Endoscopic treatment
Summary
Endoscopic resection (ER) includes endoscopic mucosal resection (EMR), wherein the
affected mucosal lesion is held or aspirated and resected with a snare, and endoscopic
submucosal dissection (ESD), which refers to en bloc resection of an extensive lesion
using an IT knife or hook knife [1–4]. Other endoscopic treatments available include
photodynamic therapy (PDT), argon plasma coagulation (APC), and electromagnetic coagulation
therapy.
General remarks
Indications for endoscopic resection
Among lesions in which the depth of invasion does not extend beyond the mucosal layer
(T1a), those confined within the mucosal EP or the LPM are only extremely rarely associated
with lymph-node metastasis; therefore, endoscopic resection is a sufficiently radical
treatment for these lesions. Lesions extending up to the muscularis mucosae or slightly
infiltrating the submucosa (up to 200 μm) are also amenable to mucosal resection;
however, they are associated with an elevated risk of lymph-node metastasis. Therefore,
these represent relative indications [5, 6]. Furthermore, about 50% of the lesions
that show deeper (more than 200 μm) invasion into the submucosa (T1b) are associated
with metastasis, and in such cases, even if they are classified as superficial carcinomas,
should be treated in the same manner as advanced carcinomas. Mucosal resection covering
3/4 of the entire circumference is likely to be associated with postoperative cicatricial
stenosis. Therefore, sufficient explanation should be given to the patient prior to
the operation and preventive measures must be taken [7, 8].
Diagnosis by histopathology of the resected tissue specimens
There are limitations to all the modes of diagnosis of the depth of tumor invasion
prior to treatment. It is also difficult to accurately determine the depth of invasion
of extensive lesions. Furthermore, preoperative diagnosis of the histologic type of
the invasive tumors or that of vascular invasion is impracticable. Histopathologic
examination of the resected tissue specimens is, therefore, important for determining
whether an additional treatment is required or not, and diagnosis of tissue specimens
obtained by en bloc resection is indispensable.
Treatment of lesions not amenable to endoscopic resection
Insufficient elevation of the mucosa after submucosal injection may pose difficulty
in additional ER of residual marginal lesions after ER, or ER after radiotherapy or
chemoradiotherapy. These cases and cases with a bleeding tendency are not suitable
for ER, and other treatment options such as PDT [9] and APC would need to be considered.
Superiority of en bloc resection
En bloc resection is desirable for histologic diagnosis of the resected specimens.
ESD enables en bloc resection of lesions that were formerly subjected to fractional
resection. Further development of equipment and spread of improved techniques are
anticipated.
Complications
Various complications, including bleeding (0.2%), esophageal perforation (1.9%), and
post-resection cicatricial stenosis (6.0–16.7%), have been reported in association
with ER [10]. Sufficient explanation should be provided to the patients, and measures
must be taken for prevention/treatment of these complications.
CQ18: is additional treatment recommended in cases detected to have pT1a-MM lesion
following endoscopic treatment for superficial esophageal cancer?
Recommendation statement
There is strong evidence to recommend an additional treatment in patients identified
as having a pT1a-MM lesion with positive vascular invasion after endoscopic treatment
(rate of consensus: 85% [17/20]; strength of evidence: D).
Explanatory note
There are no reports of randomized comparative or case–control studies demonstrating
the usefulness of additional treatment in patients in whom the resected specimens
collected at endoscopic treatment are histopathologically diagnosed as pT1a-MM lesions.
According to the reports based on the results of surgical treatment, the frequency
of lymph-node metastasis in resected specimens obtained from patients with pT1a-MM
squamous cell carcinoma was 0–27%, and summarization and analysis of data from major
reports revealed that it was present in 30/210 cases (14.2%; 95% CI 9.85–19.76) [11–18].
There are few or no reports on the frequency of metastasis in pT1a-MM adenocarcinoma
cases, however, that in cases of pT1a adenocarcinomas is reported to be in the range
of 0–5%; summarization and analysis of data from major reports revealed that it was
presented in 91/1882 cases (4.9%; 95% CI 3.95–5.9) [19–21]. Meanwhile, the frequency
of recurrent lymph-node metastasis in cases diagnosed from the resected specimens
collected at endoscopic treatment as pT1a-MM disease was 0–4.2% for squamous cell
carcinoma, with a tallied frequency of 5/223 (2.24%; 95% CI 0.73–5.15) [5, 17, 22],
and 0% for adenocarcinoma [23]. For squamous cell carcinomas, in particular, the frequency
of lymph-node metastasis differed markedly between cases with pT1a-MM disease identified
in surgical specimens and that identified in endoscopically resected specimens. This
difference in the frequency of lymph-node metastasis is considered to be mainly attributable
to the difference in the method of histopathologic diagnosis between surgical specimens
and endoscopically resected specimens. As surgical specimens are larger in size as
compared to endoscopically resected specimens, the possibility of cases diagnosed
as pT1a-MM disease of including pT1b cases cannot be ruled out. As a ground for this
presumption, it has been reported that the frequency of lymphatic invasion in pT1a-MM
cases substantially differs between cases who have undergone endoscopic resection
and those who have undergone surgery (pT1a-MM in endoscopically resected cases: 0–8.1%
[5, 17]; surgically treated cases: 18.2–41.2% [11–14, 17]).
Reports of studies conducted to identify the risk factors for lymph-node metastasis
in cases with superficial cancer of the esophagus limited to pT1a-MM cases are scarce.
It was from the analysis of the data of 50 pT1a-MM cases in one study, that the frequency
of lymph-node metastasis significantly differed between lymphatic invasion-negative
cases and lymphatic invasion-positive cases (negative cases: 4/38 (10.5%); positive
cases: 5/12 (41.7%) [14]. Multivariate analysis to identify the risk factors for lymph-node
metastasis revealed an odds ratio for positive lymphatic invasion of 3.63–6.11 for
T1 cases overall [15, 16], 3.83 for pT1a-MM/pT1b-SM1 cases [14], and 7.333 when the
analysis was limited to pT1a-MM cases [17]. Assessment of the risk factors for metachronous
metastasis in cases treated by endoscopic resection revealed a frequency of lymph-node
or distant metastasis of 3.73% (15/402) for the pT1 cases overall, 0.36% (1/280) for
pT1a-EP/LPM cases, 4.29% (3/70) for pT1a–MM cases, 11.7% (2/17) for pT1b-SM1 cases,
and 25.7% (9/35) for pT1b–SM2 cases; hence, the frequency increased progressively
with advancing depth of invasion, and multivariate analysis identified depth of invasion
as the sole significant risk factor, with a hazard ratio of 13.1 (95% CI 1.3–133.7,
p = 0.03) for pT1a-MM vs. pT1a-EP/LPM [22]. For superficial carcinomas overall, on
the other hand, positive lymphatic invasion failed to be identified as a significant
risk factor for metachronous metastasis; however, when the analysis was limited to
only pT1a cases, the 5-year cumulative incidence of metastasis was significantly higher
in the lymphatic metastasis-positive cases as compared to the lymphatic metastasis-negative
cases (46.7% vs. 0.7%, p < 0.0001) [22]. Cases diagnosed as having pT1a-MM cases after
endoscopic resection had a greater risk of recurrence of metastasis as compared to
those diagnosed as having pT1a-EP/LPM disease and positive lymphatic invasion may
be cited as a risk factor, although it is difficult to arrive at a conclusion, because
all the papers reviewed represented retrospectively accumulated case reports and an
additional treatment mainly consisting of chemoradiotherapy was administered to lymphatic
invasion-positive cases among the patients treated by endoscopic resection.
