical
resection should be considered as the first-line therapy. Radical resection without
preoperative treatment or with preoperative chemoradiotherapy could also be selected.
In cases of surgery without any preoperative treatments, administration of adjuvant
chemotherapy should be considered in accordance with the histopathologic diagnosis
confirmed in the resected specimens (especially for lymph node metastasis-positive
cases). Recently, nivolumab was reported to be useful as adjuvant chemotherapy in
patients in whom R0 resection was achieved following preoperative chemoradiotherapy.
Definitive chemoradiotherapy (≥ 50 Gy) should be considered in patients who are unable
to tolerate surgery, refuse surgery, or wish to receive esophagus-preserving therapy
as first-line therapy, in whom chemoradiotherapy is feasible. Patients in whom complete
response is achieved should be followed up, and in case of a residual or recurrent
lesion, the practicability of surgical resection or endoscopic resection as salvage
therapy should be explored. In patients unable to tolerate surgery who are not suitable
candidates for chemoradiotherapy either, radiation therapy (e.g., in patients with
depressed renal function, elderly subjects), chemotherapy (e.g., in patients with
a history of radiation), or best supportive care should be considered.
CQ7: What should be recommended—primarily surgery, or definitive chemoradiotherapy—in
patients with cStage II or III esophageal cancer?
Recommendation statement
There is weak evidence to recommend primarily surgery for patients with cStage II
or III esophageal cancer. (Rate of consensus: 100% [28/28], strength of evidence:
C).
Explanatory note
A search of the literature conducted to respond to this CQ yielded 363 PubMed articles,
56 Cochrane articles, and 241 ICHUSHI articles, which were subjected to primary and
secondary screenings. Finally, 28 papers, consisting of 3 reports of randomized controlled
studies, 22 reports of observational studies, and 3 systematic reviews were retrieved,
which were subjected to a qualitative systematic review.
There are three reports of randomized controlled studies directly comparing the results
of surgery and definitive chemoradiotherapy [56–58]. Because all these reports are
from overseas, however, they differed greatly in the therapy regimens and treatment
policies adopted as compared with those adopted in Japan. In regard to observational
studies, 22 reports of studies comparing surgery and definitive chemoradiotherapy
in patients with cStage II or III esophageal cancer, including 10 papers from Japan,
were retrieved [36, 38, 42, 59–76]. None of the studies was a randomized controlled
study, so that the background factors of the patients differed among studies, and
the therapeutic regimens adopted were different from those currently adopted as standard
treatments in Japan. As for the survival time, 10 of the 22 papers indicated that
surgery yielded a significant prolongation of the overall survival time. Only one
paper indicated prolongation of the overall survival time following definitive chemoradiotherapy.
Of the three systematic reviews, one reported a significant prolongation of the overall
survival time in patients treated by surgery, while the remaining two showed no significant
difference in the overall survival between the two modalities [77–79]. Thus, it was
rather difficult to provide a clear and definitive response to this CQ on the ground
of the evidence obtained from the systematic review.
In regard to the toxicity, the late toxicities reported in the patients who received
definitive chemoradiotherapy in the JCOG9906 Study were esophagitis (Grade 3–4; 13%),
pericardial effusion (Grade 3–4; 16%), pleural effusion (Grade 3–4; 9%), and radiation
pneumonitis (Grade 3–4; 4%); death of four cases was also reported [80]. Out of the
22 observational studies, 6 from Japan reported operation-related deaths at an incidence
rate of 0–4% among patients treated by surgery. In the JCOG9907 Study, there were
two cases of operation-related death among 330 cases. It should be noted that there
is a potential risk of serious complications among patients receiving definitive chemoradiotherapy
as well as among those treated by surgery [81].
The basis for considering that surgery may yield greater improvement of the overall
survival rate as compared to definitive chemoradiotherapy is thus rather tenuous,
and both treatment modalities entail a significant risk of toxicity. However, the
5-years survival rate obtained with preoperative chemotherapy plus surgery in the
JCOG9907 Study was 55%, as compared to 37% in the JCOG9906 Study. The JCOG1406A Study,
which is a sub-study comparing the JCOG9906 and JCOG9907 studies, reported that surgery
significantly improved the overall survival rate as compared with definitive chemoradiotherapy
(HR 1.72 [95% CI 1.19–2.50]) [80, 81]. The JCOG1109 Study, the results of which were
published in January 2022, showed that preoperative docetaxel + cisplatin + 5-fluorouracil
(5-FU) (DCF) therapy prolonged the survival as compared with preoperative cisplatin + 5-FU
(CF) therapy, which had been the standard treatment (3-year survival rate: preoperative
CF therapy, 62.6%; DCF therapy, 72.1%) (HR: 0.68 [95% CI 0.50–0.92]) [82]. In addition,
many observational studies conducted in Japan have revealed more gratifying results
in groups treated by surgery. Therefore, we concluded that “there is strong evidence
to recommend preoperative triplet chemotherapy with docetaxel + cisplatin + 5-FU plus
surgery for the treatment of cStage II or III esophageal cancer”.
The JCOG0909 Study assessed the usefulness of preoperative definitive chemoradiotherapy
followed by positive surgical intervention as salvage operation in patients with cStage
II or III esophageal cancer [83]. In the JCOG0909 Study, a three-dimensional treatment
plan and multiple-field irradiation were introduced and the fractional and total radiation
doses were modified to 1.8 Gy and 50.4 Gy, respectively, in an attempt to reduce the
risk of adverse events and the risk associated with salvage esophagectomy that was
seen in the JCOG9906 Study. According to the report of the final analysis, 2 of the
96 patients enrolled in the study were excluded from the analysis, and 55 patients
(59%) had a complete response. The 5-years overall survival rate was 64.5% (95% CI
53.9–73.3), the 5-year recurrence-free survival rate was 48.3% (95% CI 37.9–58.0),
and the 5-year esophagus preservation rate was 54.9% (95% CI 44.3–64.4). Grade 3 or
higher late toxicity was observed in 8 patients (8.5%). Twenty-five patients (26.0%)
underwent salvage surgery (esophagectomy in 20 cases and lymph node dissection alone
in 5 cases), and of these patients, 5 (20.0%) developed grade 3–4 surgery-related
complications and there was 1 case of surgery-related death. However, R0 surgery could
be achieved in 76.0% of the patients, suggesting that salvage surgery could be an
effective treatment option if the indication is carefully selected. The results of
the JCOG0909 Study suggest that definitive chemoradiotherapy at the dose of 50.4 Gy
is one of the valid treatment options for patients with cStage II or III esophageal
cancer who do not wish to undergo surgery as the primary treatment.
Both surgery and definitive chemoradiotherapy as primary treatment are covered by
the national health insurance, and taking into consideration the risk–benefit balance,
strength of evidence, and patient preferences, we concluded to state that there is
weak evidence to recommend surgery as the primary treatment for patients with cStage
II or III esophageal cancer.
