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GASTROINTESTINAL (NONCOLORECTAL) CANCER
Gastroesophageal Junction Adenocarcinoma: Is
There an Optimal Management?
Daniel Lin, MD, MSc
1
; Uqba Khan, MD
2
; Thorsten O. Goetze, MD
3
; Natalie Reizine, MD
4
; Karyn A. Goodman, MD, MS
5
;
Manish A. Shah, MD
2
; Daniel V. Catenacci, MD
4
; Salah-Eddin Al-Batran, MD
3
; and James A. Posey, MD
1
overview
The incidence of gastroesophageal junction (GEJ) adenocarcinomas has been rising over the past few
decades, creating a need for effective therapeutic strategies. Treatment of locally advanced GEJ tumors, in
particular, present a unique challenge because these tumors have generally been approached as either
esophageal or gastric cancers, and thus optimal preoperative management remains uncertain. Both neo-
adjuvant chemoradiation and perioperative chemotherapy have been widely adopted in standard practice;
however, it is unclear which approach offers the optimal outcome for the fit patient capable of receiving any
planned strategy. In this review, we debate the management of locally advanced GEJ adenocarcinoma, and
discuss areas of ongoing investigation which may provide more effective and individualized treatment of
patients with GEJ cancers.
With combined estimates of more than 1.6 million
new cases and more than 1 million related deaths in
2018, cancers of the stomach and esophagus (gas-
troesophageal cancer), which include esophageal
squamous cell carcinoma (SCC), proximal esoph-
agogastric junction (EGJ) adenocarcinomas (esoph-
ageal and gastric cardia adenocarcinomas), and distal
gastric adenocarcinoma, remain important worldwide
public health concern.
1
The incidence of EGJ ade-
nocarcinoma has notably risen in Western countries,
and population analyses in the United States have
reported a nearly 2.5-fold increased incidence since
the 1970s.
2,3
There has been a lack of a single standard system of
classification for EGJ tumors. The Siewert classifica-
tion, which establishes three types based on the en-
doscopic location of the epicenter of the tumor and its
relation with the EGJ, allows a tailored surgical ap-
proach and consistency in reporting results associated
with therapeutic interventions.
4,5
Type I EGJ tumors are
located up to 5 cm proximal to the anatomic EGJ, type
II lesions span the anatomic EGJ and have their epi-
center up to 2 cm below the EGJ, and type III cardia
tumors extend up to 5 cm into the stomach.
6
In recent
guidelines from the American Joint Committee on
Cancer 8th edition, EGJ tumors with epicenter in the
distal esophagus or less than 2 cm into the proximal
stomach (Siewert types I and II) based on surgical
resection specimens are included under the esopha-
geal cancer staging classification.
7
However, it is
sometimes difficult for endoscopists to accurately
identify the epicenter of the tumor because the
intraluminal mass often spans across these artificial
type I-III boundaries. Moreover, recent molecular
profiling studies
8,9
clearly differentiated esophageal
SCC from type I lesions, in which SCCs resembled
SCCs of other organs more than they did type I lesions,
whereas type I lesions predominantly resembled the
chromosomal unstable subtype (CIN) found in the
majority of type II/III lesions and approximately 50% of
distal gastric adenocarcinoma. Therefore, although
there are surgical distinctions between Siewert types
I-III, biologically these are considered quite molecularly
similar.
8,9
Histologically, the large majority of these
tumors are adenocarcinomas.
Surgery remains the primary curative modality for EGJ
adenocarcinomas. However, overall prognosis of this
disease remains poor because of distant and locore-
gional recurrence of disease, with 5-year survival rates
averaging around 30% with surgery alone.
10
Conse-
quently, neoadjuvant or perioperative multimodality
strategies incorporating chemotherapy, radiation, or
the combination of both, have emerged over the past
few decades, with the goal of eradicating occult
micrometastatic disease and improving both surgical
and survival outcomes.
As noted, given its anatomic location joining esophagus
and noncardia stomach, EGJ adenocarcinomas have
often been grouped together with either esophageal
or gastric cancers in large, prospective, randomized
clinical trials, and have rarely been evaluated as
a distinct entity, resulting in trials that have variable
inclusion criteria. The difficulty with clearly de-
marcating type I, II, and III EGJ tumors also affects this
Author affiliations
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article.