Surgical treatment or chemoradiotherapy is considered as a radical additional treatment
in patients diagnosed by histopathology of the endoscopically resected specimens as
having pT1a-MM disease. Gratifying therapeutic results in surgically treated T1a patients
have been reported, with a reported 5-year disease-specific survival rate of 98–100%
and overall survival rate 82–100% [17, 18, 20]. Meanwhile, the mortality rate from
postoperative complications has been reported to be in the range of 0.2–3.6% [14,
18, 21, 24]. In regard to the results of chemoradiotherapy for cStage I (cT1N0M0)
disease, the reported 4-year overall survival rate was 80.5%, 5-year overall survival
rate was 66.4%, and 5-year disease-specific survival rate was 76.8%, despite the inclusion
of a significant proportion of cT1b cases (85.2% for cT1a cases) [25, 26]. Esophageal
fistula (3.2%), esophagostenosis (3.2%), Grade 3 cardiac ischemia (1%), and respiratory
failure (2.8%) were reported as serious late complications, but there has been no
report of treatment-related death [25, 26]. In patients given additional chemoradiotherapy
after endoscopic resection, the 5-year overall survival rate and disease-specific
survival time were both 100% among pT1a-MM cases as well as T1b-SM1 cases, and the
3-year survival rate was 92.9% for pT1a-MM cases, although the sample sizes in the
studies were small; neither report contained any detailed description on adverse events,
although there were no cases of serious adverse events or treatment-related death
[5, 27]. Taking into consideration the benefit–risk balance, the additional treatment
may be useful for patients diagnosed by histopathology of the endoscopically resected
specimens as having pT1a-MM disease, who are at a high risk of recurrence.
From the above results, the strength of evidence was rated as D, considering that
most of the reports cited represented retrospective case accumulations, and no recommendation
based on high-level evidence has been made yet. Chemoradiotherapy, which is the mainly
adopted modality for additional treatment, is covered by the national health insurance.
Taking into account the benefit–risk balance, strength of evidence, and patient preferences,
we conclude that there is strong evidence to recommend additional treatment in patients
identified as having a pT1a-MM lesion with positive vascular invasion after endoscopic
treatment.
Surgical treatment
Surgery for cervical esophageal carcinoma
Summary
In the treatment of cervical esophageal carcinoma, simultaneous laryngectomy is often
required; therefore, preoperative chemoradiotherapy or definitive chemoradiotherapy
is often undertaken in an attempt to conserve the larynx. Larynx-preserving surgery
enables conservation of vocal function, although it is associated with an increased
risk of aspiration and pneumonia, necessitating the need for caution while selecting
this treatment. Lowering of the QOL due to the loss of vocal function poses a serious
problem in patients who have undergone combined laryngectomy. No significant difference
in the post-treatment prognosis has been reported so fact between cervical esophageal
carcinoma patients treated by surgery and radical chemoradiotherapy. The appropriate
treatment in these patients should be selected with due consideration given to the
QOL, etc.
General remarks
Since cervical esophageal carcinoma develops in a region densely packed with important
structures such as the trachea, large blood vessels, nerves, and the thyroid, it is
frequently associated with malignant invasions of the adjacent organs. Lymph-node
metastasis is also frequently encountered; therefore, it is not uncommon for the malignancy
to be at an advanced stage at diagnosis. There are a significant number of cases in
which surgery is indicated inasmuch as widespread metastasis is uncommon, unlike the
case in thoracic esophageal cancer. A major problem in surgery for cervical esophageal
cancer is that simultaneous laryngectomy is also indicated in many cases. Under these
circumstances, surgery may be performed after tumor shrinkage is obtained by preoperative
chemoradiotherapy in an effort to preserve the larynx, or radical chemoradiotherapy
may be administered, followed by salvage surgery in the event of detection of residual
disease or recurrence.
Larynx-preserving surgery is indicated for patients in whom the tumor has not invaded
the pharynx, larynx, or trachea. Conservation of vocal function is the utmost benefit
of this option, although it is associated with the risk of aspiration or pneumonia;
not uncommonly, primary tracheotomy is required. Therefore, sufficient consideration
should be given as to the indication and choice of operative procedure, e.g., an additional
aspiration-preventive measure such as laryngeal elevation could be employed.
Combined laryngectomy (laryngopharyngoesophagectomy) is indicated for patients with
tumors invading the pharynx, larynx, and trachea. The procedure may even be indicated
for patients without direct pharyngeal invasion, in whom sufficient preservation of
the esophagus to perform anastomosis with intestinal graft is difficult. Marked lowering
of QOL due to loss of vocal function poses a serious problem in patients who have
undergone combined laryngectomy.
Reconstruction after surgical resection of cervical esophageal carcinoma is frequently
performed using a free jejunal graft [28] or a gastric tube [29]. The method of first
choice is reconstruction using a free jejunal graft, although reconstruction using
a gastric tube is chosen for cases in which the disorder is complicated by thoracic
esophageal cancer or in which the cervical esophageal cancer extends caudad to involve
the thoracic esophagus.
The frequency of lymph-node metastasis in cases of cervical esophageal cancer is relatively
high, although it is confined in most cases to the cervical region and a part of the
upper mediastinum; therefore, lymph-node dissection is primarily targeted at lymph
nodes in these regions. Nevertheless, reports on the outcomes of lymphadenectomy in
patients with cervical esophageal cancer are few as yet, and further investigation
is needed.
No significant difference in the post-treatment prognosis has been reported until
date between cervical esophageal carcinoma patients treated by surgery alone and those
treated by radical chemoradiotherapy. Selection among the available treatment options
should be made with due consideration given to the post-treatment QOL, etc.
Surgery for thoracic esophageal carcinoma
Summary
Thoracic esophageal carcinoma is often accompanied by extensive lymph-node metastasis
in the cervical, thoracic, and abdominal regions. Therefore, it is a common practice
that, in T1b-SM 2, 3 or more advanced cases regarded as advanced cancer cases, a right
thoracotomy with esophagectomy and lymphadenectomy of the cervical, mediastinal, and
upper abdominal regions is carried out. According to the revision of the Japanese
Classification of Esophageal Cancer, supraclavicular lymph nodes [#104] are classified
in Group 2, to ensure 3-fields’ lymphadenectomy for D2 resection in the surgical treatment
of middle thoracic esophageal carcinoma.
In thoracoscopic surgery, thoracic manipulations are currently also carried out with
the patient in the prone position, whilst, previously, thoracic manipulations were
predominantly undertaken with the patient in the left-lateral decubitus position.
This is still at the stage of clinical research. A randomized comparative study to
compare the long-term outcomes of this type of surgery vs. conventional standard surgery
with thoracotomy has been started (JCOG1409 Study), and the results are awaited.
General remarks
Thoracic esophageal carcinoma is frequently associated with extensive lymph-node metastasis
in the cervical, mediastinal, and upper abdominal regions. Therefore, it is common
practice to perform a right thoracotomy to meet the need for adequate dissection of
the mediastinal lymph nodes, along with esophagectomy and lymphadenectomy in lymph-node
stations of the cervical, thoracic and abdominal regions to complete the entire extent
of resection. Depth of invasion beyond T1a-MM is a predictor of lymph-node metastasis,
and stage T1b-SM 2, 3 lesions should be counted as advanced carcinomas [17, 30].
The extent of lymph-node dissection should be determined according to individual cases
after preoperative evaluation of the location, size, and depth of invasion of the
main lesion by imaging modalities such as CT, ultrasonography (US), magnetic resonance
imaging (MRI), and PET, because the distribution and incidence of lymph-node metastasis
vary with the aforementioned parameters. Based on the analysis of data from a nationwide
registry conducted by the Japan Esophageal Society [31], the supraclavicular lymph
nodes [#104] are placed in Group 2, to ensure three fields’ lymph-node dissection
for D2 dissection in the treatment of middle thoracic esophageal carcinoma in the
11th edition of the Japanese Classification of Esophageal Cancer. It is not feasible
to dissect the supraclavicular lymph nodes [#104] via thoracic manipulation, and a
cervical approach is necessary for secure lymph-node dissection in this region.
It is common practice that radical surgery for thoracic esophageal carcinoma is usually
accomplished using a combination of three approaches: the cervical, thoracic, and
abdominal approaches. The mediastinal approach has also been proposed as an alternative
to the cervical approach for dissection of the cervical paraesophageal lymph nodes
[#101].
