Best Practice & Research Clinical Gastroenterology 29 (2015) 193e209

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Best Practice & Research Clinical

Gastroenterology

15

Chemoradiation in oesophageal cancer

Tong Dai, MD, PhD, Assistant Professor,
Manish A. Shah, MD, Associate Professor of Medicine, Director,
Gastrointestinal Oncology Program *
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medical College of
Cornell University, NewYork-Presbyterian Hospital, New York, NY 10021, USA

a b s t r a c t

Keywords: Oesophageal cancer is the 8th most common cancer worldwide,

Chemoradiation and has significant mortality and morbidity rates. The two most
Barrett's common histological types, squamous cell carcinoma and adeno-
Oesophageal cancer
carcinoma, have different localizations, distinctive risk factors, and
Definitive chemotherapy
molecular mechanisms. Survival for patients with locoregional
Definitive chemoradiation
oesophageal cancer is poor when treated with surgery only, with
5-year survival less than 10e15%. Radiation therapy has limited
efficacy when given alone. Concurrent chemoradiation improves
local-regional control and facilitates margin-free resection when
delivered preoperatively. Chemoradiation prolongs survival when
given as definitive treatment or combined with surgery. Neo-
adjuvant chemoradiation also reduces risk of distant recurrence.
To date, there is no data supporting the addition of targeted
therapy to concurrent chemoradiation. Understanding molecular
pathways regulating both radiosensitivity and tumorigenesis/in-
vasion may lead to the discovery of new targeted agents,
improving outcome of chemoradiation in terms of both locore-
gional and systemic control, ultimately resulting in prolonged
survival.
© 2014 Elsevier Ltd. All rights reserved.

* Corresponding author. Division of Hematology and Medical Oncology, Dept of Medicine, Weill Cornell Medical College of
Cornell University, Director, Centre for Advanced Digestive Care, New York-Presbyterian Hospital, 1305 York Avenue, 12th Floor,
New York, NY 10021, USA. Tel.: þ1 646 962 6200 (office); fax: þ1 646 962 1607.
E-mail address: mas9313@med.cornell.edu (M.A. Shah).

http://dx.doi.org/10.1016/j.bpg.2014.11.006
1521-6918/© 2014 Elsevier Ltd. All rights reserved.
194 T. Dai, M.A. Shah / Best Practice & Research Clinical Gastroenterology 29 (2015) 193e209

Introduction

Oesophageal cancer is the eightth most common cancer in the world [1], and the fifthth most
common gastrointestinal cancer in the U.S., with an estimated 18,170 new cases and 15,450 deaths in
2013 [2]. Oesophageal cancer histology varies by location, with squamous cell carcinoma (SCC) more
prevalent in the upper and middle thirds of the oesophagus and adenocarcinoma (ADC) more prevalent
in the lower third of the oesophagus and at the gastro-oesophageal junction (GOJ). Worldwide, SCC
represents the majority of oesophageal cancer cases and is predominant in the highest risk geographic
area referred to as the 'oesophageal cancer belt' which stretches from the Middle East to central and
eastern Asia. In Western countries, there is an increasing incidence of lower oesophageal adenocar-
cinoma accompanied by a decline in SCC, which is attributed to changes in lifestyle, including
increasing obesity and the associated gastro-oesophageal reflux disease.
Oesophageal cancer patients frequently present with dysphagia, weight loss, and/or bleeding.
Barium oesophagography can be an initial evaluation, but tissue biopsy is often obtained during
oesophagogastroduodenoscopy (OGD) to confirm diagnosis. Endoscopic ultrasound (EUS) allows
accurate assessment of invasion depth, and biopsy of regional lymph nodes. EUS-guided fine needle
aspiration to diagnose N stage has a sensitivity of 84.7%e96.7% [3]. Computed tomography (CT)
should be performed to assess for possible metastatic disease, including hepatic metastasis and
distant lymphadenopathy (such as celiac, retroperitoneal, or supraclavicular). 18F-fluorodeoxyglucose
PET (FDG-PET) is increasingly being used to detect distant metastasis [4], and is now a standard
staging modality [5].
For patients with localized disease, the goal of surgery is to remove the tumour with curative intent,
while relieving local symptoms. However, the long-term outcome of surgery alone has been disap-
pointing, with 5-year survival of only approximately 15e20% [6]. Although transthoracic resections had
significantly higher early morbidity (pulmonary) and mortality rates, 5-year survival was similar be-
tween transthoracic and trans-hiatal resections [7]. The early RTOG 85-01 trial demonstrated che-
moradiation with cisplatin and fluorouracil achieved a median survival of 14.1 months and 5-year
survival rate of 27% in localized oesophageal cancer [8], and opened a new chapter of treatment of this
disease. Understanding the pathogenesis, genetics, and mechanisms of radiosensitivity will further
improve outcome of chemoradiation. Although Barrett's oesophagus is only associated with adeno-
carcinoma of oesophagus, most trials in oesophageal cancer included patients with squamous or
adenocarcinoma of the oesophagus. As the risk factors, genetics, epidemiology, and treatment are
different between these two different cancer types, it is essential to review squamous oesophageal
cancer as well.