Accepted on May 17,
2019 and published
at ascopubs.org on
May 17, 2019:
DOI https://doi.org/
10.1200/EDBK_
236827
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variability. Several pivotal trials have established paradigms of
multimodality management with perioperative chemotherapy
or preoperative chemoradiation of locally advanced gastro-
esophageal cancers. In particular, the Dutch CROSS trial,
which included mostly type I esophageal adenocarcinoma
and some type II EGJ cancers along with esophageal SCC
(25%), demonstrated superior R0 (microscopically margin-
negative) surgical resection rates and long-term survival
outcomes with neoadjuvant radiotherapy combined with
concurrent weekly carboplatin and paclitaxel, compared with
surgery alone, and established this regimen as a standard of
care.
11
More recently, however, combination perioperative
chemotherapy strategies have been investigated. The FLOT4-
AIO trial, which included a population of EGJ cancers (56%)
along with distal gastric adenocarcinoma (44%), compared
a docetaxel-based triplet chemotherapy FLOT (5-fluorouracil
[5-FU], oxaliplatin, docetaxel) with anthracycline-based triplet
epirubicin, cisplatin, and 5-FU or capecitabine (ECF/ECX),
and demonstrated superior survival outcomes with FLOT.
12,13
Given the lack of definitive studies directly comparing che-
motherapy alone or in combination with radiation for locally
advanced EGJ adenocarcinoma, it is difficult to discern which
may be the most effective preoperative strategy for these
patients. This article will therefore debate the optimal man-
agement of locally advanced EGJ adenocarcinoma and will
provide aspects to consider “for”or “against”either strategy.
We conclude with a discussion of ongoing clinical studies that
may advance and further individualize future strategies for
EGJ cancers.
FOR PRE-/PERIOPERATIVE CHEMOTHERAPY VERSUS
NEOADJUVANT CHEMORADIOTHERAPY
The prognosis of patients with locally advanced EGJ ade-
nocarcinoma is poor with surgery alone. Although the two
approaches of perioperative chemotherapy and neo-
adjuvant chemoradiation have each improved survival
compared with surgery alone and have been widely though
heterogeneously adopted in Western countries, there have
been more consistent data in favor of perioperative che-
motherapy. In this review, we summarize the data in support
of perioperative chemotherapy, and compare this treatment
paradigm with neoadjuvant chemoradiation.
First, all available trials enrolled patients with different pri-
mary tumor locations. Although the trials of perioperative
chemotherapy often enrolled patients with distal gastric and
proximal EGJ adenocarcinomas (type I-III lesions), the
neoadjuvant chemoradiation trials, including the pivotal
CROSS trial,
11
enrolled patients with esophageal SCC as well
as patients with type I and II lesions.
The first study to predominantly focus on EGJ adenocar-
cinomas was the French perioperative FNCLCC/FFCD 9703
perioperative chemotherapy trial.
14
The majority (75%) of
the 224 patients enrolled to the study had EGJ adenocar-
cinoma, (type I 11%, type II/III 64%, and distal gastric
adenocarcinoma 24%). Patients were randomized to re-
ceive two to three cycles of cisplatin/5-FU followed by
surgery, or to surgery alone. After surgery, patients in the
chemotherapy arm who had no evidence of progressive
disease while on the preoperative therapy received addi-
tional cycles of adjuvant chemotherapy. Treatment in the
perioperative chemotherapy arm resulted in significantly
improved overall survival (OS; 5-year OS rate 38% vs. 24%;
hazard ratio [HR] 0.69; 95% CI, 0.50–0.95; p = .02). The
EGJ type II/III tumors derived the highest benefit from
perioperative chemotherapy (HR 0.57; 95% CI, 0.39–0.83).
Perioperative chemotherapy also improved progression-free
survival and the rate of R0 resection.
The MAGIC trial
15
was a landmark phase III trial of gastric
and EGJ adenocarcinoma conducted in the United King-
dom. Focused on distal gastric cancer, the study enrolled
503 patients with clinical stage II or III adenocarcinoma of
the stomach (including type III cardia) (75%), GEJ type II
(11.5%), and lower esophagus type I (14.5%) who were
treated with either three cycles of ECF pre- and postsurgery,
or with surgery alone. Similar to the FNCLCC trial, the
perioperative chemotherapy arm demonstrated a significant
improvement in progression-free survival and OS (5-year OS
rates 36% vs. 23%; HR 0.75; 95% CI, 0.60–0.93; p = .009)
compared with surgery alone. All anatomic categories (type
I, type II GEJ, and type III/stomach) derived benefit. Despite
fewer patients (11%) in the MAGIC trial having GEJ cancers,
this subgroup seemed to derive the greatest benefit from
chemotherapy (HR for death in the EGJ subgroup was
0.49; 95% CI, 0.28–0.88), similar to the FNCLCC/FFCD
9703 study. Neither the MAGIC nor the FNCLCC/FFCD
9703 trials found that preoperative chemotherapy increased
PRACTICAL APPLICATIONS
•Understand the different effective treatment
options for the fit patient presenting with po-
tentially operable GEJ adenocarcinoma.
