Perspective

What is the role of neoadjuvant chemotherapy, radiation, and

adjuvant treatment in resectable esophageal cancer?
Nasser Altorki, Sebron Harrison

Department of Cardiothoracic Surgery, Division of Thoracic Surgery, New York Presbyterian Hospital, Weill Cornell Medical College, New York,
NY, USA
Correspondence to: Dr. Sebron Harrison, MD. Division of Thoracic Surgery, Department of Cardiothoracic Surgery, Ste M404, Weill Cornell
Medicine, 525 E 68th St, New York, NY 10065, USA. Email: [email protected].

The majority of patients with operable esophageal cancers present with locally advanced disease, for which
surgical resection as a sole treatment modality has been historically associated with poor survival. Even
following radical resection, most of these patients will eventually succumb to their disease due to distant
metastasis. For this reason, there has been intense interest in the role of neoadjuvant therapy. Neoadjuvant
therapy primarily consists of either chemotherapy, radiation therapy, or a combination of the two. Multiple
studies of variable scope, design, and patient characteristics have been conducted to determine whether
neoadjuvant therapy is warranted, and—if so—what is the best modality of treatment. Despite nearly three
decades of study, decisions regarding neoadjuvant therapy for esophageal cancer remain controversial.
Regardless, the available evidence provided by large, prospective studies supports preoperative chemotherapy
as opposed to surgery alone. Therefore, in our opinion, there is no longer any question as to whether
induction therapy is appropriate for locally advanced esophageal cancer. Less clear, however, is the evidence
that the addition of radiation to chemotherapy in the preoperative setting is superior to neoadjuvant
chemotherapy alone. Our group generally advocates for neoadjuvant chemotherapy alone followed by
radical esophageal resection. The data for adjuvant therapy are soft, and particularly troubling is the high
rate of treatment drop out in trials studying adjuvant therapy. Therefore, we strongly prefer neoadjuvant
chemotherapy and reserve adjuvant chemotherapy for those rare, highly selected patients—patients with T1
tumors, for example—who do not receive neoadjuvant treatment and are found to have occult nodal disease
at the time of surgery.

Keywords: Esophageal cancer; neoadjuvant chemotherapy; radiation

Submitted Dec 06, 2016. Accepted for publication Mar 13, 2017.
doi: 10.21037/acs.2017.03.16
View this article at: http://dx.doi.org/10.21037/acs.2017.03.16

The majority of patients with operable esophageal cancers multimodality treatment approaches dating back to the
present with locally advanced disease, for which surgical early 1980s with the objective of improving survival by
resection as a sole treatment modality has been historically enhancing loco-regional disease control and eliminating
associated with poor survival. Local and systemic micrometastatic disease. Three major induction modalities
recurrences develop in over 80% of surgically treated have been employed, including preoperative chemotherapy,
patients, typically within 6–12 months postoperatively, and preoperative radiotherapy, or a combination of the two.
are often rapidly fatal. This pattern of local and systemic Despite the large number of randomized trials conducted
failure highlights the shortcomings of surgical resection to date, controversy persists regarding the treatment
alone as a modality of local tumor control, as well as the of choice for patients with locally advanced esophageal
high propensity of the disease for early occult systemic cancer. In this communication, we discuss the pertinent
dissemination. These observations have driven interest in level 1 evidence as it relates to the following questions: is

© Annals of Cardiothoracic Surgery. All rights reserved. www.annalscts.com Ann Cardiothorac Surg 2017;6(2):167-174
168 Altorki and Harrison. Neoadjuvant and adjuvant therapy in resectable esophageal cancer

Table 1 Randomized clinical trials of surgery for esophageal cancers with and without neoadjuvant chemotherapy

Patients Disease-
OS 5-yr R0 resection
Treatment randomized free 5-yr
Reference Trial Treatment cohort rate (%) (%)
(no.) rate (%)

CS only CS S CS S CS S CS S

Kelsen DP, et al. North American Cisplatin Localized esophageal cancer 216 227 20 20 _ _ 63 59
(2007) (1) (USA Intergroup + FU (50/50 adenocarcinoma/
113) epidermoid)