Thoracoscopy-assisted esophagectomy with esophageal reconstruction has been reported
as promising surgical procedures, in view of its minimal invasiveness, radical curability,
and favorable long-term outcomes, although studies are ongoing. Various procedures
such as endoscopy/laparoscopy-assisted esophagectomy with esophageal reconstruction
and mediastinoscopy- or laparoscopy-assisted transhiatal esophagectomy (blunt resection
of the esophagus) have been reported, and analysis of the reported cases during the
2011–2013 period in the National Clinical Database (NCD) revealed that 37.6% of the
patients underwent endoscopy/laparoscopy-assisted surgery, which was reported as a
safe approach with a mortality rate of 2.44%, against an overall mortality rate of
3.03%. The indications for this approach vary among institutions; it has been adopted
even for cT3 cases at some institutions, and in patients who have received preoperative
chemoradiotherapy at other institutions.
Some techniques have been introduced for ensuring safe endoscopic surgery with a reduced
operation time and improved accuracy of lymph-node dissection, including direct manipulations
through a small incision via a minor thoracotomy, video-assisted thoracoscopic surgery
(VATS) with minor thoracotomy, and hand-assisted laparoscopic surgery (HALS) involving
manipulation with one hand inserted into the abdomen. While thoracic manipulations
have been predominantly carried out with the patient in the left-lateral decubitus
position, complete endoscopic thoracic manipulations have been increasingly performed
with the patient placed in the prone position in recent years. Mediastinal lymph-node
dissection using a mediastinoscope inserted via a cervical incision and laparoscopic
transhiatal lymph-node dissection are some of the other procedures described. Reports
have suggested that endoscopy/laparoscopy-assisted surgery enables conservation of
the vasculature and nerves while confirming the microanatomy, and also increases the
accuracy of lymph-node dissection, as it allows higher power visualization. A randomized
comparative study to assess the long-term outcomes of this type of surgery as compared
to the conventional standard surgery with a thoracotomy has been initiated (JCOG1409
Study), and the results are awaited [32].
Surgery for carcinoma of the esophagogastric junction (abdominal esophageal carcinoma)
Summary
There is no unanimity of opinions as to treatment policy and surgical procedures for
carcinoma of the esophagogastric junction, particularly adenocarcinoma according to
Nishi’s classification or Siewert type II carcinoma. Based on a retrospective analysis,
the Japanese Gastric Cancer Association—Japan Esophageal Society Joint Working Group
proposed the optimal extent of lymph-node resection for esophagogastric junction carcinomas
measuring ≤4 cm in diameter. Prospective clinical studies to determine the optimal
extent of lymph-node resection for more advanced tumors are currently in progress.
General remarks
For definition of carcinoma of the esophagogastric junction, Siewert’s classification
is used overseas, whereas, in Japan, Nishi’s classification is adopted by both the
Japanese Gastric Cancer Association and the Japan Esophageal Society. In Siewert’s
classification, type I lesions are often handled as carcinomas of the thoracic esophagus
and type III lesions as cardiac carcinomas. Squamous cell carcinomas in Nishi’s classification,
on the other hand, are often treated as thoracic esophageal cancers. Opinions are
still divided as to treatment policy and surgical procedures for adenocarcinomas in
Nishi’s classification and Siewert type II carcinoma.
Carcinoma of the esophagogastric junction may be associated with extremely extensive
lymph-node metastasis involving the cervical region, mediastinum, upper abdomen, and
areas circumjacent to the abdominal aorta, and no unified view has been reached in
regard to the appropriate extent of lymph-node dissection. The Japanese Gastric Cancer
Association—Japan Esophageal Society Joint Working Group has laid down recommendations
in respect of the extent of lymphadenectomy on the grounds of the dissection effect
index (rate of metastasis × 5-year survival rate of patients with metastasis) derived
from retrospective analysis of data from surgically treated cases. The efficacy of
lymphadenectomy in accordance with this scheme is expected to be verified by future
accumulation of cases. Nevertheless, the problems with retrospective analysis of tumors
is that the patients are confined to those with tumors measuring ≤4 cm in diameter
and that the subject population includes only a small number of cases with dissection
of the lymph nodes in the upper and middle mediastinal regions and areas circumjacent
to the abdominal aorta. A prospective clinical study to evaluate the outcomes depending
on the extent of lymphadenectomy for more advanced tumors is currently in progress.
The Japanese Gastric Cancer Association—Japan Esophageal Society Joint Working Group
has proposed a definition of the esophagogastric junction based on endoscopic findings.
In the algorithm used as a guide for the extent of lymph-node dissection, as well,
lesions are defined according to the principal location of the center of the tumor,
i.e., whether it is located proximal or distal to the junction. In the clinical practice
setting, however, the junction can scarcely be identified by endoscopy in cases of
advanced carcinoma, and that frequent, concurrent hiatal herniation interferes with
positional estimation of the junction even by fluoroscopic exploration or CT. Thus,
it may be said that only but an obscure judgment about the location of the junction
can be obtained in the clinical setting. The extent of resection of the esophagus
and stomach is determined in accordance with the extent of lymph-node dissection,
and the range of operative procedures available extend from total esophagogastrectomy
to lower third esophagectomy plus proximal gastrectomy. In surgery for carcinoma of
the esophagogastric junction, the surgical invasiveness is affected not only by the
extent of resection, but also by the surgical approach; therefore, the treatment selection
must be approached by taking into consideration the balance between the surgical invasiveness
and curability of the adopted procedure.
Perioperative management and clinical path
Summary
Various improvements have been made to the clinical path system for esophageal cancer
at facilities overseas and in Japan, in an effort to implement safe perioperative
management with a reduced incidence of complications; however, convincing evidence
is still to be presented. The clinical significance of the new concept of perioperative
management introduced in recent years; namely, Enhanced Recovery after Surgery (ERAS)
or fast-track surgery in surgical resection of the esophagus has drawn increasing
attention.
General remarks
A clinical path is a standard medical practice plan containing information on the
patient’s condition, goals of medical practice, and relevant evaluations and records,
and represents a procedure for improving the quality of medical care through analysis
of deviations from the standard. With the introduction of the Diagnosis-Related Group/Prospective
Payment System (DRG/PPS) in the 1980s, clinical paths aimed primarily at shortening
the length of hospitalization and reducing the medical fees were introduced [33].
In Japan, introduction of clinical paths for many disorders began in the 1990s concurrently
with the introduction of the Diagnosis Procedure Combination (DPC) system. Clinical
paths are generally thought to be important for promoting patient-centered collaborative
(team) medical care, including perfection of informed consent as well as for improving
the quality of medical care and education of personnel.
Various improvements have been made in the clinical path system for esophageal cancer
at facilities overseas and in Japan, in an effort to implement safe perioperative
management, with a reduced incidence of complications. It has generally been recognized
that preparation of a simple clinical path for esophageal cancer entails greater difficulty
as compared to that for carcinomas of other digestive organs, because of the diversity
and interinstitutional inequity of procedures and perioperative management techniques,
and because of individual differences in the reaction to invasiveness. An increasing
number of facilities have been introducing a clinical path for esophageal cancer for
safe perioperative management, in parallel with the introduction of minimally invasive
operations including endoscopy-aided surgery; however, convincing evidence demonstrating
its clinical usefulness is still awaited [34, 35].
In recent years, the new concept of Enhanced Recovery after Surgery (ERAS) or fast-track
surgery has been introduced for perioperative management in Europe and the United
States. The ERAS Group organized in 2001 under the European Society for Clinical Nutrition
and Metabolism (ESPEN) published an ERAS protocol for colectomy in 2004 [36], which
has since been applied to perioperative management for various surgeries. Fast-track
surgery is a multimodal rehabilitation program with integrated introduction of evidence-based
procedures as an approach to patient care to expedite recovery after surgery. Currently,
this term is essentially synonymous with ERAS. The Clinical significance of ERAS and
fast-track surgery in cases of esophagectomy has recently been investigated, with
the results indicating reductions in the incidence of complications, duration of hospitalization,
and mortality rate, even though the level of evidence is still not high at present
[37–40].
Perioperative management of patients with esophageal cancer has, heretofore, been
assessed by comparative evaluation of the usefulness of clinical paths established
at individual facilities from their independent standpoints. From now on, however,
the clinical significance of ERAS/fast-track surgery as perioperative management procedures
needs to be verified.