CQ8: Which is recommended—preoperative chemotherapy or preoperative chemoradiotherapy—in
cStage II or III esophageal cancer patients scheduled to receive surgery as the primary
treatment?
Recommendation statement
In patients with cStage II or III esophageal cancer who are scheduled to receive surgery
as the primary treatment, there is strong evidence to recommend preoperative triplet
chemotherapy with docetaxel + cisplatin + 5-FU. (Rate of consensus: 84% [21/25], strength
of evidence: A).
Explanatory note
In patients with cStage II or III esophageal cancer who are scheduled to receive surgery
as the primary treatment, preoperative chemotherapy with cisplatin and 5-FU + surgery
is recommended as the standard treatment in Japan, based on the results of the JCOG
9907 Study [81]. However, the optimal preoperative adjuvant therapy regimen has remained
controversial, and numerous discussions have been held on the appropriateness of intense
chemotherapy regimens and of chemotherapy combined with radiation therapy.
A search of the literature conducted to provide a response to this CQ yielded 278
PubMed articles, 47 Cochrane articles, and 293 ICHUSHI articles, which were subjected
to primary and secondary screenings. Finally, six reports of randomized controlled
studies and three reports of observational studies were retrieved and subjected to
a qualitative systematic review.
There were three reports of randomized controlled studies [84–86] and three reports
of observational studies [87–89] from overseas, comparing the results of preoperative
chemotherapy + surgery and preoperative chemoradiotherapy + surgery. None of the studies
found a significant difference in the 5-year survival rate between preoperative chemotherapy + surgery
and preoperative chemoradiotherapy + surgery. There are 4 reports of randomized controlled
studies from overseas comparing the adverse events of preoperative chemotherapy + surgery
versus preoperative chemoradiotherapy + surgery. Although the surgery-related and
non-surgery-related mortality rates and the mortality rate within 90 days of surgery
did not differ significantly between the two modalities [86, 90], the incidence of
severe adverse events was significantly higher in the preoperative chemoradiotherapy + surgery
group [90], and odynophagia after preoperative treatment, impaired cardiac function
after surgery, and symptoms that lower the quality of life (QOL), such as cough, were
significantly more common in the preoperative chemoradiotherapy + surgery group [91,
92]. However, these studies also included many patients with esophageal adenocarcinoma
or carcinoma of the esophagogastric junction, neither of which is common in Japan,
and used different chemotherapy regimens/doses and radiation doses from those that
are currently adopted as current standard treatment in Japan. Therefore, it is considered
inappropriate to extrapolate these results to answer the CQ.
In Japan, the results of the JCOG1109 Study comparing 3 regimens of preoperative adjuvant
therapy in patients with cStage II or III esophageal cancer scheduled to undergo surgery
were presented in January 2022 [82, 93], based on which we arrived at a conclusion
to respond to this CQ (presented at ASCO-GI 2022). The JCOG1109 Study is a phase III
randomized controlled study comparing doublet preoperative chemotherapy with cisplatin + 5-FU
(preoperative CF group), which is the current standard treatment, and preoperative
triplet chemotherapy with docetaxel + cisplatin + 5-FU (preoperative DCF group), and
between CF and preoperative chemoradiotherapy with CF + radiation at 41.4 Gy (preoperative
CF-RT group). DCF yielded a significant prolongation of the overall survival time
as compared with CF, and the incidence of perioperative complications remained acceptable
in the DCF group. On the other hand, the study failed to show the superiority of CF-RT
over CF in terms of the overall survival [82].
Both preoperative chemotherapy and preoperative chemoradiotherapy are covered by the
national health insurance, and taking into consideration the risk–benefit balance,
strength of evidence, and patient preferences, we concluded that in patients with
cStage II or III esophageal cancer who are scheduled to receive surgery as the primary
treatment, there is strong evidence to recommend preoperative triplet preoperative
chemotherapy with docetaxel + cisplatin + 5-FU. However, the JCOG1109 Study included
only patients aged up to 75 years of age from institutions that manage many patients
with esophageal cancer and participate in Japan Clinical Oncology Group (JCOG) studies;
therefore, the current standard treatment, i.e., preoperative doublet chemotherapy
with cisplatin + 5-FU, will continue to remain a treatment option for elderly patients
and those with comorbidities who are considered unable to tolerate triplet chemotherapy
and for institutions with little experience in the use of triplet chemotherapy. In
addition, the significance of preoperative chemoradiotherapy in patients with borderline
resectable (br) T3 disease could not be excluded, and preoperative treatment combined
with radiation should also be considered, according to the needs of individual cases.
CQ9: Is postoperative adjuvant therapy recommended in cStage II or III esophageal
cancer patients who have undergone preoperative adjuvant therapy plus surgery?
Recommendation statement
In patients with cStage II or III esophageal cancer who failed to show a pathologic
complete response after preoperative chemoradiotherapy plus surgery with radical resection,
there is strong evidence to recommend postoperative nivolumab therapy, regardless
of the histologic type or tumor expression level of programmed death ligand 1 (PD-L1).
(Rate of consensus: 81% [21/26], strength of evidence: A)
In patients with cStage II or III esophageal cancer who have undergone preoperative
chemotherapy plus surgery with radical resection, but failed to achieve a pathologic
complete response, there is currently no evidence to recommend postoperative nivolumab
therapy. (Rate of consensus: 92% [24/26], strength of evidence: D)
Explanatory note
A search of the literature to provide a response to this CQ yielded 208 PubMed articles,
31 Cochrane articles, and 101 ICHUSHI articles, along with 2 additional articles through
primary screening; secondary screening of these articles led to the retrieval of 3
reports of randomized controlled studies [81, 94, 95], which were then subjected to
a qualitative systematic review.
Preoperative chemotherapy plus surgery is currently the standard treatment for cStage
II or III thoracic esophageal squamous cell carcinoma in Japan, as, while surgery
plus postoperative chemotherapy was demonstrated to be superior to surgery alone in
the JCOG9204 Study, the JCOG9907 Study demonstrated the superiority of preoperative
chemotherapy over postoperative chemotherapy. There was only one report of a randomized
controlled study pertinent to this CQ, which was from overseas [95]. According to
this randomized controlled study, the 5-years recurrence-free survival rate was 35.0%
in patients who received postoperative adjuvant chemotherapy after preoperative chemotherapy
plus radical surgery, and 19.1% in a matched group that did not receive postoperative
adjuvant chemotherapy (HR 0.62, p < 0.001) [95]. However, the report contains no detailed
descriptions of randomization, blinding, or preoperative staging of the disease, and
furthermore, the surgical procedures and chemotherapy described in the report differed
from those used in Japan; therefore, we consider that the results of this study are
not directly applicable to the clinical practice setting in Japan. Since the randomized
controlled studies of preoperative/postoperative chemotherapy reported from Europe
have been performed in patients with esophageal adenocarcinoma [96, 97], it would
be inappropriate to extrapolate the results of those studies to answer this CQ.