Risk factors and genetics

Frequent genetic alterations in SCC of the oesophagus include somatic copy number variations
(SCNV) involving 3q26, 9p21, 11q13.3 and 8q24.3, as well as somatic mutations in PIK3CA [9], TP53 and
NOTCH1 [10]. A recently reported whole-exome/targeted deep sequencing of 139 paired SCC cases, and
analysis of somatic copy number variations (SCNV) of over 180 oesophageal SCCs identified additional
mutated genes including FAT1, FAT2, ZNF750 and KMT2D [11]. Dysregulation of the receptor tyrosine
kinase (RTK)-MAPK-PI3K pathway, cell cycle progression, and epigenetic regulation of gene expression
appear to be the most common molecular alterations identified in oesophageal SCC. Similarly, a Chi-
nese study with 158 SCC cases, as part of the International Cancer Genome Consortium research
project, using whole-genome sequencing and array comparative genomic hybridization analysis,
identified 6 well known tumour-associated genes (TP53, RB1, CDKN2A, PIK3CA, NOTCH1, NFE2L2), and
two additional significantly mutated genes (ADAM29 and FAM135B) [12]. The study also identified
microRNA MIR548K as a novel oncogene which enhances malignant phenotypes of SCC cells. In
addition, several important histone regulator genes (MLL2/KMT2D, ASH1L, MLL3/KMT2C, SETD1B,
CREBBP and EP300) involved in the Wnt, cell cycle, and Notch pathways are also frequently altered in
ESCC. These pathways play important role in tumorigenesis, epithelial-to-mesechymal transition
(EMT), invasion, and maintaining cancer stem cell survival [13].Thus, targeting these genes or other
components of these pathways may be an effective strategy in treating SCC, particularly by eliminating
 T. Dai, M.A. Shah / Best Practice & Research Clinical Gastroenterology 29 (2015) 193e209 195