Chemotherapy for unresectable advanced/recurrent esophageal cancer
Summary
Chemotherapy is used as the only systemic therapy modality under various settings
in the treatment of esophageal cancer. Chemoradiotherapy and preoperative chemotherapy
are used for cStage I–Stage IV local esophageal cancer, and chemotherapy is also used
for unresectable advanced/recurrent esophageal cancer. Combination therapy with cisplatin + 5-FU
is used for unresectable advanced/recurrent esophageal cancer, although there is no
clear evidence of its ability to prolong the survival. Taxanes and other drugs are
used as the second-line therapy in patients who become refractory to the first-line
therapies, but these have only been reported in phase II studies involving a small
number of patients, and should be used carefully.
General remarks
Systemic chemotherapy is used as the standard therapy for unresectable advanced/recurrent
esophageal cancer. Although no comparative study with untreated controls has clearly
demonstrated the ability of chemotherapy alone to prolong the survival, both the efficacy
of monotherapy and combination therapy has been reported, and chemotherapy is used
as standard therapy.
Drugs and drug combinations that have been shown to be effective as the first-line
therapy
Monotherapy with 5-FU, platinum drugs, taxanes, vinca alkaloids, etc., has been reported
to be associated with a response rate of 15–40% and a median survival duration of
approximately 3–10 months. Combination therapy has been shown to be associated with
even higher response rates (20–60%) than monotherapy (Table 1) [41–43]. Many studies
have reported the efficacies of combination therapy with 2 or 3 drugs, whereas only
one study has compared the efficacy of combination therapy versus monotherapy. Most
of these studies were phase II studies involving a small number of patients. As two-drug
combination therapies, the combination of cisplatin and 5-FU, which are expected to
have a synergistic effect, and the combination of nedaplatin and 5-FU are used. Combined
therapy with cisplatin + 5-FU is considered to be the standard therapy for patients
with unresectable advanced/recurrent esophageal cancer. A three-drug combination therapy,
a taxane given in combination with cisplatin + 5-FU, has been shown to be highly effective,
with a reported response rate of 60% [44, 45], but it is unknown whether this therapy
can prolong the survival. Therefore, at present, it is considered desirable to use
this three-drug combination therapy in clinical studies. A comparative study of combined
cisplatin + 5-FU therapy and 2-weekly docetaxel combined with cisplatin + 5-FU is
currently ongoing (JCOG1314 Study), and the results of the study are awaited.
Table 1
Reports of the first-line therapy for unresectable advanced/recurrent esophageal cancer
Regimen
N
Response rate (%)
Progression-free survival (month)
Median survival (month)
Cisplatin 100 mg/m2 on day 15-FU 1000 mg/m2/day on days 1–5/every 3 weeks
SCC44
35
6.2
7.6
Cisplatin 70 mg/m2 on day 15-FU 700 mg/m2/day on days 1–5/every 3 weeks
SCC39
35.9
Patients with response3.5
Patients with response9.5
Nedaplatin 90 mg/m2 on day 15-FU 800 mg/m2/day on days 1–5/every 4 weeks
SCC42
39.5
2.5
8.8
Doxorubicin 30 mg/m2/day on day 15-FU 700 mg/m2/day on days 1–5Cisplatin 14 mg/m2/day
on days 1–5/every 4 weeks
SCC41
43.9
5.0
10.1
Docetaxel 30 to 40 mg/m2/day on days 1 and 155-FU 800 mg/m2/day on days 1–5Cisplatin
80 mg/m2 on day 1/every 4 weeks
SCC55
62
5.8
11.1
SCC squamous cell carcinoma
Drugs and combination therapies shown to be effective as the second-line therapy
In regard to the second-line therapy for patients who become refractory to cisplatin + 5-FU,
no drugs have been clearly shown to prolong the survival. Drugs that are likely to
show efficacy other than fluoropyrimidines and platinum drugs should be used, but
the benefit–harm (toxicity) balance should be carefully considered (Table 2). Monotherapy
with taxanes, such as docetaxel and paclitaxel, is often used [46, 47]. The significance
of readministration of drugs used in the first-line therapy and combination therapy
[48] for these patients has not been established.
Table 2
Reports of second- or subsequent-line therapy for unresectable advanced/recurrent
esophageal cancer
Regimen
N
Response rate (%)
Progression-free survival (month)
Median survival (month)
Docetaxel 70 mg/m2 every 3 weeks
SCC 46a
AC 3Others 2
20
2.3
8.1
Paclitaxel 100 mg/m2 on days 1, 8, 15, 22, 29, and 35/every 7 weeks
SCC52
44.2
3.9
10.4
Docetaxel 30 mg/m2/day on day 1Nedaplatin 50 mg/m2 on day 1/every 2 weeks
SCC48
27.1
3.1
5.9
Nivolumab 3 mg/kg/every 2 weeks
SCC64
17
1.5
10.8
SCC squamous cell carcinoma, AC adenocarcinoma
aIncluding 14 patients with the initial treatment
Although there have been a few reports on molecular-targeted drugs, epidermal growth
factor receptor (EGFR) inhibitors have been reported to be associated with response
rates in the range of 10–20%. A comparative study of an EGFR inhibitor gefitinib and
placebo in patients receiving the second-line therapy for esophageal cancer, including
adenocarcinoma, failed to demonstrate any usefulness of gefitinib [49]. In the future,
development of biomarkers, etc., may allow the usefulness of EGFR inhibitors to be
demonstrated in particular subsets of subjects, but, at present, their usefulness
in the treatment of esophageal cancer remains unknown.
Drugs and combination therapies shown to be effective as the third-line therapy
For patients who become refractory or intolerant to the first- and second-line therapies,
no drugs have been demonstrated to be effective, and palliative symptomatic treatment
is recommended. A phase II study reported the efficacy of nivolumab, an immune checkpoint
inhibitor with a new mechanism of action [50], but a phase III comparative study is
required to validate its applicability in clinical practice.
Radiotherapy
Summary
For definitive radiotherapy, concurrent chemoradiotherapy is recommended. The potential
usefulness of preoperative chemoradiotherapy for resectable advanced cancer is being
investigated in an ongoing clinical study. Chemoradiotherapy or radiotherapy alone
is indicated for unresectable patients according to the PS. Palliative radiotherapy
is considered for cStage IVb esophageal cancer patients presenting with obstruction.
A total dose of 60 or 50.4 Gy is often prescribed for chemoradiotherapy, and it is
considered that unnecessary prolongation of the treatment duration should be avoided.
General remarks
Randomized comparative studies and their meta-analyses have demonstrated that concurrent
chemoradiotherapy is more effective than radiotherapy alone for definitive treatment
of esophageal cancer [51, 52]. Therefore, concurrent chemoradiotherapy is considered
preferable, unless its use is precluded by factors such as advanced age, presence
of complications, or any other reasons.
Radiotherapy is indicated for patients with residual lesions in the local or regional
lymph nodes. An additional (chemo-) radiotherapy is considered when there is residual
cancer after endoscopic treatment for T1a or T1b cancer, or when the patient is suspected
to have lymph-node metastasis.
Preoperative chemotherapy is the standard treatments for resectable advanced cancer
in Japan. Patients who are not suitable for surgery or who do not wish to undergo
surgery are given definitive chemoradiotherapy. In addition, preoperative chemoradiotherapy
for these patients is being investigated in an ongoing clinical study. Chemoradiotherapy
is indicated for unresectable cancer patients with a good PS, and subsequently, surgery
may be considered. Radiotherapy alone may be considered for patients with a poor PS.
Palliative radiotherapy may be considered for cStage IVb esophageal cancer patients
presenting with obstruction. Radiotherapy may be used not only in patients with postoperative
residual lesions and untreated patients, but also in those with postoperative recurrence
without distant metastasis.
