Treatment of localized gastric and gastroesophageal adenocarcinoma: the role of accurate staging and preoperative therapy
Badgwell et al. Journal of Hematology & Oncology
Treatment of localized gastric and gastroesophageal adenocarcinoma: the role of accurate staging and preoperative therapy
Brian Badgwell 0
Prajnan Das 2
Jaffer Ajani 1
0 Department of Surgical Oncology, The University of Texas, Unit 1484, MD Anderson Cancer Center , 1515 Holcombe Blvd., Houston, TX 77030 , USA
1 Departments of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center , Houston, TX , USA
2 Departments of Radiation Oncology, The University of Texas MD Anderson Cancer Center , Houston, TX , USA
Gastric cancer is the third most common cause of cancer death worldwide, although it is not in the top 10 causes of cancer death in Northern America. Due to clear differences in incidence, screening, risk factors, tumor biology, and treatment between gastric cancers from Eastern and Western countries, our treatment is primarily guided by trials from Western countries. Patients undergo an extensive staging evaluation including high-quality CT imaging, endoscopic ultrasound, and diagnostic laparoscopy with peritoneal washings for cytology. Patients are presented in multidisciplinary conference with input from medical, radiation, and surgical oncology, in addition to further evaluation of existing studies and biopsy results by diagnostic radiology and pathology colleagues. Due to the well-documented difficulty in tolerating postoperative therapy, patients are frequently treated with preoperative chemotherapy and chemoradiotherapy. Extended lymph node (D2) dissection is routinely performed during subtotal or total gastrectomy. Ongoing trials in Western populations comparing preoperative chemotherapy to chemoradiotherapy will help inform the decision regarding the optimal treatment for patients with resectable gastric cancer. Additional studies are needed to identify predictors of treatment response to identify the optimal preoperative or perioperative approach. As peritoneal disease is the most common site of recurrence, studies are also urgently needed for more accurate methods of detecting peritoneal disease at diagnosis, and also investigating potential treatment modalities such as hyperthermic intraperitoneal chemotherapy.
Gastric cancer; Preoperative treatment; Neoadjuvant; Chemotherapy; Chemoradiotherapy; Surgery
Gastric cancer is a leading cause of cancer death
worldwide, although only the 15th most common cause of
cancer death in the USA [
]. Geographic variations in
incidence rates are likely multifactorial and may be due
to differences in diet, food preservation, familial risk,
and Helicobacter pylori infection rates. The biology of
gastric cancer in Eastern Asia may be very different from
the biology of tumors found in Northern America and
Europe which demonstrate higher rates of poorly
differentiated histology, signet ring cell histology, and
proximal stomach involvement—variables which are all
associated with poorer survival. The high incidence rates
of gastric cancer in Eastern Asian countries has also led
to the adoption of screening upper endoscopy, which
results in the identification of asymptomatic, early stage
gastric cancers. The differences in incidence, screening,
risk factors, tumor biology, and treatment result in a
wide gap in survival outcomes between Eastern and
Western countries that limits the generalizability of
studies between regions, as patients from Eastern Asia
demonstrate markedly improved survival. Table 1
demonstrates the variation in 5-year overall survival rates
between randomized clinical trials of surgery and
additional therapy from Eastern and Western regions.
Treatment in Eastern countries is also notable for the
preference for a surgery first approach as many early
cancers do not require adjuvant therapy, and radiation
therapy is infrequently considered. Conversely, all of the
Western trials in Table 1 utilize some component of
preoperative therapy, making cross trial comparison of
studies from Eastern and Western regions, based on
pathologic stage, quite difficult. As current U.S. national
guidelines pertaining to locoregional gastric cancer are
based primarily on Western studies, with the exception of
adjuvant chemotherapy, we will focus primarily on
treatment trials and recommendations from North America
and Western Europe that guide our current practice.
The lifetime risk of gastric cancer in the USA is
approximately 1%, with a 5-year survival rate of 30% for all
stages based on recent Surveillance, Epidemiology, and
End Results registry data [
]. Five-year relative survival
rates for patients with localized, regional, and distant
disease are 67, 31, and 5%, respectfully, highlighting the
limitations in our current treatment for advanced disease
and the benefit to earlier detection of resectable disease
]. The purpose of this review is to summarize the
recent developments in the treatment of locoregional
gastric and gastroesophageal adenocarcinoma. Although
there are some ongoing minor controversies regarding
the extent of surgery, much of the recent improvement
in the treatment of gastric cancer is attributed to the
addition of chemotherapy or chemoradiotherapy. Due to
our institutional preference for preoperative therapy, we
will also summarize our multidisciplinary approach to
staging and treatment for patients with gastric cancer.