chemotherapy-resistant cancer stem cells or cancer-initiating cells with inhibition of Wnt and Notch
signalling [14e16].
Human papillomaviruses (HPV) are the primary cause for the majority of cervical cancer and a subset
of head and neck cancers, especially in non-smokers. The role of HPV infection as a cause or risk factor for
oesophageal SCC is less clear. A recent study of 177 patients in East China detected HPV infection in only
six patients by genotyping and in five patients by immunohistochemistry (IHC) using anti-p16 (INK4a)
antibody [17]. However, a meta-analysis of 132 studies showed increased risk of SCC in patients with
HPV infection [odds ratio (OR) 2$69]. The prevalence of HPV in SCC was found to be 24$8% [18].
Adenocarcinoma of the distal oesophagus and GOJ typically arises from columnar epithelial
metaplasia, also known as Barrett oesophagus [19]. Cigarette smoking, Caucasian ethnicity, male
gender, increased age, and poor diet are predominant risk factors for adenocarcinoma [20e22].
Conversely, infection with Helicobacter pylori may lower the risk of disease development [23]. In single-
center prospective cohort studies, aneuploidy and p53 loss of heterozygosity were associated with
increased risk of progression to high-grade dysplasia and/or adenocarcinoma [24]. Comparative
genomic analysis in a small cohort of patients suggest adenocarcinoma has a substantially different
spectrum of gene mutations compared with SCC. For example, inactivating mutations of NOTCH1 were
identified in 21% of SCC but not in adenocarcinoma [10]. Recently, whole-exome sequencing of 149
adenocarcinoma identified 26 significantly mutated genes. In addition to the five previously described
adenocarcinoma-associated genes (TP53, CDKN2A, SMAD4, ARID1A and PIK3CA), chromatin-modifying
factors and candidate contributors SPG20, TLR4, ELMO1 and DOCK2 were found to be significantly
mutated in this adenocarcinoma analysis [25]. Functional analyses of adenocarcinoma-derived mu-
tations in ELMO1 identifies increased cellular invasion, suggesting the potential activation of the RAC1
pathway as a mechanism of ADC tumorigenesis.
In contrast to frequent somatic gene mutations, genetic syndromes associated with oesophageal
cancer are rare. The locus for a syndrome of focal palmoplantar keratoderma (Tylosis) associated with
squamous cell oesophageal carcinoma (TOC) was mapped to chromosome 17q25, a region frequently
deleted in sporadic squamous cell oesophageal tumours [26]. None of the putative candidate genes
corresponded to the genes mutated in SCC as discussed above [11,12]. Further mutation analysis of
genes at this locus is required to identify the gene responsible for oesophageal SCC in TOC syndrome.

Definitive chemoradiation versus radiation alone

The landmark Intergroup study RTOG 85-01 compared radiation alone with chemoradiation using
cisplatin and fluorouracil in 129 patients with T1-3N0-1M0 SCC or adenocarcinoma [8] (Table 1). With
5-year follow-up, the median survival for combined modality treatment group was 14.1 versus 9.3
months in radiation alone group, and 5-year survival rate was 27% versus 0% [27]. The most common
reason for treatment failure was persistence of disease, which was 25% in combined therapy compared
to 37% in the radiation only group, with local-regional and distant recurrence of 13% versus 16%, and 8%
versus 15%, respectively. This was a primarily SCC study (87.6% vs 19.8% adenocarcinoma), making a
comparison of the two subtypes difficult. However, SCC patients appeared to have better outcomes: a
slightly higher 5-year survival (21% versus 13%) and longer median survival (16.9 versus 12.2 months)
compared to adenocarcinoma. Overall, this is the first study demonstrating concurrent chemotherapy
with radiation improved local and systemic control, and prolonged OS, when compared with radiation
alone. Notably, the outcome was comparable to what was achieved by surgery alone in localized
oesophageal cancer. This study established definitive chemoradiation as an important therapeutic
option and provided a foundation for the development of improved multi-modality treatment regi-
mens in oesophageal cancer.

Radiation dose for definitive concurrent chemoradiation and radiation considerations

INT 0123/RTOG 94-05 compared a higher radiation dose (64.8 Gy) with the standard dose (50.4 Gy)
in 218 patients with T1-4N0-1 M0 SCC or adenocarcinoma [28] (Table 1). The high-dose radiation
increased treatment-related mortality (12% versus 2%) without improvement in locoregional failure
(56% versus 52%), median survival (13 months versus 18.1), or 2-year survival (31% versus 40%). This
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Table 1
Selected studies of definitive chemoradiation.

Study N Clinical SCC ADC Radiation dose Chemotherapy Median Survival P Persistence of Distant
N1 disease OS rate (%) disease failure
(months)