In 2021, the CheckMate 577 study provided new evidence on the usefulness of nivolumab
as postoperative chemotherapy [98]. This was an international phase III randomized
controlled study conducted in Japan and other countries in patients with cStage II
or III esophageal cancer or carcinoma of the esophagogastric junction in whom R0 resection
was achieved following preoperative chemoradiotherapy. The patients enrolled in the
study were randomized 2:1 to receive nivolumab or placebo (a total of 794 patients
consisting of 532 in the nivolumab group and 262 in the placebo group), and the disease-free
survival (primary endpoint of the study) was 22.4 months (95% CI 16.6–34.0 months)
in the nivolumab group and 11.0 months (95% CI 8.3–14.3 months) in the placebo group;
thus, the results demonstrated the superiority of nivolumab with statistically significance
(HR 0.69, 96.4% CI 0.56–0.86, p < 0.001).
While deciding to recommend nivolumab in the guidelines, we wish to make a note of
the following points in the CheckMate 577 study: (1) The efficacy and safety of nivolumab
exclusively in the Japanese population was not reported; (2) the efficacy and safety
of nivolumab following preoperative chemotherapy was not established; (3) the efficacy
of nivolumab in patients who showed pathologic complete response to preoperative therapy
was not established; and (4) no data on the overall survival were shown, and the long-term
efficacy, including the therapeutic response after recurrence remains to be established.
However, the usefulness of nivolumab as postoperative chemotherapy in the overall
subject population was demonstrated, and furthermore, nivolumab was well-tolerated,
with an acceptable incidence of adverse events.
Therefore, taking into consideration the risk–benefit balance, our recommendations
on postoperative chemotherapy are as follows:
In patients with cStage II or III esophageal cancer who have undergone preoperative
chemoradiotherapy plus surgery with radical resection, but failed to achieve a pathologic
complete response, there is strong evidence to recommend postoperative nivolumab therapy,
regardless of the histologic type or tumor expression level of programmed death ligand
1 (PD-L1). (Rate of consensus: 81% [21/26], strength of evidence: A).
In patients with cStage II or III esophageal cancer who have undergone preoperative
chemotherapy plus surgery with radical resection, but failed to achieve a pathologic
complete response, there is currently no evidence to recommend postoperative nivolumab
therapy. (Rate of consensus: 92% [24/26], strength of evidence: D).
CQ11: Is salvage surgery recommended for residual or recurrent lesions after chemoradiotherapy
in patients with untreated resectable esophageal cancer?
Recommendation statement
There is weak evidence to recommend salvage surgery for residual or recurrent lesions
after chemoradiotherapy in patients with untreated resectable esophageal cancer. (Rate
of consensus: 96.4% [27/28], strength of evidence: C).
Explanatory note
There are limited treatment options for residual or recurrent lesions after definitive
chemoradiotherapy. Although salvage surgery has been reported to be the only radical
treatment for resectable lesions, it has a high perioperative mortality rate, and
its usefulness has not been established.
A search of the literature to provide a response to this CQ yielded 337 PubMed articles,
144 Cochrane articles, and 100 ICHUSHI articles, which were subjected to primary and
secondary screenings, leading to the retrieval of 6 reports of retrospective studies
[99–104]. Examination of the 30-day mortality as a short-term outcome, and of the
3-year and 5-year survival rates as long-term outcomes resulted in the exclusion of
two papers [103, 104]. The remaining four papers [99–102], along with the results
of the JCOG0909 Study [83]. Two of the studies compared salvage surgery after definitive
chemoradiotherapy and scheduled surgery after preoperative chemoradiotherapy (using
propensity score matching in one study). One of the studies compared salvage chemoradiotherapy
and salvage surgery. The remaining two studies analyzed only salvage surgery. None
of the studies is very directly relevant to the CQ, and there are no reports of randomized
controlled studies comparing salvage surgical therapy and non-surgical therapy. Therefore,
we investigated the outcomes of salvage surgery for residual or recurrent lesions
after definitive chemoradiotherapy.
All studies comparing salvage surgery after definitive chemoradiotherapy and scheduled
surgery after preoperative chemoradiotherapy were from overseas. According to these
reports, there were no significant differences in the 30-days mortality rate after
salvage surgery (3.1–11.4%) and scheduled surgery following preoperative chemoradiotherapy
(4.6–8.4%) or in the 3-years survival rate after salvage surgery (20–48%) and scheduled
surgery following preoperative chemoradiotherapy (43.4–55%).
According to the JCOG9906 Study, which investigated the usefulness of definitive chemoradiotherapy
in patients with untreated resectable esophageal cancer (cStage II or III, excluding
T4) who did not wish to undergo surgery as initial treatment in Japan, the median
survival was 29 months, the 3-years overall survival rate was 44.7%, and the 5-years
overall survival rate was 36.8%. Seventy-six patients were enrolled, and ten of the
patients (13.2%) eventually underwent salvage surgery for residual or recurrent lesions.
The patients who underwent salvage surgery showed a median survival of 16.7 months
and a 3-year overall survival rate of 40% [80]. The JCOG0909 Study also included patients
with cStage II or III (non-T4) esophageal cancer but planned to perform salvage surgery
for residual or recurrent lesions. Ninety-six patients were enrolled, and 27 of the
94 patients analyzed (28.7%) underwent salvage surgery for residual or recurrent lesions,
with R0 resection achieved in 19 patients (76.0%). Five of the patients who underwent
salvage surgery (20.0%) developed ≥ Grade 3 complications and 1 patient (4.0%) died
in the perioperative period. The salvage surgery yielded gratifying results, with
a 3-year overall survival rate (primary endpoint) of 74.2%, indicating the usefulness
of definitive chemoradiotherapy for patients with resectable esophageal cancer in
whom salvage surgery is planned for residual or recurrent lesions.
When residual or recurrent lesions are found after definitive chemoradiotherapy, salvage
surgery is the only radical treatment for resectable lesions. In radiotherapy in definitive
chemoradiotherapy, three-dimensional treatment planning allows optimization of the
doses to the tumor and risk organs, enabling highly accurate treatment, and the optimal
total dose and irradiation area are determined highly accurately. In regard to salvage
surgery for residual or recurrent lesions, improvements in the operative procedures
and advances in perioperative management have reduced the incidence of perioperative
complications and the perioperative mortality. We concluded that there is weak evidence
to recommend salvage surgery for residual or recurrent lesions after chemoradiotherapy
in patients with untreated resectable esophageal cancer, while it is necessary to
give careful consideration to the safety of the surgery and perioperative managements,
and to obtain the patient’s informed consent after providing an explanation of the
risks of the surgery.