New patients arriving at our center are presented in a
weekly multidisciplinary conference after initial staging
with routine attendance by medical oncology, radiation
oncology, surgical oncology, pathology, and radiology.
Attendance by advanced practice providers as well as
basic science researchers also facilitates more
streamlined clinical care and integration of research projects.
Additional medical professionals not in attendance, but
in close communication, include gastroenterologists,
thoracic surgeons, and geneticists. Although we have not
published data on the frequency of the change in
management based on multidisciplinary review, anecdotally
we identify previously undescribed radiologic findings
on the order of 10–15%. Although awaiting presentation
in the conference may delay the initiation of therapy by
approximately a week, the scheduling of the endoscopic
ultrasound and laparoscopy with port placement are
ongoing during this time.
Clinical staging is critical to treatment, as outlined in
current national guidelines, but also as highlighted in
the most recent American Joint Commission on Cancer
TNM Staging system. The clinical stage in the 8th
edition of TNM staging is defined prior to treatment based
on endoscopy (possibly including endoscopic ultrasound
with fine needle aspiration), imaging, and diagnostic
laparoscopy with washings [
]. However, there are
several limitations in the accuracy of radiologic, endoscopic,
and laparoscopic staging. Endoscopic ultrasound has
acceptable accuracy in distinguishing T1 from T2–T4
lesions, which is important for deciding whether to
administer preoperative therapy. However, both CT
imaging and endoscopic ultrasound have low sensitivity for
determining nodal status which is not as critical of a
limitation when T2 or greater patients are treated
preoperatively and T1 patients have overall low rates of
nodal involvement [
Staging including endoscopic ultrasound can identify the
rare patient in the USA that presents with an early stage
gastric cancer suitable for consideration for endoscopic
mucosal resection or endoscopic submucosal dissection.
Current National Comprehensive Cancer Network
Guidelines suggest this treatment is adequate for patients with a
lesion ≤2 cm, well or moderately well differentiated
histology, that does not penetrate beyond the superficial
submucosa (early T1b), does not exhibit lymphovascular
invasion, and has clear lateral and deep margins [
tumors in Western populations meet this rigorous criteria,
and the skills and instrumentation required for endoscopic
submucosal dissection are not widely available in the USA.
Laparoscopy with peritoneal washings for cytology is a
high-yield, low-risk routine aspect of preoperative
staging. In our patient population in which 84% had T3
tumors and 66% were node positive on endoscopy,
laparoscopy identified carcinomatosis in 21% and positive
cytology only in another 13%. With the addition of a few
other important findings, such as liver cirrhosis or
locally invasive tumors, the overall yield with laparoscopy
was 36% [
]. Performing peritoneal washings is of
critical importance in staging, as positive peritoneal cytology
represents stage IV disease according to the American
Joint Commission on Cancer Staging system [
National Comprehensive Cancer Network guidelines
also note that carcinomas with positive cytology are
considered unresectable with treatment recommendations
of systemic therapy or best supportive care [
practice of initiating chemotherapy without laparoscopy,
in potentially resectable patients, with the plan to
perform laparoscopy at attempted resection after
preoperative chemotherapy is not advisable for a few reasons.
First, chemotherapy can convert positive cytology to
negative and therefore submit a patient to resection in
the setting of a history of stage IV disease. Second,
cytology from peritoneal washings is best performed in a
routine fashion with the availability of
immunohistochemical stains and collaborative assessment as
immediate intraoperative analysis may not be as accurate. Third,
a considerable delay occurs after stopping
chemotherapy, waiting 4 weeks, performing the laparoscopy with
attempted resection, identifying metastatic disease and
aborting the resection, and then resuming
chemotherapy. Although a patient in this scenario was spared the
morbidity of an unnecessary laparotomy, the delay in
continuing chemotherapy could be prevented with an
upfront laparoscopy. Lastly, the identification of
peritoneal disease at diagnosis allows for multidisciplinary
planning regarding potential clinical trials.