At present, in most facilities, CT-based three-dimensional treatment planning is performed,
which allows optimization of the doses to the tumor and risk organs, enabling highly
accurate treatment. When radiotherapy alone is performed, since the local control
rate may decrease due to accelerated repopulation of the tumor cells, it is considered
that unnecessary prolongation of the treatment duration should be avoided [53]. In
regard to the optimal total dose for definitive treatment, a randomized comparative
study of chemoradiotherapy at a total dose of 50.4 Gy versus 64.8 Gy, conducted mainly
by the US Radiation Therapy Oncology Group (RTOG), failed to demonstrate the superiority
of the higher dose [54]. In Japan, chemoradiotherapy mainly using 60 Gy has been reported,
but clinical studies using 50.4 Gy have also been reported, expecting reduction of
the late toxicities of chemoradiotherapy and salvage surgery after definitive radiation.
In clinical practice, the dose should be determined considering the several factors
such as the patient’s general condition, tumor volume, irradiation area, and doses
to the risk organs. When radiotherapy alone is performed, a total dose of 60–70 Gy
is commonly prescribed.
Multidisciplinary treatment
Preoperative/postoperative adjuvant therapy
Summary
At present, the standard treatment for cStage II and III thoracic esophageal cancer
in Japan is preoperative chemotherapy with cisplatin + 5-FU, followed by surgery.
On the other hand, in Europe and North America, the standard treatment is preoperative
chemoradiotherapy followed by surgery. A randomized comparative study to confirm the
superiority of preoperative docetaxel + cisplatin + 5-FU (DCF) therapy and that of
preoperative chemoradiotherapy (cisplatin + 5-FU, radiotherapy at 41.4 Gy) over the
currently used preoperative regimen of cisplatin + 5-FU (JCOG1109 Study) is ongoing.
General remarks
In recent years, multidisciplinary treatment, including chemotherapy, radiotherapy,
and surgery, has been used for esophageal cancer. The JCOG9204 Study conducted in
Japan compared the outcomes of surgery alone with those of surgery plus postoperative
chemotherapy with cisplatin and 5-FU [55]. While no significant difference in the
overall survival were observed between the two groups, the 5-year disease-free survival
(DFS) was significantly better in the surgery plus postoperative chemotherapy group
(55%) than in the surgery alone group (45%); furthermore, this improved prognosis
was particularly evident in the pathological lymph-node metastasis-positive cases.
As a result, surgery plus postoperative chemotherapy became the standard treatment
in Japan for patients with histopathologically diagnosed lymph-node metastasis after
surgical resection. Subsequently, the JCOG9907 Study investigated the optimal timing,
in relation to surgery, of adjuvant chemotherapy with cisplatin + 5-FU, and showed
that 5-year overall survival was significantly better in the preoperative chemotherapy
plus surgery group (55%) than in the surgery plus postoperative chemotherapy group
(43%) [56]. Thereafter, preoperative adjuvant chemotherapy with cisplatin + 5-FU followed
by radical surgery came to be adopted as the standard of care for cStage II and III
thoracic esophageal cancer patients in Japan.
On the other hand, in Europe and North America, preoperative chemoradiotherapy followed
by radical surgery is used as the standard treatment. Preoperative chemoradiotherapy
yields a higher local control rate than preoperative chemotherapy alone, but may also
increase the risk of perioperative complications and surgery-related mortality. So
far, in Japan, local control is achieved by accurate lymph-node dissection during
surgery, and preoperative radiotherapy has been thought to be unnecessary. In Europe
and North America, several randomized comparative studies investigating the usefulness
of preoperative chemoradiotherapy have been reported [57], because adequate local
control has not yet been achieved by surgery. The CROSS trial, which is a large-scale
randomized comparative study conducted in the Netherlands, showed that the overall
survival was significantly longer in the preoperative chemoradiotherapy + surgery
group than in the surgery alone group (median overall survival, 49.4 vs. 24.0 months)
[58]. On the other hand, there were no significant differences in the incidence of
postoperative complications between the two groups.
The results of a subgroup analysis in the JCOG9907 Study suggested that the additive
effect of the currently used preoperative chemotherapy with cisplatin + 5-FU may be
insufficient for improving the prognosis in patients with cStage III thoracic esophageal
cancer, and that either preoperative chemotherapy with a more intensive regimen or
preoperative chemoradiotherapy may need to be attempted in the future, aimed at better
local control. Taxane antitumor agents (paclitaxel/docetaxel) are thought to be effective
in patients with esophageal cancer. Recently, DCF therapy, in which docetaxel is added
to cisplatin + 5-FU therapy has attracted attention. The JCOG1109 Study, which was
started in 2012, is a randomized comparative study performed to confirm the superiority
of preoperative DCF therapy and that of preoperative chemoradiotherapy (cisplatin + 5-FU,
radiotherapy at 41.4 Gy) over the currently used preoperative regimen of cisplatin + 5-FU,
and the results of the study are awaited, so that the standard treatment for cStage
II and III thoracic esophageal cancer can be established in Japan [59].
Chemoradiotherapy
Summary
Chemoradiotherapy has been demonstrated to yield a greater prolongation of the survival
than radiotherapy alone in patients with locally advanced esophageal cancer. It is
considered as the standard of care in non-surgical treatment, and chemoradiotherapy
aimed at complete cure is indicated for cStage 0 to IVa cancer. Although a study comparing
chemoradiotherapy and surgery alone in resectable cases reported that chemoradiotherapy
can be expected to have equivalent efficacy to surgery, no studies have directly compared
the two, and it is speculated that the standard treatment, namely, preoperative chemotherapy + surgical
treatment, would yield better results in patients with cStage II and III cancer. Therefore,
chemoradiotherapy is considered as one of the options in patients who are intolerant
to surgery or refuse surgery. It is important to select the appropriate radiation
dose, irradiation area, and chemotherapy regimen while considering a treatment strategy,
and also consider the salvage treatments for residual and recurrent lesions after
chemoradiotherapy (Table 3).
Table 3
Summary of prospective clinical studies of chemoradiotherapy
Study name
Histological type studied
Regimen
Radiation dose (Gy)
Complete response rate (%)
Survival (%)
JCOG9708
cStage IbSCC
Cisplatin 70 mg/m2 on days 1 and 365-FU 700 mg/m2 on days 1–4 and 36–39
60
87.5
4-year survival80.5
RTOG85-01
cStage I, II, IIISCC, AC
Radiotherapy alone
64
NA
5-year survival0
Cisplatin 75 mg/m2 on days 1 and 295-FU 1000 mg/m2 on days 1–4 and 29–32
50
NA
5-year survival27
RTOG94-05
cStage I, II, IIISCC, AC
Cisplatin 75 mg/m2 on days 1 and 295-FU 1000 mg/m2 on days 1–4 and 29–32
50.4
NA
2-year survival40
Cisplatin 75 mg/m2 on days 1 and 295-FU 1000 mg/m2 on days 1–4 and 29–32
64.8
NA
2-year survival31
JCOG9906
cStage II, IIISCC
Cisplatin 40 mg/m2 on days 1, 8, 36 and 435-FU 400 mg/m2 on days 1–5, 8–12, 36–40,
and 43–47
60
62.2
3-year survival44.7
mRTOG
cStage II, IIISCC
Cisplatin 75 mg/m2 on days 1 and 295-FU 1000 mg/m2 on days 1–4 and 29–32
50.4
70.6
3-year survival63.8
JCOG9516
Unresectable localSCC
Cisplatin 70 mg/m2 on days 1 and 365-FU 700 mg/m2 on days 1–4 and 36–39
60
15
2-year survival31.5
JCOG0303
Unresectable localSCC
Cisplatin 70 mg/m2 on days 1 and 295-FU 700 mg/m2 on days 1–4 and 29–32
60
0
3-year survival25.9
Cisplatin 4 mg/m2/5 doses weekly for 6 weeks5-FU 200 mg/m2/5 doses weekly for 6 weeks
60
1.4
3-year survival25.7
KROSG0101/JROSG021
cStage II, IVAlocal SCC
Cisplatin 70 mg/m2 on days 1 and 295-FU 700 mg/m2 on days 1–5 and 29–33
60
NA
2-year survival46
Cisplatin 7 mg/m2 on days 1–5, 8–12, 29–33 and 36–405-FU 250 mg/m2 on days 1–14 and
29–42
60
NA
2-year survival44
KDOG0501
Unresectable localSCC
Cisplatin 40 mg/m2 on days 1, 15, 29, and 435-FU 400 mg/m2 on days 1–5, 15–19, 29–33,
and 43-47Docetaxel 20–40 mg/m2 on days 1, 15, 29, and 43
61.2
42.1
1-year survival63.2
SCC squamous cell carcinoma, AC adenocarcinoma, 5-FU 5-fluorouracil, NA not available
General remarks
Chemoradiotherapy for cStage 0 and I disease
Chemoradiotherapy is indicated for lesions covering ≥ 3/4th of the circumference,
which are difficult to treat endoscopically, and those invading up to the submucosa
or deeper. The JCOG9708 Study showed good results, with a complete response rate of
87.5% and a 4-year survival rate of 80.5% [26]. Although 9 patients (12.5%) had residual
cancer and 30 (41%) developed recurrence after treatment, many of these lesions could
be completely cured by endoscopic treatment or surgical resection, and only 9 patients
had lesions that could not be radically resected at recurrence. cStage I patients
are known to frequently develop recurrent or metachronous multiple lesions in the
esophagus after complete response [60], and it is important to perform CT and endoscopy
every 3–4 months for at least 2 years after complete response is obtained, and subsequently
every 6 months, for detecting recurrent or metachronous multiple lesions at a sufficiently
early stage as to allow the lesions to be treated endoscopically.