Treatment algorithm for cStage IVA esophageal cancer (Fig. 3)
Fig. 3
Treatment Algorithm for cStage IVA Esophageal Cancer
Summary
Although cStage IVA esophageal cancer is unresectable, the lesion is localized, and
chemoradiotherapy is expected to provide cure, if it is well-tolerated by the patient.
In chemoradiotherapy, attention should be paid not only to adverse events during treatment,
but also to late adverse events after completion of treatment. The possible need of
salvage surgery for residual or recurrent lesions after chemoradiotherapy may entail
an increase in the risk of operation-related death; therefore, it is necessary to
judge the situation comprehensively with due consideration given to the risk–benefit
balance, based on tumor status, patient’s condition, and other available treatment
options.
In patients who cannot tolerate chemoradiotherapy, radiation alone should be considered,
but it has been reported to be inferior to chemoradiotherapy in terms of therapeutic
response.
CQ12: Is chemoradiotherapy recommended for unresectable cStage IVA esophageal cancer?
Recommendation statement
There is only weak evidence to recommend definitive chemoradiotherapy for the treatment
of unresectable cStage IVA esophageal cancer. (Rate of consensus: 100% [28/28]; strength
of evidence: C).
Explanatory note
A search of the literature to provide a response to this CQ yielded 271 PubMed articles,
22 Cochrane articles, and 147 ICHUSHI articles, along with additional 4 other papers.
Ninety-three papers were retrieved through primary screening, and 7 papers were extracted
through secondary screening and subjected to a qualitative systematic review. There
were no reports addressing the population-intervention-comparison-outcome (PICO) question
consistent with this CQ, and 4 reports of phase I/II studies of definitive chemoradiotherapy,
1 report of a phase II study of induction chemotherapy, and 2 reports of randomized
controlled studies involving chemoradiotherapy were retrieved.
Definitive chemoradiotherapy is one of the treatment options that could offer an opportunity
for cure in patients with unresectable, locally advanced esophageal cancer. However,
fatal complications (e.g., tumor perforation, penetration) could also occur in association
with a favorable response to chemoradiotherapy. In Japan, in view of the results of
the JCOG0303 Study, definitive chemoradiotherapy is often selected for the treatment
of patients with unresectable, locally advanced esophageal cancer with a good PS.
The validity of this treatment modality was examined by comparison of the percentage
of cases showing long-term survival (merit) and the incidence of fatal complications
(demerit).
Although there is a paucity of data on the long-term survival, the 2- or 3-years survival
rate is reported to be in the range of about 20–30% [105–107], and the percentage
of patients showing long-term survival is estimated to be about 15–20%. The patient
populations in these studies included a certain proportion of patients with a performance
status (PS) score of 2, and a common feature of these studies was that the prognosis
was unfavorable in patients with factors related to a poor PS, such as “weight loss
from the usual weight,” suggesting the possibility that a significant proportion of
the long-term survivors were those with a good PS. Meanwhile, fatal complications
(perforation, penetration) were encountered in about 10–20% of unresectable cStage
IVA patients.
One of the extracted reports pertained to comparison of radiation alone vs. chemoradiotherapy
in patients with unresectable, locally advanced esophageal cancer [105]. This was
a somewhat old, low-quality randomized controlled study, and the results showed no
significant intergroup difference in the survival time, although it should be noted
that the radiation/chemotherapy schedule was greatly different from the currently
used schedules. Of the remaining five papers, three pertained to studies of chemoradiotherapy
[106–108] and two were reports of single-group prospective studies of chemoradiotherapy
administered after induction chemotherapy [109, 110] (Note: the JCOG0303 Study, a
randomized controlled study, is treated as a single-group prospective study in this
section because both treatment groups in this study received chemoradiotherapy).
The chemotherapy regimens used in the studies referred to herein were mainly fluoropyrimidine + cisplatin,
use of which is within the scope of coverage by the national health insurance in Japan.
As for definitive chemoradiotherapy for patients with unresectable cStage IVA esophageal
cancer with a good PS, there are no reports of direct comparison with other treatment
options (no treatment, radiation alone, or chemotherapy alone), although there is
a likelihood of some success in terms of cure or long-term survival with definitive
chemoradiotherapy. From the above results and taking into account the risk–benefit
balance, strength of evidence, and patient preferences, we conclude that there is
only weak evidence to recommend definitive chemoradiotherapy for the treatment of
unresectable cStage IVA esophageal cancer. However, the risk of fatal complications,
with a reported incidence of about 10–20%, may be inevitable with this treatment modality,
which should therefore be selected only after sufficient discussion between the physician
and patient about the merits and demerits of the treatment.
Recent advances in chemotherapy have led to the development of a treatment modality
with high antitumor efficacy, in which induction chemotherapy is administered to resolve
unresectable factors followed by radical surgery in patients with initially unresectable,
locally advanced esophageal cancer. A phase II study reported very promising results
with a median overall survival of about 34 months and a treatment-related mortality
rate of 0% [111], and a randomized controlled study (JCOG1510) [112] comparing definitive
chemoradiotherapy and surgery after induction chemotherapy in patients with unresectable,
locally advanced esophageal cancer is ongoing.
CQ13: Is additional chemotherapy recommended for cStage II
,
III or IVA esophageal cancer patients who show complete response after definitive
chemoradiotherapy?
Recommendation statement
There is only weak evidence to recommend additional chemotherapy for cStage II, III,
or IVA esophageal carcinoma patients who show complete response to definitive chemoradiotherapy.
(Rate of consensus: 96.4% [27/28]; evidence level: C).
Explanatory note
A search of the literature to provide a response to this CQ yielded 36 PubMed articles,
92 Cochrane articles, and 253 ICHUSHI articles. Ten papers were extracted through
primary screening, and three papers extracted through secondary screening were subjected
to a qualitative systematic review [113–115]. There was no report of any study comparing
additional chemotherapy vs. follow-up observation in patients showing complete response
to chemoradiotherapy.
All the three papers were reports of retrospective studies from China, and two of
the reports compared the therapeutic outcomes between patients who received and did
not receive additional chemotherapy after chemoradiotherapy. In one of the reports,
patients treated by chemoradiotherapy were divided into two groups according to the
therapeutic response (complete response [CR]/partial response [PR] group and stable
disease [SD]/progressive disease [PD] group), and therapeutic outcomes were compared
between patients who received and did not receive additional chemotherapy [113]. Both
of the studies which included patients treated by chemoradiotherapy showed that the
patients who received additional chemotherapy showed a better overall survival (OS)
[114, 115]. On the other hand, in the report in which the efficacy of additional chemotherapy
was evaluated in two groups divided according to the therapeutic response, additional
chemotherapy resulted in a better OS in the SD/PD cases, but not in the CR/PR cases.
Based on these three reports, the benefit of additional chemotherapy in patients showing
complete response to chemoradiotherapy could not be established.