Allum WH, et al. European Cisplatin Localized esophageal 400 402 23 17.1 _ _ _ _
(2009) (2) (OEO2) + FU cancer (>60% each arm)

Cunningham D, MAGIC ECF Adenocarcinoma of lower 250 253 36.3 23 _ _ 69.3 66.4
et al. (2006) (3) esophagus, GEJ, or stomach

Ycou M, et al. FNCLCC/FFCD Cisplatin Adenocarcinoma of lower 113 111 38 24 34 19 87 74

(2011) (4) Multicenter + FU esophagus, GEJ or stomach
Phase III

CS, neoadjuvant chemotherapy followed by surgery; ECF, epirubicin, cisplatin, and infused fluorouracil; FU, fluorouracil; OS, overall
survival; S, surgery alone.

neoadjuvant treatment warranted? If so, what is the optimal was identical at 5 and 7 years (20%). The larger European
neoadjuvant regimen? What is the role of surgery in the trial (OEO2) (2) randomized 400 patients to CS and 402
setting of modern chemotherapy and radiation therapy, patients to S only. The rate of adenocarcinoma was over
where definitive chemoradiotherapy is increasingly utilized? 66% in both arms. Both R0 resection rates and number of
Is there a role for adjuvant therapy? With these questions in nodal metastases favored the CS arm (CS: 60% vs. S: 54%
mind, we have reviewed what we consider to be some of the and CS: 48% vs. S: 58%, respectively). Overall survival
most important recent studies highlighting the management at 5 years also favored the CS arm (CS: 23% vs. S: 17%)
of esophageal cancer— particularly in the neoadjuvant and was consistent for both squamous cell carcinoma and
setting—and offer our perspective on managing such a adenocarcinoma. Unfortunately, these conflicting results did
complex and deadly disease. not bring the desired clarity to the utility of chemotherapy
in the preoperative setting.
In the ensuing decade two additional trials investigated
Is neoadjuvant therapy warranted? the role of preoperative chemotherapy specifically in
Neoadjuvant chemotherapy patients with adenocarcinoma of the esophagus and
gastroesophageal junction (GEJ). The larger of these trials
At least 14 randomized trials (1-6) have compared by Cunningham, et al. (MAGIC Trial) (3) randomized 503
preoperative chemotherapy followed by surgery (CS) with patients with carcinoma of the stomach, GEJ, and distal
surgery alone (S). The majority of these trials are vastly esophagus to either 3 preoperative cycles of epirubicin,
statistically underpowered to permit meaningful conclusions cisplatin, and fluorouracil (ECF) followed by surgery and
from their results. The four appropriately powered trials 3 additional cycles of ECF or to surgery alone. Patients
that are frequently cited in the esophageal literature are with cancers of the GEJ and lower esophagus accounted for
summarized in Table 1. Two of these trials, reported around roughly 25% of patients in each arm. Overall 5-year survival
the turn of the millennium, compared perioperative cisplatin was 36.3% in the perioperative chemotherapy arm and 23%
(Cis) and fluorouracil (FU) followed by surgery with surgery in the surgery alone arm without evidence of heterogeneity
alone. The North American trial (USA Intergroup 113) (1) of treatment effect based on tumor location.
randomized 443 patients (50% adenocarcinoma). The rate Based on the size and rigorous design of the MAGIC
of R0 resection was essentially equivalent between the two trial, preoperative chemotherapy with ECF is now
arms (CS: 63%; S: 59%), and the overall 5-year survival considered one standard of care for the treatment of

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Annals of cardiothoracic surgery, Vol 6, No 2 March 2017 169

Table 2 Randomized clinical trial of surgery for esophageal cancers with and without chemotherapy and radiation

Patients Disease- R0
OS 5-yr
Treatment randomized free 5-yr resection
Reference Trial Treatment cohort rate (%)
(no.) rate (%) (%)

CRS CRS S CRS S CRS S CRS S

van Hagen P, Dutch Cancer Carboplatin Esophageal or GEJ cancer or 178 188 47 34 _ _ 92 69
et al. (2012) (7) Foundation + Paclitaxel, squamous (23%), adenocarcinoma
CROSS Trial concurrent (75%), other (2%) origin.
radiation