In addition, it has been reported that 10–50% of patients with obvious submucosal
invasion or intramucosal lesions with vascular invasion after endoscopic treatment
develops lymph-node metastasis, and these patients were likely to have non-curative
resection [61]. For additional treatment of these patients, radical surgery with lymph-node
dissection is currently used as the standard of care, while one report has suggested
the usefulness of prophylactic chemoradiotherapy in combination with cisplatin + 5-FU
for regional lymph nodes [62]. In the JCOG0508 Study, cT1bN0 esophageal cancer with
a limited depth of invasion (up to SM2), which was estimated to be treatable endoscopically,
was treated endoscopically, and patients with pathologically confirmed complete resection
who had pT1a with positive vascular invasion or pT1b received prophylactic chemoradiotherapy.
With such treatment, these patients showed a 3-year survival rate (primary endpoint
of the study) of 90.7% (90% CI 84.0–94.7). On the other hand, 3 (20%) of the 15 patients
who had positive surgical margins after endoscopic treatment and received definitive
chemoradiotherapy died of the disease. It should be carefully investigated as to which
subpopulation of patients with cT1bN0 disease would be suitable candidates for this
treatment. The clinical study was presented at the Annual Meeting of the American
Society of Clinical Oncology in June 2016, and its publication is awaited.
Chemoradiotherapy for cStage II and III disease
According to one report, chemoradiotherapy was equivalent to surgery alone for cStage
II and III cancer [63]. However, according to the JCOG9906 study, chemoradiotherapy
was associated with a complete response rate of 62.2%, 3-year survival rate of 44.7%,
and 5-year survival rate of 36.8%, which were considered to be inferior results to
those of preoperative chemotherapy + surgery in the same subject population (5-year
survival rate of 55%, JCOG9907 Study), although no direct comparison can be made.
Therefore, chemoradiotherapy is recommended for patients who refuse surgery or are
intolerant to surgery, as a treatment with which complete cure can be expected [64].
The RTOG9405/INT0123 study conducted by the US RTOG compared cisplatin (75 mg/m2 on
days 1 and 29) + 5-FU (1000 mg/m2 on days 1–4 and 29–32) chemotherapy with radiotherapy
at a radiation dose of 50.4 Gy, and the same chemotherapy with radiotherapy at a radiation
dose of 64.8 Gy, and revealed that, while the survival was not prolonged any further,
higher toxicity was obtained in the 64.8 Gy group [54]. Based on this, chemotherapy
with cisplatin (75 mg/m2 on days 1 and 29) + 5-FU (1000 mg/m2 on days 1–4 and 29–32)
combined with radiotherapy at a radiation dose of 50.4 Gy (RTOG regimen) is considered
as one of the standard chemoradiotherapy treatment regimens. A phase II study of a
modified RTOG (mRTOG) regimen in Japan reported that addition of prophylactic irradiation
of the regional lymph nodes to the original RTOG regimen yielded good results, with
a complete response rate of 70.6% and 3-year survival rate of 63.8% [65]. Late toxicity
was reduced in the mRTOG regimen when the radiation dose of 50.4 Gy was used, as compared
with that in the JCOG9906 study, in which the radiation dose used was 60 Gy. However,
attention should be paid to the development of myelosuppression, mucositis, and gastrointestinal
symptoms associated with the increased doses of the chemotherapeutic agents. In addition,
active salvage treatment, described below, also contributed to the improved treatment
outcomes, and it is necessary to consider treatment strategies including salvage treatments
after chemoradiotherapy. Criteria for indications of the mRTOG regimen combined with
salvage treatment and the safety of salvage treatment are under investigation in the
JCOG0909 Study.
Chemoradiotherapy for cStage IVa esophageal cancer
When a lesion that is not amenable to surgical resection is limited to the irradiation
area, chemoradiotherapy is used as a standard treatment. A single-center phase II
study of cisplatin + 5-FU in combination with radiotherapy at a radiation dose of
60 Gy reported a complete response rate of 33% and a 3-year survival rate of 23%,
and a multicenter study, the JCOG9516 Study, reported a complete response rate of
15% and a 2-year survival rate of 31.5% [66, 67]. As a result, chemoradiotherapy with
cisplatin + 5-FU has come to be used as a standard treatment. Two randomized studies
comparing standard chemotherapy with 5-FU (700 mg/m2 on days 1–4 and 29–32) + cisplatin
(70 mg/m2 on days 1 and 29) and low-dose chemotherapy with 5-FU (200 mg/m2) + cisplatin
(4 mg/m2) on days 1–5, 8–12, 15–19, 22–26, 29–33, and 36–40, both combined with radiation
at the dose of 60 Gy, failed to find any clear advantage of the low-dose chemotherapy
[68, 69]. A clinical study of DCF therapy, in which docetaxel is added to cisplatin + 5-FU,
in combination with radiotherapy reported good results with a complete response rate
of 42.1%; however, Grade 3–4 esophagitis or febrile neutropenia occurred in ≥ 30%
of the subjects. Therefore, adoption of this treatment needs to be carefully considered
[70]. Multidisciplinary treatment in which surgery or chemoradiotherapy is performed
after intensive induction chemotherapy has been shown to yield good short-term results
with a 1-year survival rate of 67.9% [71], and a comparative study (JCOG1510) is planned.
Radiation dose and chemotherapy regimens used in chemoradiotherapy
The RTOG8501 study recommended chemoradiotherapy as a standard treatment, because
comparison of radiotherapy (64 Gy) alone and concurrent chemoradiotherapy (cisplatin + 5-FU + 50 Gy)
for esophageal cancer revealed significantly superior treatment outcomes of chemoradiotherapy
[72]. In addition, a meta-analysis of studies of chemotherapy and radiotherapy reported
that concurrent chemotherapy and radiotherapy yielded a significantly greater prolongation
of the survival than sequential chemotherapy and radiotherapy [73]. Furthermore, the
above-mentioned RTOG9405/INT0123 study revealed no superior outcomes in terms of the
survival or local control rate in the high-dose group, concluding that a radiation
dose of 50.4 Gy should be used in combination with cisplatin (75 mg/m2 on days 1 and
29) + 5-FU (1000 mg/m2 on days 1–4 and 29–32) chemotherapy. Many studies in Japan
have used a radiation dose of 60 Gy in combination with lower doses of the antitumor
agents, such as cisplatin (70 mg/m2 on days 1 and 29) and 5-FU (700 mg/m2 on days
1–4 and 29–32) [74, 75]. For multidisciplinary treatment including salvage treatment,
the mRTOG regimen has also been increasingly used, and its usefulness is now under
investigation in the JCOG0909 Study.
Adverse effects of radical chemoradiotherapy
Adverse effects of chemoradiotherapy are mainly classified into acute and late toxicity.