There is no evidence to support additional chemotherapy for patients showing complete
response to concurrent chemoradiotherapy, and the significance of such therapy has
not been clarified. In past large-scale clinical studies of current chemoradiotherapy,
however, two cycles of additional chemotherapy were included and are generally recognized
as an international standard [116, 117]. Nevertheless, careful consideration should
be given, because the risks may outweigh the benefits depending on the patient’s condition.
Thus, taking into account the risk–benefit balance, strength of evidence, and patient
preferences, there is only weak evidence to recommend additional chemotherapy for
cStage II, III, or IVA esophageal carcinoma patients who show complete response to
definitive chemoradiotherapy.
CQ14: Is surgical resection recommended for patients with unresectable, locally advanced
esophageal cancer (cT4 [e.g., aorta, trachea, bronchus] N0-3M0) that becomes resectable
after definitive chemoradiotherapy or induction chemotherapy?
Recommendation statement
There is only weak evidence to recommend surgical resection for patients with unresectable,
locally advanced esophageal cancer (cT4 [e.g., aorta, trachea, bronchus] N0-3M0) that
becomes resectable after definitive chemoradiotherapy or induction chemotherapy. (Rate
of consensus: 89.3% [25/28]; evidence level: C).
Explanatory note
A search of the literature to provide a response to this CQ yielded 1527 PubMed articles,
35 Cochrane articles, and 168 ICHUSHI articles, along with one additional article.
Sixty-four papers were extracted through primary screening, and 13 papers were extracted
through secondary screening (including 9 reports of Japanese single-center retrospective
cohort studies, 1 report of an observational study based on the United States National
Cancer Data Base, 2 reports of the short-term and long-term outcomes, respectively,
in a Japanese multicenter phase II study, and 1 systematic review).
The usefulness of surgery in patients with locally advanced esophageal cancer that
is judged to be unresectable at diagnosis, but becomes resectable following definitive
chemoradiotherapy or induction chemotherapy was examined; however, as there was no
report of any randomized controlled study conducted to compare surgical and non-surgical
treatments, reports of the outcomes of surgery after the initial treatment were reviewed.
The current standard treatment for unresectable, locally advanced esophageal cancer
in Japan, based on the data of the JCOG0303 Study, is concurrent standard-dose cisplatin + 5FU + 60 Gy
radiotherapy; patients who received the protocol-specified treatment showed a 1-year
overall survival rate of 55.9% and a 3-years overall survival rate of 25.9%, and 16.9%
of the patients (12 of the 71 patients) underwent surgery for residual or recurrent
lesions after completion of the protocol-specified treatment [106].
The Japanese retrospective cohort studies reported 3-drug combined regimens consisting
of docetaxel in addition to cisplatin and 5-FU as the main drugs, or regimens containing
nedaplatin or adriamycin, as the chemotherapy component of chemoradiotherapy for the
initial treatment, as well as 3-drug combined regimens, consisting mainly of cisplatin,
5-FU and docetaxel, as induction chemotherapy. The initial treatment regimens as well
as the radiation doses varied among the studies. The sample sizes ranged from as small
as 12, to 72 [118–127], and a large number of patients dropped out of some of the
studies. Patients who underwent surgery after the initial treatment showed a 1-year
overall survival rate of 45.7–88.9% [119, 120, 123, 127], a 3-years overall survival
rate of 35.2–65.0% [118, 121, 125, 127], a 5-years overall survival rate of 5.7–51.6%
[119–122], and an R0 resection rate of 42.4–92.1% [118–126]; thus, the outcomes varied
among the studies. The in-hospital mortality rate was 0.0–8.6% [118–125], the overall
incidence of ≥ Grade III postoperative complications according to the Clavien-Dindo
classification was 20.0–33.0% [120, 122, 123], and the major postoperative complications
were pneumonia in 12.5–28.6% of the cases [118–120, 125], anastomotic leakage in 8.3–25.0%
of the cases [118–121, 123, 125], and recurrent laryngeal nerve paralysis in 9.7–44.4%
of the cases [118–121].
In a Japanese, multicenter, phase II study evaluating the efficacy of induction chemotherapy
(three cycles of cisplatin + 5-FU + docetaxel) followed by radical resection (COSMOS)
based on evaluation of the effect of induction chemotherapy, resectable patients underwent
surgery, while unresectable patients received definitive chemoradiotherapy, and if
the cancer became resectable after irradiation at 40–60 Gy, conversion surgery was
undertaken. Of the 48 patients enrolled, 42% (20 patients) underwent surgery, corresponding
to an R0 resection rate of 95.0% (19/20 cases). In the enrolled patient population
overall, the 1- and 3-years overall survival rates were 66.7%, 46.6%, respectively,
and the 1- and 3-years progression-free survival rates were 50.6% and 39.6%, respectively.
In the 19 patients with R0 resection, the 1- and 3-year overall survival rates were
100.0% and 71.4%, respectively, and the 1- and 3-year progression-free survival rates
were 83.6% and 61.3%, respectively. There were no intraoperative complications such
as organ injury, and the Grade 3 postoperative complications according to the CTCAE
were recurrent laryngeal nerve paralysis, respiratory infection, wound infection,
pulmonary fistula, and dysphagia, in 4.8% of the patients each; there were no ≥ Grade
4 serious complications or postoperative in-hospital deaths [111, 128].
The systematic review revealed that patients who underwent surgery following the initial
treatment generally showed good long-term outcomes. Although it should be noted that
the study included mainly patients who became operable, the entire treatment including
the initial treatment was associated with a 3-years overall survival rate of 31.0–46.6%,
and the long-term outcomes of all patients, including those who did not undergo surgery,
were better than those in the JCOG0303 Study. The in-hospital mortality rate and incidence
of complications were somewhat higher than that in patients undergoing general surgical
procedures for cStage II or III esophageal cancer, but were still considered to be
within acceptable range because of the absence of other effective treatment options
and good outcomes after R0 resection. When R0 resection is expected to be achieved
based on the results of preoperative examination, there is only weak evidence to recommend
surgical resection for patients with unresectable, locally advanced esophageal cancer
(cT4 [e.g., aorta, trachea, bronchus] N0-3M0) that becomes resectable after definitive
chemoradiotherapy or induction chemotherapy; in addition, it is essential to give
careful consideration to the safety of surgery and perioperative management and to
obtain the patient’s informed consent after explaining the risks of surgery.
At present, a randomized phase III study (JCOG1510) comparing definitive chemoradiotherapy,
followed if necessary, by salvage surgery vs. induction chemotherapy with patients
who become resectable undergoing conversion surgery, is ongoing.