•Learn the key discussion point when discussing
management of GEJ adenocarcinoma.
•Learn of novel approaches to management in
GEJ adenocarcinoma.
•Learn about the factors that influence the use of
perioperative chemotherapy versus neoadjuvant
chemoradiation for this patient population.
•Recognize the need for multidisciplinary dis-
cussion when planning a treatment course for
patients diagnosed with T3N1 adenocarcinoma
of the gastroesphageal junction.
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morbidity, mortality, or hospitalization time compared with
surgery alone.
The argument for a perioperative chemotherapy approach for
EGJ adenocarcinoma has been further strengthened by the
results of the recent FLOT4-AIO trial.
12,13
In this German trial,
a total of 716 patients with locally advanced, resectable gastric
or EGJ adenocarcinoma were randomly assigned to either the
MAGIC regimen consisting of three preoperative and three
postoperative 3-week cycles of ECF/ECX) or four preoperative
and four postoperative cycles of FLOT. Most patients (56%)
had EGJ adenocarcinoma (24% with Siewert type 1, 32% with
type II/III and 15% with Barrett), whereas 44% had distal
gastric adenocarcinoma. Approximately 80% of patients had
a T3 or greater tumors, with 8% having T4 lesions (whereas
the CROSS study, discussed next, had no T4 lesions). FLOT4-
AIO enrolled 80% of patients having node-positive disease
(the CROSS trial had only 65% with node-positive disease).
The primary study outcome, median OS, was significantly
improved with FLOT; OS of 35 months was noted in the ECF/
ECXgroupandcomparedwith50monthsintheFLOTgroup
(HR 0.77; 95% CI, 0.63–0.94; p = .012). Median disease-free
survival was also significantly improved: 18 months in the ECF/ ECX
group compared with 30 months in the FLOT group (HR
0.75; 95% CI, 0.62–0.91; p = .004). FLOT was associated
with significant tumor down-sizing (≤ypT1 tumors, 25%
with FLOT vs. 15% with ECF/ECX; p = .0008) and increased
rate of R0 resection (85% vs. 78%; p = .0162) as assessed
in the intention-to-treat (ITT) population. As shown in the
phase II part of the FLOT4-AIO trial, FLOT was associated
with significantly higher proportions of patients achieving
pathologic complete regression (pCR) grade 1a (16%; 95%
CI, 10–23 vs. 6%; 95% CI, 3–11; p = .02), which was more
pronounced in the intestinal histology subgroup (23%) com-
pared with the mixed (0%) and diffuse (3%) types. This is
notable because most EGJ tumors are intestinal CIN type,
whereas most diffuse/mixed types are distal gastric cancers not
EGJ tumors molecularly considered (genomically stable).
8,9
Importantly, the quality of surgery—a major point of
criticism generally raised in trials involving multimodality
therapy—was excellent in the FLOT4-AIO trial. Nearly all
patients (98%) received at least the protocol-recommended
D2- or two-field resections; the median number of lymph
nodes removed was 25. The benefits observed in the
FLOT4-AIO trial were consistent across the subgroups,
specifically with regard to age, anatomic site, histology, and
clinical stage. When assessed for interaction statistically, the
corresponding HRs of death were 0.76 for EGJ and 0.77 for
the stomach, respectively, p = .94. Furthermore, despite the
challenges associated with patients completing planned
post-operative therapy (50%), the FLOT4-AIO trial is the first
study to show an improvement in OS compared with another
effective bimodal perioperative strategy as opposed to a
surgery alone comparator arm.
In contrast to the studies involving perioperative chemo-
therapy, support for neoadjuvant chemoradiation is mostly
derived from smaller clinical trials with heterogeneity in the
patients. The use of neoadjuvant chemoradiation for EGJ
cancers is based primarily on the CROSS trial.
11
The CROSS
study was the only randomized study evaluating the benefit
of neoadjuvant chemoradiotherapy to show a survival
benefit from chemoradiation in esophageal and GEJ ade-
nocarcinomas. In this study, 366 patients with esophageal
SCC or esophageal adenocarcinoma type I (73.2%) or EGJ
type II (24%) were randomly assigned to chemotherapy
with weekly paclitaxel and carboplatin combined with radi-
ation therapy followed by surgery or to surgery alone. Al-
though the median OS in the ITT population clearly favored
neoadjuvant chemoradiation over surgery alone (HR 0.66;
95% CI, 0.495–0.871; p = .003), the adenocarcinoma sub-
group, the predominant group accounting for 75% of accrual,
benefited to a lesser extent (HR 0.741; 95% CI, 0.536–1.