CRS, neoadjuvant chemoradiotherapy followed by surgery; OS, overall survival; S, surgery alone.

operable adenocarcinoma of the esophagus and GEJ in trials were underpowered to satisfactorily answer the
Europe and to some extent in the United States. question. The largest of these trials were reported by
Further support for preoperative chemotherapy for Burmeister, Bosset, and Van Hagen, but only the latter trial
esophageal adenocarcinoma comes from a phase III trial (CROSS) met its primary endpoint of improved overall
conducted in France by the Fédération Nationale dex survival (7). CROSS was a multi-institutional phase III trial
Centres de Lutte contre le Cancer (FNCLCC) and the that randomized 366 patients with either squamous cell
Fédération Francophone de Cancérologie Digestive or adenocarcinoma of the esophagus/GEJ to preoperative
(FFCD), comparing perioperative chemotherapy (Cis chemoradiation followed by surgery (CRS) or surgery alone
+ FU) and surgery to surgery alone (4). In contrast to (S) (Table 2). Nearly 23% of patients had squamous cell
MAGIC, the French trial had a much higher percentage cancer. Preoperative chemoradiotherapy consisted of weekly
of patients with lower esophageal or GEJ adenocarcinoma carboplatin and paclitaxel for 5 weeks with concurrent
(75% vs. 26%). The investigators reported a significant radiotherapy of 41.4 Gy delivered in 23 fractions. Ninety-
improvement in 5-year overall survival in the chemotherapy five percent of patients in the CRS arm completed their
and surgery group compared to surgery alone (38% vs. assigned preoperative treatment. The R0 resection rate was
24%, respectively). There were some obvious limitations significantly higher in the CRS group versus surgery alone
to these large perioperative chemotherapy trials, including (92% vs. 69%). The pathologic complete response was
the lack of modern staging modalities such as endoscopic 29% (23% for adenocarcinoma versus 49% for squamous
ultrasound /positron emission tomography. Additionally, cell carcinoma). Five-year survival was significantly higher
fewer than 50% of eligible patients received their in the CRS arm (47% vs. 33%). The difference in overall
assigned post-operative chemotherapy. Nevertheless, survival was far more prominent in patients with squamous
the available evidence supports the superiority of cell carcinoma (median survival: CRS: 81 months, S: 21 months)
preoperative chemotherapy over surgery alone as an than adenocarcinoma (CRS: 43 months, S: 27 months),
acceptable multimodality standard of care for patients with likely reflecting the higher pathological response rate in
adenocarcinoma of the esophagus and GEJ. patients with squamous cell cancers. Patients in the CRS
arm had lower rates of locoregional (22% vs. 38%) and
distant failures (39% vs. 48%).
Neoadjuvant chemoradiation
The CROSS trial established the superiority of
At least 13 randomized trials (7-13) have investigated the preoperative chemoradiation to surgery alone in patients
role of preoperative chemoradiation (CRS) versus surgery with locally advanced esophageal cancer and confirmed CRS
alone (S). Seven trials investigated CRS exclusively in as a standard of care for squamous cell and adenocarcinoma
patients with squamous cell carcinoma, two in patients of the esophagus and GEJ. However, there are potentially
with adenocarcinoma, and 5 included patients with both important limitations to the CROSS trial, including its
cell types. All utilized platinum/FU chemotherapy with wider applicability to patients with esophageal cancer. For
20–50 Gy of radiation delivered concurrently. As in the example, fewer than 45% of the 837 patients screened
preoperative chemotherapy trials, the majority of these for this trial were eventually eligible for randomization.