Treatment algorithm for cStage IVB esophageal cancer (Figs. 4 and 5)
Fig. 4
Treatment Algorithm for cStage IVB Esophageal Cancer
Fig. 5
Chemotherapy Regimen for cStage IVB Esophageal Cancer
Summary
cStage IVB esophageal cancer represents cancer progression to the stage beyond localized
disease and requires systemic treatment. First, the patient’s general condition and
organ functions should be assessed. If judged to be potentially tolerable, chemotherapy
is considered. If the patient has malnutrition due to reduced oral intake, dehydration,
or respiratory infection due to aspiration, treatment should be administered to alleviate
the symptoms to the extent possible before chemotherapy is considered. Chemotherapeutic
drugs and doses should be selected according to the tolerability of the patient judged
by the general condition and organ functions. Pain should be actively controlled by
reference to the World Health Organization (WHO) guideline for cancer pain relief,
etc. Chemotherapy should be considered as a systemic treatment; however, in patients
with local lesions such as esophageal stenosis, airway obstruction, or bone metastasis
causing pain, which may greatly interfere with the daily life or directly affect life
prognosis, chemoradiotherapy is also considered as a local treatment. Patients in
poor general condition for chemotherapy may be treated by radiotherapy alone. In this
case, treatment to reduce the symptoms associated with cancer should continue to be
actively undertaken.
The purpose of treatment was not to completely cure the cancer, but to allow patients
to live their daily lives while keeping the cancer manifestations under control, and
it is important to monitor the patient’s condition periodically to evaluate and decide
about whether treatment should be continued.
CQ15: What chemotherapy would be recommended as first-line therapy for patients with
unresectable, advanced/recurrent esophageal cancer?
Recommendation statement
① There is strong evidence to recommend pembrolizumab + cisplatin + 5-FU therapy as
first-line therapy for the treatment of patients with unresectable, advanced/recurrent
esophageal cancer. (Rate of consensus: 92.3% [24/26]; strength of evidence: A).
② There is strong evidence to recommend nivolumab + cisplatin + 5-FU therapy or nivolumab + ipilimumab
therapy as first-line therapy for unresectable, advanced/recurrent esophageal cancer,
but the patient’s general condition, tumor PD-L1 expression level (tumor proportion
score [TPS]), and treatment tolerability should be taken into account. (Rate of consensus:
88.0% [22/25]; strength of evidence: A).
Explanatory note
A search of the literature to provide an answer to this CQ yielded 866 PubMed articles,
193 Cochrane articles, and 156 ICHUSHI articles, along with 3 additional papers. Fifty-eight
papers were retrieved through primary screening, and 28 papers were extracted through
secondary screening. There were five reports of randomized controlled trials pertinent
to this CQ and 23 reports of prospective studies of intervention by chemotherapy.
These studies were subjected to a qualitative systematic review.
There are no chemotherapy regimens that have demonstrated clear prolongation of the
survival as compared with best supportive care alone in patients with unresectable,
advanced/recurrent esophageal cancer. Relatively old studies comparing cisplatin monotherapy
and cisplatin + 5-FU combination therapy failed to demonstrate the superiority of
combination therapy. Studies comparing cisplatin + 5-FU combination therapy with and
without cetuximab as first-line therapy did not show any clear add-on effect of cetuximab.
Similarly, studies investigating the additional effect of panitumumab, another anti-EGFR
antibody, on cisplatin + 5-FU combination therapy could not confirm efficacy. Combined
cisplatin plus 5-FU therapy yielded a response rate of about 30% and a median survival
time of 6.6–9.5 months [129–133], which have been recognized as the standard treatment.
Chemotherapy regimens using cisplatin in combination with paclitaxel [134], irinotecan
[135], or capecitabine [136], instead of 5-FU, have been reported to show comparable
efficacy to combined cisplatin + 5-FU therapy; however, these regimens have not been
recognized as standards. The adverse events were ≥ Grade 3 neutropenia, nausea, and
malaise, in about 10% of the cases each. Combined treatment with 5-FU and nedaplatin,
as an alternative to cisplatin, was also assessed in a phase II study, with the results
showing a response rate of about 39.5% and a median survival time of 8.8 months, so
that nedaplatin has come to be recognized as the drug of choice in patients in whom
cisplatin cannot be used due to renal function and/or cardiac function [137]. Clinical
studies of combined 5-FU plus oxaliplatin reported from overseas showed that oxaliplatin
as well as nedaplatin can be used even in patients with renal disfunction and those
who cannot receive large amounts of fluids. However, oxaliplatin must be administered
with intermission, dose reduction, or withdrawal because oxaliplatin accumulation
causes peripheral neuropathy.
Triplet chemotherapy regimens have recently been reported to show high efficacy, with
a reported response rate of about 60% and median survival of ≥ 10 months [138–142].
However, the superior efficacy in terms of overall survival to combined cisplatin + 5-FU
therapy, which is the standard treatment, has so far not been established. This regimen
should be used with care. At present, a randomized controlled study, JCOG1314, comparing
a triplet regimen, in which docetaxel is added every 2 weeks to cisplatin + 5-FU,
vs. combined cisplatin + 5-FU therapy is ongoing [143] and the results are still awaited.
Recently, immune checkpoint inhibitors were shown to be useful as second-line treatment,
and their usefulness as first-line chemotherapy was also evaluated. The KEYNOTE-590
study compared additional use of pembrolizumab vs. placebo in combination with the
standard treatment cisplatin + 5-FU in patients with advanced/recurrent esophageal
cancer as the first-line treatment. In squamous cell carcinoma patients with a combined
positive score (CPS) of ≥ 10, the median overall survival was 13.9 months (95% CI
11.1–17.7 months) in the pembrolizumab + chemotherapy group and 8.8 months (95% CI
7.8–10.5 months) in the placebo + chemotherapy group, demonstrating the superiority
of pembrolizumab + chemotherapy (HR 0.57, 95% CI 0.43–0.75, p < 0.0001). In patients
with squamous cell carcinoma, in patients with a CPS of ≥ 10, and in the overall population,
pembrolizumab + chemotherapy yielded a significantly better overall survival than
placebo + chemotherapy. The incidence of adverse events in the pembrolizumab + chemotherapy
group was somewhat higher, but it was still considered to be within acceptable range
[144]. The CheckMate 648 study compared the treatment outcomes of standard chemotherapy
cisplatin + 5-FU, nivolumab + chemotherapy, and 2 immune checkpoint inhibitors (nivolumab + ipilimumab)
alone in patients with advanced/recurrent, esophageal squamous cell carcinoma, as
the first-line treatment. In patients with a Tumor Proportion Score (TPS) of ≥ 1,
the median overall survival time was significantly longer in the nivolumab + chemotherapy
group (15.4 months; 95% CI 11.9–19.5 months) and nivolumab + ipilimumab group (13.7 months;
95% CI 11.2–17.0 months) as compared with that in the chemotherapy alone group (9.1 months;
95% CI 7.7–10.0 months). In the all randomized population, the median overall survival
time was also significantly longer in the nivolumab + chemotherapy group (13.2 months;
95% CI 11.1–15.7 months) and nivolumab + ipilimumab group (12.7 months; 95% CI 11.3–15.5 months)
as compared with that in the chemotherapy alone group (10.7 months; 95% CI 9.4–11.9 months).