024; p = .07) than the SCC group (HR 0.422; 95% CI,
0.226–0.788; p = .007). Moreover, after multivariate
analysis adjusting for known clinicopathologic prognostic
variables, the survival benefit in the adenocarcinoma group
was not statistically important. The specific results differ-
entiating the type I and type II adenocarcinoma subgroups
were not presented or published and are therefore un-
known. Further examination of the subgroups of the CROSS
study shows that the relative benefit from neoadjuvant
chemoradiation was observed in patients with node-
negative disease (HR 0.422; 95% CI, 0.239–0.747; p =
.003), whereas patients with node-positive disease, and
thus signs of an initial systemic spread, did not benefit from
neoadjuvant chemoradiation (HR 0.807; 95% CI, 0.576–
1.130; p = .21).
16
With only 364 analyzed patients, of which
75% had EGJ adenocarcinoma, the CROSS study is a rel-
atively small and heterogenous study, and its results need
confirmation by other randomized trials. Moreover, it is often
overlooked that the CROSS study compared neoadjuvant
chemoradiation versus surgery only, whereas the FLOT4-
AIO trial compared FLOT against another effective regimen
known to improve survival. The results with FLOT should
therefore be considered and advancement to those achieved
with ECF/ECX.
The only randomized trial to compare neoadjuvant che-
moradiation with chemotherapy alone in EGJ cancer was
the German study by Stahl and colleagues (POET).
17
In this
small study, which closed early because of poor accrual,
126 patients with adenocarcinoma of the esophagus, GEJ,
or gastric cardia were randomly assigned to chemotherapy
followed by surgery or to chemotherapy followed by che-
moradiation and then surgery. There was a statistical trend
toward improved 3-year OS rates (p = .07) in the chemo-
radiation arm. Nonetheless, the POET study was formally
a negative trial and had several substantial limitations,
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including that the analysis was not performed on an ITT basis
because only 119 of the 126 patients were analyzed, with
most of the dropouts occurring in the chemotherapy arm.
There are other arguments against the routine incorporation
of radiotherapy in EGJ adenocarcinoma patients with locally
advanced disease. Despite the notion that radiotherapy is
“required”to optimize R0 resection, pCR, and as a con-
sequence, local recurrence rates, evidence has suggested
otherwise. The R0 resection rate in the ITT population of the
CROSS study in the EGJ adenocarcinoma subgroup was not
explicitly reported but was approximately 82%–85%, and
therefore is similar (84%) to that of the FLOT4-AIO ITT
analysis. The pCR rate (grade 1a by Becker criteria) was
23% in the CROSS study, and similar to the 23% in the
intestinal subtype (of which EGJ is mostly comprised, as
discussed previously, from TCGA profiling) of the FLOT4-
AIO study. Moreover, a pCR achieved with chemotherapy
alone implies systemic benefit perhaps not derived from
chemoradiotherapy—carboplatin/paclitaxel as in CROSS.
Ultimately, the response observed with measurable disease
is believed to impact micrometastatic more so than a dou-
blet with radiation locally. Finally, the predominant pattern
of recurrence of EGJ adenocarcinoma is systemic or distant.
As demonstrated in the FFCD 9703 study,
14
only 24% of
patients had local recurrence (12% with local only and 12%
with both local and distant recurrence), and the remainder
with distant disease alone. Similarly, the CROSS trial re-
ported 22% of patients with localized recurrence (9.6% with
local only, and 12.4% with both local and distant re-
currence). Furthermore, the FLOT4-AIO trial reported
18.5% of patients with local and distant recurrence (12% with
local only, and 6.5% with both local and distant recurrence).
Although cross-trial comparisons should be approached
with caution, the addition of radiotherapy does not seem to
decrease local recurrence to a greater extent.
In each of the contemporary studies discussed, the majority
of patients had clinical T3 and node-positive tumors, which
remains the most common presentation of EGJ adeno-
carcinoma. Thus, until further direct comparative evidence
of perioperative chemotherapy versus neoadjuvant che-
moradiation is available for these patients, given the strong
evidence demonstrating efficacy with consideration of
treatment toxicities, cost, and convenience compared with
chemoradiotherapy, FLOT is emerging as a sound choice for
fit patients with locally advanced EGJ adenocarcinoma.
