Current Definitions and Therapeutic
Strategies for Esophagogastric Cancer: A Medical Oncologist¡¯s Perspective
Jian
Ming Xu
Jian Ming Xu, Affiliated Hospital Cancer Center (307 Hospital of PLA),
Academy of Military Medical Sciences, Beijing 100071, China
Correspondence
to: Jian Ming Xu, Affiliated
Hospital Cancer Center (307 Hospital of PLA), Academy of Military Medical
Sciences, Beijing 100071, China
Email:
jmxu2003@yahoo.com
Received: June 25, 2013
Revised:
October 4, 2013
Accepted:
October 10, 2013
Published
online: Febuary 18, 2014
ABSTRACT
Gastroesophageal junction carcinoma is a challenge to medical oncologist
due to issues in staging and classification and uncertainties reagrding optimal
treatment approach. As a comprehensive review of Status of Arts in
gastroesophaeal junction carcinoma, this article discusses its anatomical,
histological, and endoscopic definition, classification, and advances in
surgery, neoadjuvant therapy, adjuvant therapy, and innovative molecualr
targeting therapy. In general, anatomical and histological definitions are
important for diagnosis and treatment of gastroesophaeal junction carcinoma.
Combination of surgery and adjuvant therapy is more beneficial for patients
with gastroesophaeal junction carcinoma than surgery alone.
© 2014 ACT. All rights reserved.
Key words: Gastroesophageal junction carcinoma;
Definition; Therapeutic strategy
Xu JM. Current
Definitions and Therapeutic Strategies for Esophagogastric Cancer: A Medical
Oncologist¡¯s Perspective. Journal of Tumor 2017; 2(2): 83-86 Available
from: URL: http://www.ghrnet.org/index.php/JT/article/view/601
The prevalence of
distal gastric carcinomas (GC) has decreased worldwide; in contrast, the
prevalence of proximal GCs including esophagogastric junction (EGJ) carcinoma
and distal esophageal adenocarcinoma (EAC) has dramatically increased over the
past two decades[1]. EGJ carcinoma is quite similar to distal EAC in
age distribution, sex predilection, and pathological characteristics. However,
whether it is a subtype of EAC or GC remains controversial. It has been also
suggested that carcinoma of EGJ be regarded as an independent entity equivalent
to EAC and distal GC. Although radical resection remains to be the only curable
treatment, approximately 3/4 of proximal GC carcinoma patients are in their
later-stage upon diagnosis, which are not suitable for surgery. And proximal GC
tends to be more malignant with poorer differentiation and prognosis than GC in
general. Diagnosis and treatment of proximal GC including EGJ carcinoma are
reviewed in this article.
DEFINITION
OF EGJ
Anatomical and histological definitions
Proximal GC usually
refers to carcinoma located in the proximal third of gastric mucosa, i.e. the
C-zone, and is generally termed as cardiac carcinoma (CC). This definition may
not be precise, because the precise definition of gastric cardia is not clear. Is
it merely a strip that separates the esophagus from the stomach or a particular
region? In fact, both strip and region definitions can be found in literatures.
According to the Cancer Principles & Practice of Oncology[2],
the cardia is the portion of the stomach surrounding the esophagogastric
connection, characterized by the absence of acid cells; and its mucosa, a few
centimeters in extension, is a continuation of transitional mucosa descending
from the squamous columnar junction (SCJ). However, this conception has been
challenged. Three large-scale studies on the distribution of cardiac mucosa at
EGJ argued that the extension of cardiac mucosa descending from SCJ is less
than 4 mm[3]. EGJ is anatomically defined as the junction of tubular
esophagus and saccate stomach. From a histopathological perspective, EGJ
carcinoma refers to the malignant tumor located at the zigzag junction where
the stratified squamous epithelium of the distal esophagus meets the simple
columnar epithelium of the stomach, i.e. carcinoma near the cardia. In normal
conditions, anatomical EGJ coincides with histological SCJ or Z-line[4].