However, it should be noted that nivolumab + chemotherapy and nivolumab + ipilimumab
tended to have variable effects depending on the tumor PD-L1 expression level (TPS).
Namely, in patients with a TPS of < 1, the overall survival of nivolumab + chemotherapy
and nivolumab + ipilimumab was comparable to that of chemotherapy. The incidence of
adverse events tended to be higher in the nivolumab + chemotherapy group as compared
with that in the nivolumab + ipilimumab group or chemotherapy alone group, but it
was still considered to be within acceptable range [145].
Thus, taking into account the risk–benefit balance, strength of evidence, and patient
preferences, we concluded that “there is strong evidence to recommend pembrolizumab + cisplatin + 5-FU
therapy as first-line therapy for the treatment of unresectable, advanced/recurrent
esophageal cancer” and that “there is strong evidence to recommend nivolumab + cisplatin + 5-FU
therapy or nivolumab + ipilimumab therapy as first-line therapy for the treatment
of unresectable, advanced/recurrent esophageal cancer, while it is also necessary
to take into account the patient’s general condition, tumor PD-L1 expression level
(TPS), and patient’s treatment tolerability”.
CQ16: What chemotherapy would be recommended as second-line therapy for patients with
unresectable, advanced/recurrent esophageal cancer refractory to first-line chemotherapy,
including fluoropyrimidine + platinum therapy?
Recommendation statement
(In patients without a history of anti-PD-1 antibody therapy).
In patients without a history of anti-PD-1 antibody therapy, there is strong evidence
to recommend nivolumab therapy (squamous cell carcinoma). (Rate of consensus: 100%
[25/25]; strength of evidence: A)
In patients without a history of anti-PD-1 antibody therapy, there is only weak evidence
to recommend pembrolizumab therapy (squamous cell carcinoma with a CPS of ≥ 10 or
MSI-H or TMB-H). (Rate of consensus: 96.2% [25/26]; strength of evidence: B)
(In patients without a history of taxane therapy).
c.
In patients without a history of anti-PD-1 antibody therapy or taxane therapy, there
is only weak evidence to recommend paclitaxel therapy. (Rate of consensus: 96.4% [27/28];
strength of evidence: C)
d.
In patients with a history of anti-PD-1 antibody therapy, but no history of taxane
therapy, there is only weak evidence to recommend paclitaxel therapy. (Rate of consensus:
100% [28/28]; strength of evidence: C)
Explanatory note
A search of the literature to provide a response to this CQ yielded 248 PubMed articles,
122 Cochrane articles, and 126 ICHUSHI articles, along with 2 other additional papers,
all of which were subjected to primary screening. Four papers dealing with randomized
controlled studies and 11 papers dealing with intervention studies were retrieved
through a secondary screening and subjected to a qualitative systematic review. The
following two randomized controlled studies demonstrated the efficacy of the anti-PD-1
antibodies nivolumab and pembrolizumab, respectively, as second-line therapy in patients
with unresectable, advanced/recurrent esophageal cancer refractory to first-line chemotherapy,
including combined fluoropyrimidine + platinum therapy [146, 147].
The ATTRACTION-3 study demonstrated the superiority of nivolumab (240 mg/body, every
2 weeks) over chemotherapy with paclitaxel or docetaxel in terms of the overall survival,
which was the primary endpoint of the study, in patients with squamous cell carcinoma
(median overall survival: 10.9 months in the nivolumab group and 8.4 months in the
chemotherapy group; HR 0.77 [95% CI 0.62–0.96]) [146]. Although nivolumab did not
show the superior progression-free survival, about a half of the patients received
taxanes as after-treatment. This suggested the efficacy of the subsequent-treatment
for the overall survival. The incidence of ≥ Grade 3 treatment-related adverse events
was 18% in the nivolumab group and 64% in the chemotherapy group. Although nivolumab
was superior in the overall population, no difference was observed in the progression-free
survival and nivolumab was suggested to be inferior in some patients, and administration
of paclitaxel may be considered in such patients.
The KEYNOTE-181 study in patients with squamous cell carcinoma or adenocarcinoma failed
to demonstrate the statistical superiority of pembrolizumab (200 mg/body, every 3 weeks)
over chemotherapy with paclitaxel, docetaxel, or irinotecan in terms of the overall
survival in the following three prespecified main analysis populations: (i) patients
with positive tumor PD-L1 expression (CPS ≥ 10); (ii) patients with squamous cell
carcinoma; and (iii) intention-to-treat population [147]. Although the analysis was
exploratory, pembrolizumab showed a longer overall survival than chemotherapy (HR
0.64 [95% CI 0.46–0.90]) (median overall survival: 10.3 months in the pembrolizumab
group and 6.7 months in the chemotherapy group) in squamous cell carcinoma patients
with positive tumor PD-L1 expression. The incidence of ≥ Grade 3 adverse events whose
relationship to the treatment could not be ruled out was 18% in the pembrolizumab
group and 41% in the chemotherapy group. The phase II KEYNOTE-158 study in patients
with solid tumors refractory to previous treatment showed a promising reduction of
the tumor size in patients with microsatellite instability high (MSI-H) or tumor gene
mutation burden high (TMB-H) treated with pembrolizumab (200 mg/body, every 3 weeks),
demonstrating the efficacy of this drug, regardless of the cancer type [148, 149].
According to a randomized controlled study of gefitinib, which is an inhibitor of
the epidermal growth factor receptor (EGFR) pathway, gefitinib did not prolong the
overall survival as compared with placebo in patients with adenocarcinoma or squamous
cell carcinoma of the esophagus or esophagogastric junction with a history of previous
treatment (median overall survival: 3.73 months in the gefitinib group and 3.67 months
in the placebo group; HR 0.90 [95% CI 0.47–1.09]) [150].
Of the 11 reports of intervention studies, two reports pertained to single-arm phase
II studies of paclitaxel and docetaxel, respectively [151, 152], and 1 report pertained
to a randomized phase II study of paclitaxel (100 mg/m2 administered weekly for 6 weeks
in a 7-week cycle) and docetaxel (70 mg/m2, every 3 weeks) as second-line chemotherapy
in patients with esophageal squamous cell carcinoma refractory to fluoropyrimidine-
and platinum-based chemotherapy [8, 153]. According to this randomized phase II study,
overall survival (median: 8.8 months in the paclitaxel group and 7.3 months in the
docetaxel group; HR 0.62 [95% CI 0.38–0.99]) and progression-free survival (median
4.4 months in the paclitaxel group and 2.1 months in the docetaxel group; HR 0.49
[95% CI 0.30–0.78]) were significantly longer in the paclitaxel group than in the
docetaxel group. Grade 3 or higher neutropenia (28% in the paclitaxel group and 80%
in the docetaxel group) and febrile neutropenia (0% in the paclitaxel group and 46%
in the docetaxel group) were more common in the docetaxel group.