OPPOSED TO PRE-/PERIOPERATIVE FOR
NEOADJUVANT CHEMORADIOTHERAPY
The rationale for trimodality therapy, which incorporates
chemotherapy and radiation before surgery, stems from
the unique anatomic features of the EGJ.As it spans from the
distal esophagus across the diaphragmatic crus into the
most proximal aspect of the stomach, the cardia, the EGJ
remains anatomically distinct from the more distal stomach.
Because the esophagus is not covered by a serosal lining
and is in close proximity to many organs and structures,
spread by direct extension is frequent. In addition, the rich
submucosal lymphatic network of the esophagus and GEJ
leads to a high risk of lymph node involvement.
18
Indeed,
because the proximal EGJ tumors (Siewerts types I and II,
specifically) behave like esophageal cancer, both in terms of
nodal patterns of spread and in terms of survival, the
American Joint Committee on Cancer thus classifies EGJ
tumors with esophageal cancer. Anatomically, these tumors
are most similar to distal esophageal adenocarcinoma.
Biologically, distal esophageal tumors are identical to EGJ
tumors and to the CIN subtype of gastric cancer (which is
predominantly seen in the proximal stomach). This is one
reason to consider preoperative chemoradiation for EGJ
tumors: they should be approached similarly to distal
esophageal tumors given their similar behavior.
Furthermore, the data supporting trimodality therapy are
based on the high rate of local failure after esophagectomy
alone, as well as concerns about achieving curative negative
margin resection. For example, the results for patients on
the surgery control arm of the INT-0113 trial,
19
which
randomized patients to preoperative cisplatin/5-FU versus
surgery alone, revealed a 31% local failure rate in patients
who underwent an R0 resection. When all patients entered
on study were examined, an overall 61% rate of failure in
controlling local disease was observed if patients failed to
achieve R0 resection or developed progressive disease on
preoperative therapy are included.
19
In addition, INT-0113
failed to demonstrate differences in R0 resection rate,
treatment mortality, or OS (3-year OS rates of 23% vs. 26%;
p = .53) between patients receiving preoperative chemo-
therapy versus surgery alone, and the failure patterns were
similar.
19
The R0 resection rate was 62% in the preoperative
chemotherapy arm and 59% in the surgery alone group.
Several studies and meta-analyses have demonstrated an
association with positive circumferential resection margin
status and OS.
20,21
Thus, the potential for locoregional
failure and positive circumferential resection margin after
surgery has engendered interest in the use of radia-
tion therapy as part of combined modality surgery-based
therapy.
The landmark study that established the benefit of pre-
operative chemoradiotherapy was the Dutch CROSS trial.
11
As noted previously, this study randomized 366 patients
with SCC or adenocarcinoma of the esophagus or EGJ to
treatment with (1) preoperative carboplatin at an area under
the curve of 2 mg per minutes per milliliter and paclitaxel
50 mg/m
2
once weekly for 5 weeks, and concurrent ra-
diotherapy (1.8 Gy daily to 41.4 Gy in 23 fractions, followed
by transthoracic esophagectomy or transhiatal esoph-
agectomy for GEJ cancers), or (2) immediate surgery. All
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patients were staged by endoscopic ultrasound and com-
puted tomography scan and were required to have either
node-positive or T2-3 disease. The majority of patients
treated had adenocarcinoma (75%) and most tumors in-
volved the distal one-third of the esophagus (58%). The
majority of patients were node positive (65%), and slightly
more patients on the chemoradiotherapy arm had T3 tu-
mors (84%) compared with the surgery-alone arm (78%).
At a median follow up of 45 months, the trial showed
a significant survival benefit for chemoradiotherapy added
to surgery, with median survival increasing from 24 to
49 months (HR, 0.0657; p = .003), and improvement in
2- and 5-year OS (67% and 47% vs. 50% and 34%; HR
0.665). The rate of R0 resection was significantly improved
on the chemoradiotherapy arm (92% compared with 69%;
p,.001). Pathologic complete responses (pCR) were seen
in 23% of adenocarcinomas. Therapy was well tolerated
with grade 3 or 4 hematologic toxicity seen in 7% patients,
and grade 3 or 4 nonhematologic toxicity seen in less than
13%. There was no difference in either operative morbidity
or mortality, and mortality was below 4% in each arm, which
is considered consistent and appropriate with modern-day
surgical outcomes in high-volume centers. Long-term follow
up indicated a maintained survival benefit for preoperative
therapy over surgery alone for both SCC and adenocarci-
noma.