© Annals of Cardiothoracic Surgery. All rights reserved. www.annalscts.com Ann Cardiothorac Surg 2017;6(2):167-174
170 Altorki and Harrison. Neoadjuvant and adjuvant therapy in resectable esophageal cancer

Table 3 Comprehensive systematic review and meta-analysis of neoadjuvant chemoradiotherapy versus chemotherapy

Pathological complete
3-yr survival (%) 3-yr survival (%) R0 resection (%)
Reference response (%)

CRS C CRS (ADC) CRS (SCC) C (ADC) C (SCC) CRS C CRS C

Deng HY, et al. 22.1 3.7 46.3 56.8 41.0 42.8 52 42 89.1 76.9
(2016) (14)

Meta-analysis: pathological complete response rate is significantly improved with neoadjuvant chemoradiotherapy compared to
chemotherapy alone. [RR: 5.71; 95% CI, (3.06–10.65); P<0.001]; 3-yr survival significantly improved in patient with SCC undergoing
neoadjuvant chemoradiotherapy compared to chemotherapy alone. [RR: 1.31; 95% CI, (1.10–1.58); P=0.003]; 3-yr survival not
significantly improved in patients with ADC undergoing neoadjuvant chemoradiotherapy compared to chemotherapy alone. [RR: 1.13;
95% CI, (0.88–1.45); P=0.34]; 3-yr survival significantly improved in patients undergoing neoadjuvant chemotherapy (all cell types)
compared to chemotherapy alone. [RR: 1.23; 95% CI, (1.06–1.43); P=0.006]; R0 resection rate significantly improved with neoadjuvant
chemoradiotherapy compared to neoadjuvant chemotherapy alone. [RR:1.15; 95% CI, (1.08–1.23); P<0.001]. Accumulating evidence
suggests that esophageal SCC responds better to CRS, whereas esophageal ADC responds best to neoadjuvant chemotherapy alone to
avoid adverse effects of radiation.

Another factor to consider is that the adjusted hazard ratio recommendation in favor of a specific induction strategy.
for patients with adenocarcinoma was not statistically
significant (P value: 0.059). These considerations will
Does esophagectomy have a role after
probably generate more interest in defining the optimal
chemoradiation?
induction strategy for patients with adenocarcinoma of the
esophagus. The high pathological complete response rate reported
after chemoradiotherapy has prompted some to question
the role of esophagectomy after such therapy. This
What is the optimal preoperative strategy?
view has been gaining traction in the United States,
Meta-analysis has been performed to determine the best especially in patients with squamous cell carcinoma. The
preoperative strategy (14,15). A recent meta-analysis (14) evidence supporting omission of esophagectomy after
identified 5 randomized trials that compared preoperative chemoradiation is derived mainly from FFCD 9102 (10,11),
chemotherapy with preoperative chemoradiation a French randomized trial, in which 259 patients with
(Table 3). Two trials were done exclusively in patients locally advanced esophageal cancer (cT3N0-1M0) were
with adenocarcinoma, two in patients with squamous cell randomly allocated to either chemoradiation followed
carcinoma and one trial that included both cell types. by surgery or definitive chemoradiation. Nearly 90% of
The chemotherapy regimen in all trials was Cis/FU and patients had squamous cell carcinoma. Chemotherapy
the radiotherapy dose varied between 30 and 40 Gy. consisted of two cycles of FU and Cis and either
Notably, all of these trials were either not adequately conventional (46 Gy in 4.5 weeks) or “split-course” (15 Gy,
powered or were closed prematurely and therefore were days 1 to 5 and 22 to 26) concurrent radiotherapy. Patients
inadequately powered to detect a survival advantage. The who responded were then randomized to either surgery
meta-analysis showed that preoperative chemoradiation or continuation of chemoradiotherapy (three cycles of FU
significantly increased the rates of R0 resection (89% vs. and Cis and either conventional 20 Gy or split-course 15 Gy
77%) and complete pathological response (22% vs. 3.7%). radiotherapy). Two-year survival and median survival were
Nonetheless, a survival advantage was only observed in both higher in the chemoradiotherapy alone arm (40%
patients with squamous cell carcinoma (57% vs. 42.8%). In vs. 34% and 19.3 vs. 17.7 months, respectively). However,
patients with adenocarcinoma, 3-year survival did not differ two-year local control rate was significantly better in the
significantly between preoperative chemoradiation and surgery arm (66% vs. 57%) and fewer patients required
preoperative chemotherapy (46% vs. 41%). As previously stent placement after esophagectomy (5% vs. 32%).
stated, since these trials were grossly underpowered, the Three-month mortality was much higher in the surgery
level of evidence provided is insufficient to make a robust group (9.3% vs. 0.8%). The authors thus concluded that