In addition, there were also reports of combined irinotecan plus docetaxel therapy
[154] and combined docetaxel plus platinum drug therapy [155, 156]; neither reported
a great difference in efficacy between the combined therapy and monotherapy, however,
combined therapy tends to show higher toxicity than monotherapy.
In patients who received anti-PD-1 antibody therapy + chemotherapy as first-line therapy,
patients who received anti-PD-1 antibody therapy as adjuvant therapy following esophagectomy,
and patients who received chemotherapy including taxanes as preoperative chemotherapy,
it is necessary to select the appropriate second-line therapy for recurrence, considering
the history of treatment with these drugs and the time to recurrence.
Thus, taking into account the risk–benefit balance and strength of evidence, we formulated
different recommendation statements depending on the history of anti-PD-1 antibody
therapy and taxane therapy, as follows: in patients without a history of anti-PD-1
antibody therapy, there is strong evidence to recommend nivolumab therapy (squamous
cell carcinoma) and there is only weak evidence to recommend pembrolizumab therapy
(squamous cell carcinoma with a CPS of ≥ 10 or MSI-H or TMB-H), and in patients with/without
a history of anti-PD-1 antibody therapy and without a history of taxane therapy, there
is only weak evidence to recommend paclitaxel therapy.
CQ17: What would be recommended as third-line therapy for patients with unresectable,
advanced/recurrent esophageal cancer who received fluoropyrimidine + platinum combination
therapy as first-line therapy and anti-PD-1 antibody therapy as second-line therapy?
Recommendation statement
In patients without a history of taxane therapy, there is only weak evidence to recommend
paclitaxel therapy. (Rate of consensus: 100% [28/28], strength of evidence: C).
Explanatory note
A search of the literature conducted to respond to this CQ yielded 173 PubMed articles,
220 Cochrane articles, and 144 ICHUSHI articles, along with 4 other additional papers,
which were subjected to primary and secondary screenings. Finally, one report of a
randomized controlled study and five reports of intervention studies were retrieved
and subjected to a qualitative systematic review.
Although the results of intervention studies of EGFR inhibitors/monotherapies/combination
chemotherapies have been reported, there is no clear evidence to indicate whether
third-line therapy might be effective for prolonging the survival [150, 157–161].
In addition, the safety and efficacy of anti-PD-1 antibody therapy have not yet been
reported. However, in the ATTRACTION-3 study, the study treatment group received the
anti-PD-1 antibody nivolumab as second-line therapy after combined fluoropyrimidine + platinum
therapy, and about a half of the subjects received taxanes as after-treatment [146].
Although there was no significant difference in the progression-free survival between
the nivolumab and chemotherapy groups, the overall survival was significantly prolonged
in the nivolumab group. The results indirectly suggest that taxane therapy following
anti-PD-1 antibody therapy is safe and prolongs the survival.
As for taxanes as second-line chemotherapy, there is a report of a randomized phase
II study of paclitaxel and docetaxel in patients who were refractory to combined fluoropyrimidine + platinum
therapy [153]. The overall survival and progression-free survival were significantly
longer in the paclitaxel group than in the docetaxel group, and the incidences of ≥ Grade
3 neutropenia and febrile neutropenia were lower in the paclitaxel group. Although
taxanes were used as second-line chemotherapy in the study, the results suggest that
paclitaxel is a more appropriate choice than docetaxel even when taxanes are used
as third-line chemotherapy.
Thus, taking into account the risk–benefit balance and strength of evidence, we concluded
that in patients without a history of taxane therapy, there is only weak evidence
to recommend paclitaxel therapy.
CQ18 Is palliative radiotherapy recommended for the treatment of patients with cStage
IVB esophageal cancer presenting with obstruction?
Recommendation statement
There is only weak evidence to recommend palliative radiotherapy for the treatment
of patients with cStage IVB esophageal cancer presenting with obstruction. (Rate of
consensus: 100% [28/28]; strength of evidence: C).
Explanatory note
A search of the literature conducted to respond to this CQ yielded 192 PubMed articles,
139 Cochrane articles, and 236 ICHUSHI articles; of these, 25 papers were extracted
through primary screening, and 5 of these were extracted through secondary screening
and subjected to a qualitative systematic review.
A randomized comparative study of radiotherapy alone vs. chemoradiotherapy for the
treatment of esophageal cancer that could not be treated radically in patients presenting
with obstruction (TROG 03.01) revealed no significant difference in the percentage
of patients who showed improvement in the dysphagia between the radiotherapy alone
and chemoradiotherapy groups (35% vs. 45%, p = 0.13) and a significantly lower incidence
of Grade 3–4 adverse events in the radiotherapy alone group (16% vs. 36%, p = 0.0017)
[162, 163]. There was no difference in the median survival time between the radiotherapy
alone group (6.7 months) and chemoradiotherapy group (6.9 months). Although 56 of
the 220 subjects (26%) in this study had squamous cell carcinoma, 156 subjects (71%)
had cStage IVB disease, and radiotherapy with external irradiation at 35 Gy/15 Fr
or 30 Gy/10 Fr and combined chemoradiotherapy with cisplatin + 5-FU were adopted;
therefore, this study was closely related to this CQ.
There were two reports of randomized comparative studies conducted to compare the
therapeutic responses to radiotherapy and stenting [2, 3, 164, 165]. Earlier improvement
of dysphagia was observed in the metallic stent group in both reports, but the improvement
in the symptoms was better sustained in the radiotherapy (intracavitary brachytherapy)
group. The contents of these studies were perhaps not very pertinent to this CQ, because
intracavitary brachytherapy, which was used in both the studies, is scarcely adopted
in Japan; however, the results suggest that the local antitumor effect of radiotherapy
is more effective for providing sustained relief from dysphagia as compared with that
of stenting.
In regard to the irradiation methods, according to a prospective cohort study of intracavitary
brachytherapy and external irradiation, the percentage of patients who showed improvement
of the dysphagia tended to be higher in the external irradiation group than in the
intracavitary brachytherapy group (83% vs. 64%, p = 0.048), and the incidence of ≥ Grade
3 adverse events was lower in the external irradiation group (3% vs. 13%) [4, 166].
To sum up, radiotherapy is effective for improvement of dysphagia, and serious adverse
reactions are not necessarily common, although some adverse events do occur. Desire
for symptomatic amelioration is generally profound in patients with dysphagia and
this treatment is covered by the national health insurance. Taking into account the
risk–benefit balance, strength of evidence, cost burden, and patient preferences,
we concluded that there is only weak evidence to recommend palliative radiotherapy
for the treatment of patients with cStage IVB esophageal cancer presenting with obstruction.