In many circumstances, however, particularly in adults with gastroesophageal
reflux disease (GERD), slightly up-shifting or irregular Z line was frequently
found, and the histological SCJ was usually above the anatomical EGJ. In such a
context, this small portion of intestinal epithelium, which is composed of pure
mucous glands or a mixture of mucous and gastric glands, histologically mimics
the true cardia[5-7]. Biopsies from this region can be mistaken as
the gastric cardia, but actually they were specialized intestinal metaplasia
originated from the distal esophagus.
Endoscopic definition
Endoscopy is the
most common tool for EGJ carcinoma diagnosis[8,9]. Western
researchers prefer proximal gastric plicae as the anatomical landmark for
identification of esophagogastric boundary during endoscopy[10]. They
believe that paliform blood vessels are sometimes indistinguishable from other
vessels, and in some situations these vessels are even undetectable[11,12].
However, Japanese endoscopists argue that location of the proximal gastric
plicae can be affected by inflation or respiration, particularly in cases of
deep inspiration (the plicate boundary markedly shifts downwards). Then the
judgment of precise tumor location will be misled. They argue the lower edge of
paliform vessels provides a more definite boundary between the esophagus and
stomach[13,14].
DEFINITION
AND CLASSIFICATION OF EGJ CARCINOMA
According to the
World Health Organization (WHO) classification of gastrointestinal tumors
(2000), EGJ carcinoma is defined as adenocarcinoma affecting the EGJ area
irrespective of its primary origin. By this definition, adenocarcinoma entirely
located above EGJ is EAC while that entirely located below EGJ is GC[15].
This definition is rather simple for clinical practice but it is not helpful
for determination of primary origin. Primary origin is difficult to be
determined especially for tumor occupying both the lower esophagus and EGJ, or
EGJ and proximal stomach, or even all the three sites.
The etiology, pathogenesis,
and progress mechanism of EGJ carcinoma remains poorly understood, and the
carcinoma has two different lymph node (LN) metastatic routes (spread to the
thorax or to the epigastrium). In 1998, in order to objectively evaluate the
efficacy of surgery and chemo-radiotherapy, the International Gastric Carcinoma
Association (IGCA) and the International Society for Disease of the Esophagus
(ISDE) guidelines jointly announced the definition and classification of EGJ
carcinoma[16]. According
to IGCA/ISDE guidelines, adenocarcinoma at EGJ (AEG, adenocarcinoma of the
esophagogastric junction) was defined as the adenocarcinoma with epicenter
located between 5 cm proximal and distal to the anatomical cardia. The tumors
were further classified into three types. Type I AEG is the adenocarcinoma
arising at the distal esophagus, which is usually derived from the specialized
intestinal metaplasia (SIM) of esophageal epithelium, e.g. the Barrett¡¯s
esophagus, which usually infiltrates the proximal esophagus. Type II AEG is
derived from the true anatomical cardia or the short segment of intestinal
metaplasia at the EGJ, which is also named ¡°junction adenocarcinoma¡±. And type
III AEG refers to the subcardial GC which infiltrates the EGJ and distal
esophagus.
Although different types of
AEGs share many epidemiological and morphological features, latest researches
have demonstrated differences in their pathology and biological behavior. For
example[16]: (1) Type I AEG is more predominant in male patients
than types II and III; (2) Patients with type I AEG are more likely to have
hiatal hernia with a prolonged history of GERD; (3) SIM of distal esophagus
(Barrett¡¯s esophagus) may progress to high-grade dysplasia, which has been
identified as a main precancerous lesion for distal esophagus adenocarcinoma;
but dysplasia is rare for intestinal metaplasia of the cardia and subcardia
mucosa; (4) Cytokeratin expression and P53 mutation are more common in the
adenocarcinoma at or above the gastric cardia; (5) Lymphangiography has
revealed different patterns of lymphatic spread: distal esophageal
adenocarcinomas (EAC) mainly spread to the mediastinum in cephalad and to the
celiac artery in caudad, while carcinomas at or below gastric cardia tend to
invade the celiac artery, splenic hilum and the area besides abdominal aorta. This
classification, which divides AEGs into distal esophagus carcinoma (type I),
narrowly defined gastric cardia adenocarcinoma (type II), and subcardial
gastric adenocarcinoma (type III), well favors the surgical decision as well as
researches on pathogenesis and pathological behavior of AEGs.