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Annals of cardiothoracic surgery, Vol 6, No 2 March 2017 171

in patients with squamous cell carcinoma who respond to 70% of patients had T3 or T4 tumors, and over 80% had
chemoradiotherapy, there is no benefit from the addition nodal metastasis. Median overall survival in the surgery
of surgery after chemoradiation compared with the alone group was 27 months compared to 36 months in the
continuation of additional chemoradiation. However, the chemoradiotherapy group. Local recurrence was higher in
trial has been criticized for only randomizing responders to the surgery alone group compared to the chemoradiotherapy
chemoradiation, since it can be argued that non-responders group (29% vs. 19%). While the Intergroup trial offers
would be as or even more likely to benefit from surgical some support to the use of adjuvant therapy, particularly in
resection. Furthermore, the bulk of the available level I node-positive patients, the fact that the trial was designed
evidence on chemoradiation and squamous cell cancer of to evaluate advanced gastric cancers, together with the
the esophagus is derived from trials of trimodality therapy significant toxicity of its regimen, make its relevance to the
versus surgery alone. Therefore, we prefer to treat patients treatment of esophageal cancer less clear. Furthermore, the
with locally advanced squamous cell cancer with induction majority of patients in the trial did not have what most would
chemoradiation with preoperative intent. Esophagectomy consider oncologically adequate lymph node dissection.
may be omitted in patients with poor performance status At the 2016 American Society of Clinical Oncology
or those with prohibitive co-morbidities. Patients with a annual meeting, the results of a large phase III trial, the
complete clinical response, defined as physiological uptake CRITICS study, were presented (21). Although this trial was
on PET scanning and absence of endoscopic evidence of designed to evaluate adjuvant therapy in gastric cancers, 17%
disease, may also elect to defer surgical resection. The of patients had GE junction adenocarcinomas. Patients with
data supporting non-operative therapy in patients with Ib-Iva resectable gastric adenocarcinoma were randomized
adenocarcinoma are even less compelling. Pathological to either preoperative chemotherapy followed by surgery and
complete responses after chemoradiation in this subset adjuvant chemotherapy versus preoperative chemotherapy
of patients ranges between 15% and 25%. Notably, followed by surgery and adjuvant chemoradiotherapy.
we and others have shown that even in patients with Neoadjuvant chemotherapy in both arms consisted of 3 cycles
adenocarcinoma who achieve complete clinical response, of epirubicin, cisplatin/oxaliplatin, and capecitabine (ECC/
as previously defined after chemoradiation, approximately EOC). Surgery was either total or partial gastrectomy with
30–40% have residual disease (16,17). Therefore, absent en bloc lymphadenectomy and a minimum of 15 lymph nodes
compelling contraindications, surgical resection remains an removed. Adjuvant chemotherapy consisted of an additional
essential component of the treatment plan. 3 courses of ECC/EOC and adjuvant chemoradiotherapy
consisted of 45 Gy total dose radiation with concurrent
weekly Cis and daily capecitabine. The primary endpoint
Adjuvant therapy
was overall survival. Five-year survival was 41.3% in the
Few trials have evaluated postoperative therapy for chemotherapy group versus 40.9% in the chemoradiotherapy
esophageal cancer (18-20), and much of the data emanates group. These results suggest that performing an adequate
from trials designed using a perioperative regimen, mostly for node dissection might eliminate the need for radiation as an
gastric cancers. An important early trial, the SWOG-directed added modality of local control.
Intergroup 0116, compared adjuvant chemoradiotherapy The data supporting adjuvant therapy are soft, and
following curative resection of gastric cancer versus therefore we place priority on neoadjuvant treatment. We
observation (18,19). Twenty percent of these patients had believe patients better tolerate treatment in this setting,
primary GE junction tumors, and therefore the results have particularly in light of the high rate of treatment drop out
often been used to justify similar adjuvant treatments for in the adjuvant trials as noted above. We reserve adjuvant
esophageal cancer. Following R0 resection of gastric or GE chemotherapy for those rare, highly selected patients—
adenocarcinomas, patients were randomly assigned to either patients with T1 tumors, for example—who do not receive
observation or chemoradiotherapy. Chemoradiotherapy neoadjuvant treatment and are found to have occult nodal
consisted of bolus FU and leucovorin (LV) before, during, disease at the time of surgery.
and after radiotherapy. The total radiation dosage was 45 Gy.
Treatment toxicity was significant, and the trial regimen
Future directions
is no longer used. Only 64% of patients in the adjuvant
chemoradiotherapy group completed the full course. Nearly There no longer remains any question as to whether