Acute toxicity occurs mainly during concurrent chemotherapy and radiotherapy, within
1–2 months after the start of treatment. Late toxicity is often associated with radiation
and occurs a few months to a few years after completion of treatment. Symptoms of
acute toxicity include gastrointestinal toxicity, nausea, vomiting, renal impairment,
leukopenia, esophagitis, and dysphagia, and should be treated according to guidelines
such as the “Guidelines for Proper Use of Antiemetics” and “Practical Guideline of
Febrile Neutropenia (FN)”. Symptoms of late toxicity include radiation pneumonitis,
pleural effusion, pericardial effusion, pericarditis constrictive, and hypothyroidism,
which interfere with daily life in approximately 10% of patients [76–78]. Since late
toxicity may be lethal, regular follow-up, medical interviews to obtain information
on subjective symptoms such as dyspnea, and early treatment are important.
Salvage treatment for local residual/recurrent lesions after radical chemoradiotherapy
When there is a local residual or recurrent lesion after chemoradiotherapy for esophageal
cancer, salvage surgery or endoscopic treatment may allow long-term survival. It has
been reported that, in salvage surgery, R0 resection allows long-term survival, but,
at the same time, increases the incidence of postoperative complications and in-hospital
mortality [79–83]. When a residual lesion remains confined in the mucosa, salvage
endoscopic treatment can be performed safely [84, 85]. Photodynamic therapy (PDT)
has been reported to yield good results even in cases with suspected invasion of the
submucosa or muscularis propria, and PDT is considered as one of the potentially useful
treatment options [86].
Follow-up after treatment of esophageal cancer
Summary
The purpose of follow-up after treatment of esophageal cancer is (1) to detect and
treat recurrence early, and (2) to detect and treat multiple/double cancers early.
Furthermore, follow-up is also important from the standpoint of systemic management
and knowing the QOL of the patients after treatment.
Methods of follow-up after treatment of esophageal cancer vary depending on the type
of initial treatment and on the stage of cancer progression at the time of the initial
treatment. During follow-up, it is important to keep in mind that the early detection/treatment
may allow long-term survival and to pay attention to the occurrence of metachronous
multiple esophageal cancers and metachronous double cancers in other organs, mainly
high-incidence cancers, i.e., gastric cancer and head and neck cancer. Establishment
of a consensus-based follow-up system and verification of its effectiveness are required.
General remarks
Follow-up after endoscopic resection
No certain method of follow-up after endoscopic resection has been established. Local
recurrence often occurs within 1 year after the initial treatment, although it, sometimes,
takes up to 2–3 years after the initial treatment, and long-term-follow-up is required
[87, 88]. Esophagoscopy with iodine staining is mainly used to screen for local recurrence,
and many studies have reported that screening for local recurrence is performed every
3 or 6 months for 1 year after resection [3, 4, 87–89]. Patients with piecemeal resection
and those with multiple iodine-unstained areas have a high risk of local recurrence,
requiring a more strict esophagoscopy protocol [3, 4, 87, 88, 90]. Lymph-node recurrence/organ
recurrence may be detected 2–3 years later, and regular, long-term follow-up is required
[5, 91].
In regard to the methods of examination, follow-up is usually performed every 6–12 months
using several equipments such as contrast-enhanced thoracoabdominal CT and EUS [92].
For example, in the JCOG0508 Study “Single-arm confirmatory study on efficacy of combined
treatment of endoscopic mucosal resection and chemoradiotherapy for clinical stage
I esophageal carcinoma,” medical examinations and contrast-enhanced neck to abdominal
CT and measurement of squamous cell carcinoma (SCC) antigen, a tumor marker, are to
be performed every 4 months for 3 years after EMR.
Follow-up after radical surgery
Recurrence after radical surgery occurs in 29–43% of cases in Japan. Although, in
approximately 85% of cases, the recurrences occur early, often within 2 years after
surgery, in some cases, they occur much later, and this should be borne in mind [93–95].
The patterns of recurrence include lymph-node recurrence, local recurrence, organ
recurrence and disseminated recurrence, and mixed type of recurrence [95].
The actual method of follow-up after radical resection of esophageal cancer is currently
determined by each institution, and no studies have clarified the usefulness of regular
follow-up or an effective method of follow-up. A nationwide survey conducted by the
Guideline Committee [96] revealed that many institutions perform follow-up with tumor
markers and diagnostic imaging, mainly CT, ≥ 4 times a year during the first 2 years
after resection and at least twice a year from the third year until the fifth year,
and that some institutions perform follow-up for up to 10 years. Mainly contrast-enhanced
thoracoabdominal CT and upper gastrointestinal endoscopy are performed as follow-up
examinations, and neck/abdominal US, bone scintigraphy and PET-CT are performed as
necessary. CT is performed every 3–6 months in many institutions, and the frequency
of CT often varies depending on the stage of cancer progression and on the number
of years after surgery.
Follow-up after radical chemoradiotherapy
CT, esophagoscopy, and other examinations are usually used for follow-up after radical
chemoradiotherapy, but there are no reports clarifying the optimal frequency of these
examinations or the optimal follow-up period. According to a nationwide survey [96],
follow-up is performed every 3 months during the first year after chemoradiotherapy
at most institutions. For patients with cStage II or more advanced cancers, follow-up
similar to that in the first year is performed up to the third year at many institutions,
and follow-up is continued for at least 5 years after treatment at all the institutions
surveyed. Primary esophageal lesions and lymph-node metastasis are commonly encountered
as residual/recurrent lesions after chemoradiotherapy, and in most of these cases,
these are detected within 1 to 2 years after the start of treatment.
After definitive chemoradiotherapy for esophageal cancer, not only screening for detecting
recurrence, but also follow-up for the early identification of the late effects of
radiotherapy such as radiation pneumonitis, pleural effusion, and pericardial effusion
is necessary [76]. These late effects may greatly impair the patients’ QOL, and patients
could die of the late effects.
Points to consider in patients with metachronous multiple esophageal cancers and double
cancers in other organs
Esophageal cancer is characterized by relatively frequent occurrence, metachronously,
of multiple cancers in the esophagus. In addition, development of metachronous cancer
in other organs, such as gastric cancer and head and neck cancer, is also not rare
[97, 98]. Bearing this in mind, upper gastrointestinal endoscopy needs to be regularly
performed to carefully observe the pharynx, entire esophagus (remnant esophagus in
surgical cases), and stomach. Particular attention needs to be paid to the development
of metachronous head and neck cancer in patients with multiple iodine-unstained areas
and those with head and neck cancer [98, 99]. Magnifying endoscopy with narrow-band
imaging (NBI) is useful for detecting superficial head and neck cancer [100]. Furthermore,
attention also needs to be paid to the development of colorectal and other cancers.
Treatment of recurrent esophageal cancer
Summary
Since there are a variety of initial treatments for esophageal cancer, such as endoscopic
treatment, radical surgery, and definitive chemoradiotherapy, treatment for recurrent
esophageal cancer needs to be considered individually according to the type of initial
treatment. Furthermore, treatment varies depending on whether the pattern of recurrence
is lymph-node recurrence, local recurrence, distant organ recurrence, or mixed recurrence,
and the general condition of the patient at the time of recurrence also affects the
choice of treatment. It is difficult to conduct large-scale clinical studies on the
treatment of recurrent esophageal cancer, and there is currently little evidence of
the usefulness of any type of treatment used. While cure may be achieved depending
on the type of recurrence, for example, by salvage therapy after radical chemoradiotherapy,
treatment for suppressing tumor exacerbation or improving QOL is also often used.
General remarks
Treatment of recurrence after endoscopic resection
Local recurrence after endoscopic mucosal resection often develops within 1 year after
the initial treatment, but may sometimes take until 2 to 3 years after the initial
treatment. Recently, indications for endoscopic resection have been expanded in clinical
studies. There are no certain indications for, or evidence for the type of additional
treatment after endoscopic resection, and some patients receive follow-up alone (see
Chapter “Endoscopic treatment”).