Intergroup (RTOG 85-01) 61 13% 84% 16% 50 Gy/5 wks Cisplatin/5-FU 14.1 5-year: 27% <0.0001 25% 8%
Herskovic [8] Al-Sarraf [27] 60 17% 92% 8% 64 Gy/6.4 wks none 9.3 0 37% 15%
INT 0123 109 27% 87% 13% 64.8 Gy (1.8 Gy) Cisplatin/5FU 13 2-year: 31% e 33% 9%
(RTOG 94-05) Minsky [28] 109 17% 84% 16% 50.4 Gy (1.8 Gy) Cisplatin/5FU 18.1 40% 34% 16%
Ruppert [31] 19 84% 42% 58% 50.4e61.2 Gy Carboplatin/paclitaxel e 3-year: 56.1% 0.022 68.4% 10.5%
38 87% 45% 55% 50.4e61.2 Gy Cisplatin/irinotecan e 19.7% 78.9% 22.9%
Honing [32] 55 76% 58% 42% 46.8e70 Gy Carboplatin/paclitaxel 13.8 e 0.899 e e
47 83% 40% 60% 46.8e70 Gy Cisplatin/5-FU 16.1 e e e
PRODIGE5/ACCORD17 134 66% 85% 14% 50 Gy (5 wks) FOLFOX 20.2 3-year: 19.90% 0.7 33% 32%
Conroy [32] 133 69% 86% 14% 50 Gy (5 wks) Cisplatin/5-FU 17.5 26.90% 35% 27%
RTOG 85-01 61 e e e 50 Gy/5 wks Cisplatin/5-FU e 26% <0.001 25% 16%
Long-term follow up [75] 62 64 Gy/6.4 wks none 0 37% 30%
 T. Dai, M.A. Shah / Best Practice & Research Clinical Gastroenterology 29 (2015) 193e209 197

study failed to demonstrate an improvement in survival with increasing the dose of RT. However, the
value of increasing the RT dose using modern RT techniques like 3D-conformal radiation therapy (3D-
CRT) or intensity modulated radiation therapy (IMRT), has not been prospectively evaluated. Thus, 50.4
Gy remains the RTOG standard dose for radiation delivered concurrently with 5-FU and cisplatin.
However, these newer techniques offer improvements in identifying the target radiation volume while
minimizing the radiation to adjacent normal organs, and are commonly employed. 3D-CRT uses
computed tomography to define the target volume and spare adjacent organs, whereas IMRT partitions
the larger radiation field applied by 3D-CRT into multiple smaller fields of varying shapes and sizes and
intensity of radiation to achieve even a greater dose conformality to the target [29].

Alternative regimen for definitive chemoradiation

In gastro-oesophageal cancer, oxaliplatin is considered equivalent to cisplatin, but with reduced

toxicity. This similarity was examined in definite chemoradiation for oesophageal carcinoma. Recently
reported PRODIGE5/ACCORD17 trial used the scheme of concurrent chemoradiation followed by
chemotherapy, and randomized 267 patients with stage I-IVA SCC, adenocarcinoma, or adenosqu-
amous cancer to either six cycles of oxaliplatin, leucovorin, fluorouracil, and infusional fluorouracil
(FOLFOX), or four cycles of fluorouracil and cisplatin [30] (Table 1). Both groups also received radio-
therapy. FOLFOX did not increase progression-free survival (PFS) or overall survival (OS) compared
with chemoradiation with fluorouracil and cisplatin (9.7 versus 9.4 months and 20.2 versus 17.5
months, respectively), but concurrent FOLFOX with radiation might be a better option for selected
patient as it is associated with less frequent mucositis (27% versus 32%) and increase in creatinine (3%
versus 15%). The ongoing phase II/III CONCORDE study is testing dose escalation to 66 Gy versus the
standard 50 Gy dose with FOLFOX as definitive chemoradiation (NCT01348217). A small study ran-
domized 57 patients with locally advanced oesophageal cancer (both SCC and adenocarcinoma) to
concurrent chemoradiotherapy with cisplatin/irinotecan or carboplatin/paclitaxel [31]. The estimated
3-year OS was 19.7% for the cisplatin/irinotecan group versus 56.1% for the carboplatin/paclitaxel group
(P ¼ 0.022). A multicenter Dutch study of 102 patients with SCC or adenocarcinoma reported similar OS
between the cisplatinum/5-FU and carboplatin/paclitaxel group with a median survival of 16.1 and 13.8
months respectively (P ¼ 0.879) [32]. Patients in the carboplatin/paclitaxel group experienced
significantly less frequent haematological and nonhematological toxicity (grade 3) (4% versus 19%
and 18% versus 38%, respectively) than in the cisplatin/5-FU group (P ¼ 0.001), results which will need
confirmation in a larger phase III study.
Following the results demonstrating efficacy of chemoradiation over radiation, there were several
studies evaluating neoadjuvant chemoradiation. This was examined in the context of chemoradiation
with and without surgery, and surgery with and without chemoradiation.