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172 Altorki and Harrison. Neoadjuvant and adjuvant therapy in resectable esophageal cancer

preoperative treatment should be given in some manner for and we did not routinely use radiation therapy in the
patients with resectable locoregionally advanced esophageal preoperative setting. Given that most patients who succumb
cancer. However, the best preoperative treatment is still to esophageal cancer do so because of distant disease, we
not clearly established. Several ongoing randomized believe that chemotherapy is an important component
trials are investigating the optimal preoperative regimen. of treatment, and we have typically administered such
For example, the FLOT-4 trial (22), a phase II/III trial treatment in the neoadjuvant setting. However, we also
from Germany, has randomly allocated 714 patients with believe that by performing a more radical en bloc resection,
cancer of the stomach and GEJ to the MAGIC regimen we can achieve higher rates of R0 resection and superior
(ECF/ECX) or to perioperative fluorouracil, leucovorin, local control, which is in our view the primary benefit of
oxaliplatin, and docetaxel (FLOT). Preliminary analysis radiation therapy, yet without subjecting patients to the
of the phase II portion of the trial shows that patients added potential toxicity and post-operative adverse events
receiving the FLOT regimen have a higher rate of that may result from trimodality therapy (26-29). Spicer
pathological complete response and minimal residual recently reported (30) on the experience of three large
disease compared with patients receiving the MAGIC institutions, including our own, with en bloc resection
regimen (29% vs. 15%). Three additional phase III trials for patients with cT3N1 esophageal cancer treated with
are directly comparing preoperative chemotherapy with either preoperative chemoradiation (100 patients) or
preoperative chemoradiation. The Neo-AEGIS trial (23) preoperative chemotherapy (114 patients). He found
will randomize 366 patients with adenocarcinoma of the no difference between the two groups of patients in
GEJ and esophagus to the MAGIC regimen followed by either overall or disease-free survival. Notably, there
surgery or the CROSS protocol. The ESOPEC trial (24) was no difference between the groups in locoregional
will randomize 438 patients with adenocarcinoma of the recurrence rates suggesting that an en bloc esophagectomy
esophagus to either the previously mentioned FLOT after chemotherapy alone achieves local control rates
regimen followed by surgery or the CROSS protocol. comparable to those reported after trimodality therapy,
Finally the NExT trial (JCOG 1109), a 3-arm phase II thus emphasizing the role of surgery as a sufficient
trial (25), will randomize over 500 patients with squamous modality for local control. A more streamlined bimodality
cell cancer to either of two chemotherapy regimens (Cis/ approach serves a suitable platform for the addition of novel
FU or DCF) followed by surgery or chemoradiation additional therapies such as targeted or immunotherapy.
followed by surgery. It is hoped that these trials will provide
clarity regarding the optimal induction strategy. Finally, the
Acknowledgements
introduction of immune checkpoint inhibitors has literally
transformed the care of patients with melanoma, non-small None.
cell lung cancer, kidney, and bladder cancer. Several phase
III trials are currently ongoing using immune checkpoint
Footnote
inhibitors in patients with advanced gastric and esophageal
cancers based on promising results from early phase trials. Conflicts of Interest: The authors have no conflicts of interest
Our group has recently initiated a phase II trial combining to declare.
the immune checkpoint inhibitor pembrolizumab (anti-
PD1) with preoperative chemoradiation followed by
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Cite this article as: Altorki N, Harrison S. What is the role of

neoadjuvant chemotherapy, radiation, and adjuvant treatment
in resectable esophageal cancer? Ann Cardiothorac Surg
2017;6(2):167-174. doi: 10.21037/acs.2017.03.16

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