Since EGJ as an area is
difficult to be determined by endoscopy or autopsy, researchers argue that
deviding esophagus from stomach with a strip is more practical. Based on the
WHO definition and IGCA/ISDE classification, EGJ boundary can be defined with
either the proximal gastric plicae or the lower edge of paliform vessel in the
distal esophagus. Therefore, the clinical phrase ¡°gastric cardia carcinoma¡± and
anatomical term ¡°EGJ carcinoma¡± are two distinct concepts: cardiac carcinoma is
confined to a smaller region, equal to the IGCA-ISDE Type II tumor, and EGJ
carcinoma includes all 3 types of IGCA-ISDE AEGs.
TREATMENT
Surgery
There has been
little improvement in overall survival (OS) of EGJ carcinoma in recent decades,
because 80% of patients had lymphatic metastases upon diagnosis. However, it is
worth noting that the five-year rate of surgical resection alone has exceeded
35% to 50% in some surgical centers. Moreover, 5-year survival rate in Stage
III carcinoma (T3-4N1) also reached 25%-35%. According to a meta-analysis,
surgical resection alone can achieve a 5-year survival rate of more than 35%
with less lymph nodes (LN) involved; once number of LNs involved exceed more
than 6 or existence of distal LN metastases, the rate will drop to lower than
10%[17].
Neoadjuvant therapy
Currently, there is
a general consensus that surgery alone may not be the treatment of choice even
for resectable gastric carcinoma. MAGIC trial is regarded as the milestone
study in aspect of treatment compliance, in which distal esophagus and EGJ
adenocarcinomas accounted for 26% of the samples[18]. In the study,
most patients completed full-dose preoperative neoadjuvant therapy, while only
about 40% completed full-dose postoperative adjuvant therapy. The well
tolerance is one of the factors contributing to preference of neoadjuvant
therapy. In the CROSS study, a multi-center clinical trial conducted in France,
patients underwent surgical resection plus preoperative concurrent
chemoradiotherapy had a better survival than those treated with surgery alone[19],
which also supports the use of preoperative neoadjuvant therapy in resectable
EGJ carcinoma.
Although preoperative
neoadjuvant therapy can induce pathological complete remission in 20% patients
and a higher 5-year survival rate than surgery alone, there are still more than
50% of patients fail to respond. It is worth noting that of those
non-responders, the 5-year survival rate will drop to 12%. Currently there is
no biological marker for reliable prediction of response. Some even suspect
that the course of the therapy, usually lasts 3-4 months, reduce the
opportunity of resection by postponing surgery. Therefore, targeted patients
who may benefit from therapy remains to be the focus. Previous studies
demonstrated that decline of tumor glucose uptake showed by PET after
chmotherapyp can be a predictor of response. Study of Lordick et al
found that metabolic response (defined as decrease of 35% or more in tumor
glucose SUV) after 2 weeks of induction chemotherapy is associated with the
long term efficacy after several cycles of chemotherapy. The MUNICON trial, a
prospective study involving 110 patients with EGJ carcinoma, showed that 49% of
patients had initial metabolic response, who continued to receive neoadjuvant
chemotherapy for 12 weeks and then proceeded to surgery. Metabolic
non-responders discontinued chemotherapy and switched to surgery. Results
showed that the median event-free survival was 29.7 months in metabolic
responders, significantly longer than that of non-responders (14.1 moths)[20].