Chemoradiation with and without surgery

The issue of whether patients can be spared surgery after chemoradiation was addressed by the
randomized study FFCD 9102 [33] (Table 2). 259 patients with T3N0-1M0 thoracic oesophageal cancer
(88.8% SCC, 11.2% ADC) received two cycles of fluorouracil and cisplatin, coupled with either conven-
tional or split-course concomitant radiotherapy. Patients with objective response were randomly
assigned to surgery or continuation of chemoradiation. Two-year survival rate was 34% in the surgery
group versus 40% in the continued chemoradiation group (HR: 0.90; adjusted P ¼ 0.44). Median sur-
vival time and 2-year local control rate was 17.7 versus 19.3 months and 66.4% versus 57.0%, respec-
tively, suggesting surgery following chemoradiation in responding patients does not provide additional
survival benefit, and therefore completing definitive chemoradiation may be an alternative to surgery.
A German study randomized 172 patients with oesophageal SCC to either induction chemotherapy
followed by chemoradiation and surgery, or induction chemotherapy followed by chemoradiation
without surgery [34]. After median observation time of 6 years, 2-year and 3-year OS, and median
survival were equivalent between the two treatment groups (39.9% versus 35.4%, 31.3% versus 24.4%,
and 16.4 versus 14.9 months, in surgery versus continuing chemoradiation group), although local
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Table 2
Studies of chemoradiation with or without surgery.

Study N Clinical N1 SCC ADC Initial radiation dose Chemotherapy CR/PR rate Treatment after Median OS 2-year P
disease (%) (%) (%) (%) initial treatment (months) Survival
rate (%)

FFCD 9102 130 40 89 11 Conventional 46 Cisplatin/5-FU: Either x 2 10.8/89.2 20 Gy or Split 19.3 39.8 Non-inferiority
Bedenne [32] Gy or Split course followed by Cisplatin/5-FU, course 15 Gy P ¼ 0.03
129 48.1 89 11 30 Gy or 3 concurrently with RT 10.1/89.9 Surgery 17.7 33.6
Stahl [34] 86 65 100 0 Up to 40 Gy Cisplatin/5-FU/LV/etoposide e Radiation 50 or 14.9 35.4 Equivalence
x 3 followed by cisplatin/etoposide 60 Gy P ¼ 0.007
86 65 100 0 40 Gy x 1 concurrently with RT e Surgery 16.4 39.9
 T. Dai, M.A. Shah / Best Practice & Research Clinical Gastroenterology 29 (2015) 193e209 199

Fig. 1. Treatment algorithm for oesophageal cancer. CRT: chemoradiation.

progression-free survival was higher in the surgery group (2-year PFS, 64.3% versus 40.7%; HR:2.1;
P ¼ .003).
RTOG 0246 tried to address the question of whether surgery can salvage treatment failure of
definitive chemoradiation. Chemotherapy with 5-FU, cisplatin, and paclitaxel followed by concurrent
chemoradiation with 5-FU/cisplatin was administered [35]. Twenty-one of the 41 patients with locally
advanced (>T1N0) SCC (n ¼ 11) or ADC (n ¼ 30) had residual or recurrent cancer (as assessed by EUS,
OGD, or CT, optional PET) and proceeded to surgery. The estimated 1-year survival for all evaluable
patients (n ¼ 41) is 71%, and the 1-year survival rate for the 15 patients who underwent surgery after
chemoradiation for residual disease is 83%, which is superior to what would be expected based on
historical controls.
Taken together, these data suggest that patients with locally advanced SCC with positive response to
initial chemoradiation should complete chemoradiation and may be spared surgery, and patients with
residual disease may be salvaged with surgery (Fig. 1). Because these studies include few patients with
adenocarcinoma, it is unclear whether omitting surgery after definitive chemoradiation will result in
increased recurrence and shortened survival in adenocarcinoma. Therefore, these patients are still
evaluated for surgery following chemoradiation.