Preoperative, perioperative, or postoperative treatment
Upfront surgery is unusual and primarily utilized for
early gastric cancer, defined as T1aN0 and T1bN0
lesions. Not infrequently, the endoscopist will not be able
to tell the difference between a T1b and T2 lesion, and
in those situations, we treat as the less invasive tumor
with upfront surgery, to avoid the potential for
overtreatment. Otherwise, we rarely approach tumors with
upfront surgery, due to the oft-reported difficulty in
administering therapy after gastrectomy. Figure 1 reports
the completion rates for trials of perioperative or
postoperative chemotherapy or chemoradiotherapy. Often,
experts will refer to T2N0 lesions as early lesions, but
our institutional experience is that patients with T2
cancers have a long-term survival rate of only 66% and we
therefore consider those patients for full multimodality
The MD Anderson Algorithm for advanced, resectable gastric cancer
After CT imaging, endoscopic ultrasound, and
laparoscopy (with central venous catheter port placement), we
initiate chemotherapy as soon as possible. Chemotherapy
is most often 5FU and oxaliplatin administered every
2 weeks for 4 cycles (2 months total). Then patients
undergo chemoradiotherapy of 45 Gy with concurrent
5FU/capecitabine, with or without oxaliplatin. Patients
tend to experience the most severe side effects of
chemoradiotherapy during the last week of treatment, and the
first 2 to 3 weeks post treatment completion. We
currently plan for surgery 7 to 8 weeks after completion of
chemoradiotherapy, as the optimal time to allow for
treatment response yet prior to tumor regrowth, but also to
allow the patient to recover prior to gastrectomy. Figure 2
illustrates our general algorithm with timeline.
The choice of chemotherapy and length of treatment
is an area of active debate. One study which guides our
current practice is the OEO5 study, in which 2 cycles of
cisplatin and fluorouracil was equivalent to 4 cycles of
epirubicin, cisplatin, and fluorouracil or epirubicin,
cisplatin, and capecitabine (ECF/ECX), based on overall
survival and progression-free survival [
]. The mounting
evidence suggests that epirubicin should not be used in
patients with gastric adenocarcinoma [
other investigators have supported the use of ECF/ECX
or fluorouracil, oxaliplatin, and docetaxel, triplet
regimens produce more toxic effects than doublet regimens,
with 30-day mortality rates of 2–4% . Further
evidence against the use of taxanes comes from a
randomized clinical trial showing modest survival advantage in
the first-line advanced gastric adenocarcinoma setting
]. Therefore, we most often treat patients with
potentially resectable gastric cancer with 5FU and oxaliplatin,
which also leaves more treatment options for the
metastatic setting, should recurrence occur after surgery.
The use of preoperative chemoradiotherapy for gastric
cancer is based on multiple phase II trials, which show a
20–30% pathological complete response rate from the
combination of preoperative chemotherapy and
]. In the postoperative setting,
chemoradiotherapy results in a 9% improvement in overall survival
compared to surgery alone [
]. Level 1 evidence also
exits to support the use of preoperative
chemoradiotherapy for tumors of the gastroesophageal junction [
phase II trials on gastric cancer, in combination with trials
from gastroesophageal junction cancers, have justified
inclusion of preoperative chemoradiotherapy in current
NCCN guidelines [
]. A large international randomized
trial (TOPGEAR) is currently evaluating the role of
preoperative chemoradiation for gastric cancer; interim
results have shown that preoperative chemoradiation can be
administered safely [
]. Although the investigators for
this important trial utilized ECF for the chemotherapy
regimen, they are planning to modify the trial to allow for
the incorporation of docetaxel, oxaliplatin, and
fluorouracil/leucovorin (FLOT)-type regimens based on recently
presented results of a phase III trial demonstrating
improved survival with FLOT versus ECF/ECX [
results of this trial will likely have a major impact on our
current practice pattern and will influence national
guidelines for the preoperative treatment of gastric cancer in
Western populations, but the debate will continue
regarding the optimal perioperative chemotherapy regimen.
There are also some differences in the technique of
chemoradiotherapy between the TOPGEAR trial and our
institutional approach. The TOPGEAR trial investigators
deliver radiotherapy to the entire stomach, any perigastric
tumor extension, and regional lymph nodes. In brief, the
technique at our institution varies slightly in that we
utilize the results of our extensive preoperative staging
including imaging, endoscopic ultrasound, and laparoscopy
to map the primary tumor and treat with a minimum
4 cm mucosal margin along with involved nodes, as well
as regional and D2 lymph node basins.
Resection is either subtotal or total gastrectomy with
roux-en-y reconstruction. Non-anatomic (wedge)
resection, such as in patients not candidates for formal
gastrectomy, is rare and performed infrequently for
palliation of symptoms of bleeding or local tumor
control. Proximal gastrectomy is not currently performed
due to concerns over the oncologic equivalency of this
approach and severe reflux. Gastroesophageal junction
tumors require a tailored approach based on the Siewert
classification and the extent of gastric involvement. The
outgoing AJCC guidelines classified gastric cardia
tumors with up to 5 cm of gastric involvement as
esophageal cancers, but thankfully this misclassification has
been corrected in the 8th edition [
]. The 8th edition
gastric cancer staging system now incorporates a
postneoadjuvant therapy classification, but unfortunately
does not contain a complete pathologic response
category, which can occur 18% of the time for patients
treated with preoperative chemoradiotherapy [
Similar to esophageal cancer staging, patients with a
pathologic complete response (ypT0N0) may be considered
for inclusion in the ypStage I group [
Extended lymph node dissection is routinely
performed, as illustrated in Fig. 3, and only excluded for
patients with T1a lesions or prohibitive comorbidities.