Adjuvant therapy
Although there have
been numerous researches on adjuvant therapy published in the past three
decades, the role of the therapy in the treatment of GC remains uncertain until
the early 21st century. The intergroup 0116 study estalished adjuvant
5Fu/LV chemoradiotherapy as the standard of care of GC and EGJ adenocarcinoma
in the USA[21]. However, this strategy has not been accepted outside
the USA due to the associated toxicity, especially for patients who have
undergone D2 dissection, radiotherapy is widely considered to be unnecessary. Attitude
for adjuvant therapy shifted based on three evidences: (1) Four recent
meta-analyses concluded patients underwent adjuvant therapy benefited more than
those reported in the meta-analysis by Hermans in 1993[22]; (2) In
ACTS-GC study[23], a Japanese phase III clinical trial including
1,059 patients with stage II or III gastric carcinoma having gastrectomy with
extended (D2) lymph-node dissection were randomly assigned to receive adjuvant
therapy with S-1, an oral fluoropyrimidine, or surgery alone. Results showed
that the three-year survival rate in S1 group was 80.5%, markedly higher than
that in surgery alone group (70.1%); In addition, adjuvant chemotherapy reduced
32% of mortality risk. (3) In another Asian Classic study, 1,035 stages II/III
GC patients who underwent D2 surgery were treated with or without XELOX
(Capecitabine plus Oxaliplatin), an adjuvant chemotherapy regimen. Results
showed that three-year survival rate was 83% in XELOX group, significantly
higher than that (78%) in the control arm[24]. Asian physicians are
more positive towards adjuvant therapy in the treatment of GC than their
counterparts in western countries, who emphasize more on individualized
treatment decisions. In general, therapeutic strategy in the treatment of EGJ
carcinoma is accustomed to the preoperative neoadjuvant
therapy¡ªsurgery¡ªadjuvant therapy model.
Emerging treatment
Recently, increased
awareness about tumor biology and molecular mechanisms responsible for tumor
proliferation and growth have resulted in the development of active drugs that
targeted in such mechanisms. These agents include the EGFR with subtypes Her-1,
Her-2, Her-3 and Her-4, VEGF and its receptor(VEGFR), and mammalian target of
rapamycin (mToR)[25-29]. However, most of these agents had not
demonstrated significantly improved OS and PFS of advanced GC and EGJ cancer. The
recent ToGA (Trastuzumab for Gastric Carcinoma) is a milestone clinical trial
which studied Trastuzumab in combination with chemotherapy for HER2-positive
advanced gastric or EGJ carcinoma[25]. It should be emphasized that
this is the first regimen which has induced more than 1-year survival in
patients with advanced GC. Particularly in this study, a stratification
analysis revealed that the positive rate of HER-2 was significantly higher in
EGJ carcinomas than that in GCs, suggesting that patients with advanced EGJ
carcinoma may benefit more from the combination. In the near future, new
pathways with more specific biological rationales in EGJ cancer need to be
explored. Promising new targets, such as HGF/MET pathway, is under evaluation.
PROGNOSIS
It is traditionally
recognized that the prognoses of EGJ carcinoma, GC and EAC as well as their
gene expression profiles vary significantly. However, according to a
meta-analysis of four clinical studies involving 1,775 subjects, significant
difference exists in neither response nor survival rate among patients with
advanced stages of esophageal adenocarcinoma, EGJ adenocarcinoma, or gastric
adenocarcinoma, who received fluorine pyrimidines and/or platinums treatment[30].
It seems that the primary tumor origin is a less important prognostic factor
for patients with metastasis; whereas gene mutation and activation of signal
transduction pathway all contribute to the similar poor outcome of advanced
diseases.
SUMMARY
Both anatomical and
histological definitions are important for diagnosis and treatment of AEGs. Medical
oncologists, surgeons, pathologists, and endoscopists should devote much more
time and efforts to EGJ carcinoma studies.
Combination of adjuvant
therapy and surgery is more beneficial for patients with AEGs than surgery alone.
CONFLICT
OF INTERESTS
There are no
conflicts of interest with regard to the present study.
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Peer reviewer: Angelo Paradiso, Head Experimental
Medical Oncology, National cancer institute, IRCCS Istituto Tumori
"Giovanni Paolo II", Viale Orazio Flacco, 65, 70124 - BARI, Italy.
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