Treatment of recurrence after radical surgery
Recurrence after radical surgery for esophageal cancer has been reported to occur
in 28–47% of cases in Japan [93, 101], while the reported recurrence rates of ≥ 50%
are not rare in reports from Europe and North America [102, 103]. In regard to the
patterns of recurrence, 22–68% of cases show lymph node/local recurrence, 12–51% show
distant organ metastasis, and 7–27% show a mixture of both types of recurrence. Recurrence
in the neck/superior mediastinum is common in cases of lymph-node recurrence, while,
in cases of distant organ metastasis, the lung is the most common site of recurrence,
followed in frequency by the liver, bone, and brain. Even metastases to the small
intestine and colon have been reported.
Patients with recurrence after radical resection for esophageal cancer have extremely
poor survival rates, with a median survival duration of 5–10 months after diagnosis.
On the other hand, cases of long-term survival and those of complete cure have also
been reported, and active treatment for recurrent lesions should be considered [93,
101–113].
Treatment of recurrence after radical resection for esophageal cancer is selected
according to the site, pattern, and extent of recurrence. Treatment varies depending
on the condition in each individual, such as the general condition of the patient
at the time of recurrence, whether recurrence is in the surgical area, and whether
irradiation was given preoperatively or postoperatively. Therefore, there have been
a few reports of large-scale studies of the treatment outcomes according to various
pathological conditions.
Treatment of recurrence developing after complete response to definitive chemoradiotherapy
In recent years, definitive chemoradiotherapy has been increasingly chosen as the
initial treatment, not only for unresectable esophageal cancer, but also for cases
with esophageal cancer that is judged as being resectable. Although complete response
has been achieved in many cases, recurrences, including local recurrence, are often
encountered. The treatment of recurrence varies depending on the pathology and general
condition of the patient, and no consensus has been reached. However, when the recurrence
is localized, salvage treatment such as surgery and endoscopic resection may be adopted
[79, 84, 85, 105, 114–117] (see chapter “Multidisciplinary treatment”, Chemoradiotherapy).
Palliative care
Summary
While palliative care should be commonly provided for cancers at any site, in esophageal
cancer patients, dysphagia, malnutrition, cough due to fistula formation with the
airways, and other symptoms often decrease the QOL, and provision of treatment for
relieving these symptoms and maintaining/improving the QOL of the patients should
be considered from even the early stages of treatment. However, the method of palliation
adopted is determined by the prevailing practice at individual institutions, and further
evaluation is required. All medical professionals need to master the knowledge and
skills needed in palliative care.
General remarks
The World Health Organization (WHO) (2002) defines palliative care as “an approach
that improves the quality of life of patients and their families facing problems associated
with life-threatening illness, through the prevention and relief of suffering by means
of early identification and impeccable assessment and treatment of pain and other
problems, physical, psychosocial, and spiritual.” The Second Basic Plan to Promote
Cancer Control Programs in fiscal year 2012 states that “promotion of palliative care
from the time of cancer diagnosis” is an issue that needs to be focused on. The above-mentioned
palliative care is common to all cancer patients and provided in daily practice, not
only the attending physicians and nurses, but also palliative care specialists, psycho-oncologists,
clinical psychologists, dentists, pharmacists, certified social workers, physical
therapists, and other professionals need to engage and provide team care. Methods
based on the “Guidelines for Pharmacotherapy of Cancer Pain” established by the Japanese
Society for Palliative Medicine are recommended for cancer pain.
Patients with esophageal cancer often suffer from dysphagia and malnutrition due to
esophageal obstruction, cough due to aspiration/fistula, and chest pain due to the
tumor, resulting in a lowered QOL already at the time of diagnosis. Even while providing
treatment for cure, it is important, from the early stage, to provide treatment for
the relief of symptoms and for maintaining/improving the QOL of the patients [118].
In palliative care for patients with terminal esophageal cancer, problems that need
to be handled are, in particular, dysphagia due to esophageal obstruction and malnutrition
caused by dysphagia, symptoms caused by airway obstruction or fistula formation with
the airway, cachexia, and other symptoms due to distant metastases and hypercalcemia.
To improve the symptoms of esophageal obstruction and airway obstruction and those
caused by fistula, palliative radiotherapy, chemoradiotherapy, esophageal stenting,
airway stenting, esophageal bypass surgery, and/or other treatments may be used [119,
120] (see Chapter “Radiotherapy”; Chapter “Multidisciplinary Treatment”, Chemoradiotherapy).
For improving dysphagia in unresectable esophageal cancer, a Cochrane Database Systematic
Review in 2014 showed that self-expandable esophageal metallic stents are more effective
and faster-acting than plastic stents and other methods [121]. However, it should
be kept in mind that stenting may also cause complications, causing pain and further
decreasing the QOL, and the treatment(s) should be undertaken after providing adequate
explanation to the patient and obtaining informed consent. In addition to esophageal
stenting, intracavitary irradiation, laser irradiation, hyperthermia, ethanol injection,
etc., have been reported as treatments for providing relief from esophageal obstruction.
While intracavitary irradiation may act more slowly in providing relief from esophageal
obstruction than esophageal stenting, it could be a useful alternative treatment to
esophageal stenting, as it is associated with a lower incidence of complications,
provides more sustained relief from esophageal obstruction, and may be expected to
prolong the survival and improve the QOL [121]. However, intracavitary irradiation
alone is scarcely adopted as a treatment option in Japan (see Chapter “Radiotherapy”).
Patients with tracheoesophageal fistula formation have a reduced QOL due to repeated
episodes of aspiration and pneumonia, but placement of a covered self-expandable esophageal
stent, and in some cases, placement of an airway stent in addition to the esophageal
stent, have been reported to be effective [122].
In patients with severe obstruction who have already undergone definitive chemoradiotherapy
or radiotherapy and in whom radical resection cannot be expected, if it is considered
that esophageal stenting would be difficult or dangerous, a nutritional fistula may
be created to allow the patient to be switched to home care. Percutaneous endoscopic
gastrostomy, which can usually be performed using an endoscope, is effective, and
may be performed even before the start of the multidisciplinary treatments in patients
with severe obstruction [123]. In cases in which percutaneous endoscopic gastrostomy
is difficult due to severe obstruction, such that even a small-diameter endoscope
is difficult to negotiate through, or in patients with a history of abdominal surgery,
open gastrostomy or jejunostomy may be performed.
In addition, medical professionals involved in the treatment of esophageal cancer
often encounter potentially fatal complications, such as sudden respiratory arrest
due to airway obstruction and massive hematemesis due to aortic perforation. Since
it is difficult to save the lives in most of these cases, it is important to provide
a thorough explanation in advance, particularly to the patients’ families. Patients
and their families are thus often forced to live in fear of sudden change/death, and
psychological support and mental care for them are indispensable.
Diagnosis and treatment of Barrett’s esophagus and Barrett’s carcinoma
Summary
An esophagus lined with Barrett’s mucosa is called Barrett’s esophagus [124]. Barrett’s
mucosa is endoscopically recognizable columnar epithelium extending from the stomach
to the esophagus and does not require histological confirmation of specific columnar
epithelial metaplasia [125–129]. Identification of the esophagogastric junction is
required for the diagnosis of Barrett’s mucosa, and the endoscopically identifiable
distal end of the lower esophageal palisade vessels is defined, in principle, as the
esophagogastric junction. Barrett’s mucosa is characterized by at least one of the
following histological findings: (1) esophageal gland ducts in the mucosa beneath
the columnar epithelium or esophageal glands proper in the submucosa; (2) squamous
islands within the columnar epithelium; (3) double muscularis mucosae beneath the
columnar epithelium. Barrett’s carcinoma is defined as adenocarcinoma arising from
Barrett’s mucosa. Early, superficial, and advanced cancer are defined in the same
manner as for the case of esophageal squamous cell carcinoma, in general, but the
deep muscularis mucosae is handled as the genuine muscularis mucosae. Barrett’s carcinoma
is treated in accordance with the treatment principles for esophageal squamous cell
carcinoma at the cancer site. Endoscopic resection is currently indicated for lesions
extending in depth down to the lamina propria (EP: remaining in the epithelium, non-invasive
lesion; SMM [superficial muscularis mucosae]: remaining in the superficial muscularis
mucosae; LPM [lamina propria mucosae]: not reaching the deep muscularis mucosae);
however, accumulation of cases is necessary for establishing the optimal treatment.