Utilizing the Japanese classification of nodal stations,
our extended lymph node dissection most often includes
removing stations 8, 9, and 11p [
]. Eastern studies
consistently demonstrate a benefit to extended lymph
node dissection, while Western studies do not. The
MRC trial and the Dutch trial failed to show a benefit
with extended lymphadenectomy, primarily due to the
increased complications attributed to pancreatectomy
and splenectomy, although the Dutch trial showed an
improvement in locoregional recurrence and
diseaserelated survival for the D2 arm on long-term follow-up
]. We acknowledge the lack of evidence, based on
prospective randomized trials, and therefore routinely
perform extended lymph node dissection, but only if it
can be performed safely. The safety of D2
lymphadenectomy without routine pancreatectomy and
splenectomy is supported by the Italian IGCSG-R01 trial,
although benefit to extended dissection was only
identified on subgroup analysis for patients with locally
advanced gastric cancer and positive nodes [
]. As an
example of how these studies impact our current
practice, if the extended lymph node dissection would result
in blood transfusion, that otherwise would not be
required, we would exclude the extended dissection.
Based on the likely benefit in patients with advanced
malignancy, impact of stage migration, low risk
reported from expert centers, and single institution
reports of an independent association with survival,
numerous national gastric cancer guidelines
recommend extended lymphadenectomy [
Increased postoperative morbidity and mortality after
preoperative chemoradiotherapy is an important
concern that has only recently been addressed in the setting
of a randomized clinical trial for patients with resectable
gastric cancer [
]. Preoperative chemotherapy and
preoperative chemoradiotherapy for tumors localized to the
esophagus or gastroesophageal junction have been
demonstrated as safe treatment modalities with similar
postoperative complication rates, death rates, and length of
hospital stay based on Phase III trials [
]. In a
retrospective review at MD Anderson of 200 patients
undergoing upfront surgery, and 235 patients treated with
preoperative chemoradiotherapy, we found similar
postoperative morbidity and mortality rates [
]. The overall
leak rate and symptomatic intra-abdominal fluid
collection rate were 3.5 and 7.5%, respectively, and did not
differ between treatment groups. Based on the level 1
evidence from other types of preoperative therapy, and
our intra-institutional data, we consider preoperative
chemoradiotherapy safe for patients with gastric cancer,
although we continue to strive to improve tolerance and
minimize complications in our frail patients [
As a selective approach to patients with gastric cancer,
and given the well-documented difficulty in administering
postoperative therapy, patients treated with preoperative
chemoradiotherapy should demonstrate improved survival
compared to series of patients treated with upfront
surgery. That appears to be the case based on retrospective
data reporting overall survival in patients completing
preoperative chemoradiotherapy and resection. In an MD
Anderson series of 192 patients treated from 1995 to
2012, patients with AJCC pathologic stage 0, I, II, and III
disease demonstrated 5-year overall survival rates of 69,
63, 56, and 38% [
]. On multivariate analysis, nodal
status was the primary determinant of survival with 5-year
overall survival rates of 67, 42, 43, and 0% for patients
with AJCC N stage 0, 1, 2, and 3 disease, respectively [
The patterns of recurrence after treatment with
preoperative therapy and gastrectomy can help identify
future treatment modalities to improve survival. In a study
of almost 500 patients who underwent margin negative
resection, a total of 125 (26%) developed recurrence with
the peritoneum as the most common organ of
recurrence (49%), followed by the liver (21%) [
Recurrences were classified as locoregional in 15%, peritoneal
in 49%, and nonperitoneal distant organ in 54% [
The use of prophylactic HIPEC is being investigated as a
means to prevent peritoneal recurrence for locally
advanced gastric cancer [
In summary, the rationale for preoperative therapy is
strong due to the difficulty in completing postoperative
treatment. Patients with gastric and gastroesophageal
adenocarcinoma demonstrate long-term survival on the
order of 60% with induction chemotherapy and
chemoradiotherapy. Trials in Western populations are needed
comparing preoperative chemotherapy to
chemoradiotherapy, which are currently ongoing and will inform the
decision regarding the optimal treatment [
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated
or analyzed during the current study.
BB drafted the manuscript. BB, PD, and JA coordinated, edited, and finalized
the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
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