16
At a median follow up of 84.1 months in surviving
patients, benefits were maintained for both adenocarci-
noma and SCC patients. For adenocarcinoma, median OS
was increased from 27.1 months to 43.2 months (HR 0.73).
Preoperative chemoradiotherapy significantly reduced the
risk of both locoregional disease progression (38% with
surgery alone reduced to 22% with chemoradiotherapy)
and distant disease progression (48%–39% with chemo-
radiotherapy). Based on these results, a new standard of
care for adenocarcinomas of the distal esophagus or GEJ
was established.
As mentioned earlier, the POET trial
17
was a major phase III
trial designed to compare preoperative chemotherapy and
chemoradiation versus chemotherapy alone, followed by
surgery. This trial only enrolled patients with GEJ cancer, but
was terminated prematurely because of poor accrual, with
afinal study enrollment of just 119 eligible patients. Eligible
patients were randomly assigned to receive (1) 2.5 cycles of
a 6-week schedule of weekly 5-FU 2 g/m
2
, 24-hour infusion
and leucovorin 500 mg/m
2
, 2-hour infusion plus biweekly
cisplatin 50 mg/m
2
, or (2) two cycles of the same regimen,
followed by 3 weeks of radiotherapy given in 15 fractions at
a dose of 2 Gy combined with cisplatin 50 mg/m
2
on days 1
and 8 and etoposide 80 mg/m
2
on days 3 to 5. The pCR rate
(16% vs. 2%, p = .03) and lymph node–negative status
(64% vs. 37%, p = .01) were significantly higher in the
chemoradiotherapy arm. Although the R0 resection rate in
operated patients was increased from 79% to 88% by
chemoradiotherapy, the ITT probability of complete re-
section was not different between treatment arms. With
a median follow-up time of 45.6 months, 3-year survival
trended toward improvement in the chemoradiotherapy
group (47.4%) compared with the chemotherapy group
(27.7%; p = .07), and freedom from local tumor progression
also favored the chemoradiotherapy group (76.5% vs. 59%;
p = .06). Despite the small sample size, OS also showed
a trend in favor of preoperative chemoradiation (HR 0.65;
95% CI, 0.42–1.01, p = .055), suggesting that chemo-
radiation may be superior to chemotherapy alone.
Meta-analyses of neoadjuvant chemoradiotherapy versus
surgery-alone trials attempted to synthesize these data, and
one study concluded that chemoradiotherapy was associ-
ated with a 13% absolute benefit in survival at 2 years. The
investigators also compared trials of neoadjuvant chemo-
therapy (without radiation) versus surgery alone and found
a smaller survival benefit of 7% at 2 years.
22
A more recent
update with more than 4,100 patients further demonstrated
a survival benefit of neoadjuvant chemoradiotherapy versus
chemotherapy alone.
23
Given the risk of systemic disease in patients with GEJ and
the importance of better tailoring therapy to tumor biology,
an emerging option for patients with esophageal and EGJ
adenocarcinomas is induction chemotherapy followed by
chemoradiotherapy. The Alliance/CALGB 80803 is a ran-
domized phase II study that was designed to evaluate the
early assessment of chemotherapy responsiveness by
positron emission tomography (PET) imaging to direct
further therapy in patients with esophageal cancer to im-
prove their response to therapy as demonstrated by pCR
rates.
24
A total of 257 patients with resectable T3/4 or node-
positive esophageal adenocarcinoma underwent a baseline
PET/CT scan to determine maximum standardized uptake
value (SUVmax), followed by random assignment to either
modified FOLFOX6 or carboplatin/paclitaxel. After approx-
imately 6 weeks of induction therapy, patients had a repeat
PET scan. If SUVmax decreased by more than 35% from
baseline, as was the case in 50%–57% of evaluable pa-
tients, these individuals were deemed PET responders,
continued on their assigned chemotherapy, and received
concurrent radiotherapy. If the decrease in SUVmax did not
meet this threshold, which occurred in 30%–38% of
evaluable patients, these patients were considered PET
nonresponders and crossed over to receive the alternative
chemotherapy regimen in conjunction with radiotherapy.
Surgery occurred approximately 6 weeks after the com-
pletion of chemoradiotherapy. The study met its primary
endpoint of increasing pCR rates from 5% to 20% in PET
nonresponders by changing chemotherapy during radio-
therapy. The survival outcomes were also very encouraging.
Although the median survival was higher in the group of
patients that responded to induction chemotherapy than in
Lin et al
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the group that did not respond (46 months for responders
and 27 months for nonresponders) this was not statistically
significant (p = .09), suggesting that the change from an
ineffective chemotherapy regimen may have improved
outcomes in the group that was initially not responding.
Moreover, the median survival of 50 months and 4-year OS
of 52% in the patients who had FOLFOX induction che-
motherapy and were responders demonstrates that by
enriching the population for good responders using PET as
a biomarker results in more favorable outcomes in this high-
risk population.
25
A follow up to this study is to evaluate the
use of FLOT induction chemotherapy followed by a CROSS
chemoradiotherapy regimen to address both the high risk of
systemic and local recurrence. By combining these ap-
proaches in the neoadjuvant setting, there is also the benefit
that patients will receive all planned therapy, rather than in
the postoperative setting, where many patients are not able
to receive adjuvant chemotherapy.
DISCUSSION
Although several well-conducted randomized clinical trials
over the past couple of decades have clearly demonstrated
that multidisciplinary management with neoadjuvant che-
moradiation or perioperative chemotherapy for locally ad-
vanced EGJ cancers improve both surgical and survival
outcomes, the optimal strategy remains in question. How-
ever, several ongoing clinical trials may further elucidate
a preferred approach. The multicenter German ESOPEC
study is a randomized phase III trial that directly com-
pares perioperative chemotherapy according to the FLOT
protocol with preoperative chemoradiation according to
the CROSS regimen in patients with adenocarcinoma of
the esophagus with clinical stage cT1N+ M0 or cT2-4a
N0/N+, M0 (NCT02509286). Similarly, the Neo-AGIS
ICORG 10-14 trial is randomizing patients with ≥T2 or
node-positive adenocarcinoma of the esophagus or EGJ to
preoperative chemoradiation per CROSS protocol or peri-
operative chemotherapy with ECF or ECX per the MAGIC
approach (NCT01726452). Finally, the TOPGEAR study, an
international phase III trial led by the Australasian Gastro-
Intestinal Trials Group, randomizes patients with adenocar-
cinoma of the stomach or EGJ to receive either perioperative
chemotherapy alone (ECF, or recently changed to FLOT) or
preoperative chemotherapy (ECF or FLOT) followed by pre-
operative chemoradiation with 5-FU or capecitabine (NCT
01924819).
In addition to treatment with standard cytotoxic chemo-
therapy, immune checkpoint inhibitors have emerged as
a therapeutic option in the advanced or metastatic setting,
and have the potential to enhance preoperative therapeutic
strategies. At present, checkpoint inhibitors for gastro-
esophageal cancers are U.S. Food and Drug Administration
approved for all patients with tumors that are mismatch
repair deficient as characterized by microsatellite instability
high, after failure of first-line cytotoxic chemotherapy, and
for those with tumors that have positive programmed cell
death ligand 1 (PD-L1) expression, after two lines of stan-
dard therapy. Recent studies have demonstrated single
agent anti–PD-1 or anti–PD-L1 activity of up to 20%–30% in
patients with gastroesophageal cancer (particularly those
with PD-L1+ expression, defined as ≥1% staining of tumor
cells) who progressed after two or more lines of prior
therapy.
26-28
Moreover, trials evaluating the efficacy of
immunotherapy in earlier lines of therapy have shown
encouraging signals. The phase III KEYNOTE 181 trial
compared pembrolizumab with systemic chemotherapy
(investigator’s choice of paclitaxel, docetaxel, or irinotecan)
in 628 patients with esophageal or EGJ (Siewert type I)
cancers who had progressed after one line of standard
therapy. Although there was no important difference in OS
between the two treatment arms in the entire ITT population,
in those patients whose tumors had with high PD-L1 ex-
pression, combined positive staining (CPS ≥10), pem-
brolizumab demonstrated superior OS compared with
chemotherapy (9.3 vs. 6.7 months; HR 0.69; 95% CI,
0.52–0.93; p = .0074). Furthermore, preliminary analyses
from the phase II KEYNOTE 059 trial
29
demonstrated that in
a cohort of patients with previously untreated gastric and
GEJ cancer, fluoropyrimidine, and cisplatin plus pem-
brolizumab yielded response rates of 60% in all patients and
around 69% in PD-L1+ tumor patients.
29
Several randomized
phase III trials are investigating the role of immunotherapy in
the preoperative setting for gastroesophageal cancers. The
ICONIC trial is evaluating perioperative anti–PD-L1 anti-
body, avelumab, with chemotherapy (FLOT) in patients with
gastric, GEJ, or esophageal cancers (NCT03399071). An-
other phase II/III trial will evaluate anti–PD-1 and anti–
CTLA-4 agents, nivolumab and ipilimumab, respectively,
in patients with esophageal and EGJ cancers who are un-
dergoing surgery, with an initial randomization to pre-
operative chemoradiation with or without nivolumab, and
a second randomization to either adjuvant nivolumab or
nivolumab/ipilimumab postresection (NCT03604991). The
DANTE trial evaluates atezolizumab with FLOT in the per-
ioperative thera py of gastric and EGJ cance rs
(NCT03421288). Finally, the PANDA trial will evaluate
neoadjuvant capecitabine, oxaliplatin, and docetaxel in
combination with anti–PD-L1 antibody, atezolizumab, in
resectable gastric or GEJ cancers (NCT03448835).
Amplified or overexpressed in about one-third of gastro-
esophageal adenocarcinomas, human epidermal growth
factor receptor 2 (HER2) has remained a key therapeutic
target in advanced or metastatic disease. The benefitof
trastuzumab, a humanized monoclonal antibody targeting
the HER2 receptor, was first established in the ToGA trial,
a phase III study that randomized patients with gastric or
Optimal Management of Gastroesophageal Junction Adenocarcinoma
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GEJ adenocarcinoma that were HER2-positive, to receive
standard chemotherapy (infusional 5-FU or capecitabine
with cisplatin) with or without trastuzumab. The addition of
trastuzumab improved response rates (47% vs. 35%) as
well as the primary endpoint of OS, from 11.1 months
without trastuzumab to 13.8 months with trastuzumab (HR
0.74; 95% CI, 0.60–0.91; p = .0046).
30
Furthermore, the
benefit of adding trastuzumab to perioperative chemo-
therapy has been preliminarily demonstrated in small,
single- arm phase II trials using a CAPOX or FLOT che-
motherapy backbone, with reported pCR of up to 20% in
these cohorts.
31,32
Moreover, Schokker and colleagues
33
demonstrated the feasibility of adding dual anti-HER2
therapy with trastuzumab and pertuzumab to preoperative
chemoradiation per CROSS regimen in the phase IB TRAP
study, with reported pCR rate of 33%.
33
Ongoing randomized
clinical trials may clarify the benefit of adding HER2-targeted
therapy in the preoperative setting. These studies include the
randomized phase III RTOG 1010 trial evaluating neoadjuvant
chemoradiation using the CROSS approach with or without
trastuzumab in esophageal cancers (NCT01196390). PET-
RARCA is a randomized phase II/III trial investigating peri-
operative FLOT with or without trastuzumab/pertuzumab
(NCT02581462). The INNOVATION trial is a randomized
phase II study comparing perioperative fluoropyrimidine and
platinum-based chemotherapy withthesamechemotherapy
plus trastuzumab with or without pertuzumab in patients with
gastric or EGJ adenocarcinoma (NCT02205047).
Ultimately, the right approach should involve a multidisci-
plinary team assessment and consideration of patient fac-
tors that may influence choice of therapeutics. As we
acquire final study results that should help refine the
therapeutic approach in the node-positive disease patient,
we still need to consider the margin of benefit, quality of life,
and best pratice for all patients with the diagnosis of EGJ
tumors. What we have thus far is a strong signal for systemic
therapy prior to operation for most patients. What we need,
as in many malignancies, is predictive noninvasive surro-
gates of response and outcome. We are getting close with
PET imaging to assess response during chemotherapy. We
are still steps away from identifying targetable, differentially
expressed pathways that yield higher response rates and
resullt in improvements in overall survival. Therefore, clin-
ical trial participation is highly necessary toward advancing
our understanding.
AFFILIATIONS
1
Thomas Jefferson University Hospital, Sidney Kimmel Cancer Center,
Philadelphia, PA
2
Weill Cornell Medicine, NU Presbyterian Hospital, New York, NY
3
Institute of Clinical Cancer Research, UCT University Cancer Center,
Krankenhaus Nordwest, Frankfurt, Germany
4
University of Chicago Medical Center and Biological Sciences,
Chicago, IL
5
University of Colorado, Denver, CO
CORRESPONDING AUTHOR
James A. Posey, MD, Thomas Jefferson University Hospital, Sidney
Kimmel Cancer Center, 1025 Walnut St. Suite 700, College Building,
Philadelphia, PA 19107; email: james.poseyIII@jefferson.edu.
AUTHORS’DISCLOSURES OF POTENTIAL CONFLICTS OF
INTERESTAND DATA AVAILABILITY STATEMENT
Disclosures provided by the authors and data availability statement (if
applicable) are available with this article at DOI https://doi.org/10.1200/
EDBK_236827.
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