Surgery with and without chemoradiation

Several studies examined neoadjuvant chemoradiation compared with surgery alone in early-stage
tumours (Table 3). A recent large phase II study randomized 282 patients with stage I and II SCC to
preoperative treatment with radiotherapy and cisplatin or surgery alone, and disappointingly found
median survival was 18.6 months for both groups [36]. Although chemoradiation appeared to have
some efficacy, with a longer disease-free survival (DFS) (P ¼ 0.003), local relapse free survival
(P ¼ 0.01), a lower rate of cancer-related deaths (P ¼ 0.002), and a higher frequency of curative
resection (P ¼ 0.017), neoadjuvant chemoradiation was also associated with more postoperative deaths
(P ¼ 0.012) which negated the anticancer benefits. The phase III trial FFCD 9901 compared surgery
alone (n ¼ 97), chemoradiation followed by surgery (n ¼ 98) in localized stage I or II SCC or with ADC
patients [37]. Neoadjuvant chemoradiation did not increase R0 resection rate (93.8% versus 92.1%), or
3-year OS rate (47.5% versus 53.0%), but was associated with increased postoperative mortality from
3.4% to 11.1% (p ¼ 0.049). The trial was closed after interim analysis.
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Table 3
Selected studies of neoadjuvant chemoradiation (single arm or vs. surgery alone).

Study N Clinical N1 disease Histology Radiation dose Chemotherapy Resection rate pCR Median OS 3-year Survival P
(months) rate (%)

Le Prise [36] 41 Unknown SCC 20 Gy/2 wks Cisplatin/5-FU 35/41 85.4% 4/35 (11.40%) 10 19.20% NS
45 (stage I or II AJCC 1978) None None 42/45 93.3% 10 13.80%
Bosset [36] 143 23.10% SCC 37 Gy/2 wks Cisplatin 112/143 78.3% 29/112 (25.90%) 18.6 26.6% 0.78
139 23.00% None None 94/139 67.60 e 18.6 25.2%
Walsh [39] 58 Unknown ADC 40 G/3 wks Cisplatin/5-FU 100% 25.00% 16 32% 0.01
55 None 100% e 11 6%
FFCD 9901 97 29.60% SCC 70.3% 45 Gy/5 wks Cisplatin/5-FU 93.8% 27/81 (33.30%) 31.8 47.5% 0.94
Mariette [37] 98 25.80% ADC 29.2% None None 92.1% e 41.2 53.0%
CALGB 9781 30 33% SCC 25% 50.4 Gy/5.5 wks Cisplatin/5-FU 22/30 (26 to OR) 10/26 (38.40%) 4.48 yr 5-yr: 39% 0.002
Tepper [40] 26 15% ADC 75% None 23/26 e 1.79 yr 16%
CROSS van 178 65% SCC 23% 41.4 Gy/4.6 wks Carboplatin/ 94% (R0: 92%) 29% (SCC 49% 49.4 58% 0.003
Hagen [41] ADC 75% Paclitaxel ADC 23%)
188 64% Large Cell 2% None 99% (R0: 69%) e 24 44%
SWOG 8037 113 Unknown SCC 30 Gy/3 wks Cisplatin/5-FU 55/113 (49%) 18/55 (32.7%) 12 16% NA
Poplin [92] (locoreginal) (2-yr: 28%)
RTOG 41 Unknown (T1-3NxM0) SCC 30 Gy/3 wks Cisplatin/5-FU 27/41 8/27 13 7.50% NA
Seydel [93] 65.90% (29.60%) (2-yr: 14.6%)
 T. Dai, M.A. Shah / Best Practice & Research Clinical Gastroenterology 29 (2015) 193e209 201

Neoadjuvant chemoradiation may lead to increased postoperative cardiopulmonary complications

depending on radiation dose and location of cancer. Cardiopulmonary complications were associated
with an increased risk of pneumonia (p ¼ 0.001, odds ratio 2.896), pleural effusion (p ¼ 0.041, odds ratio
2.268), and arrhythmia (p ¼ 0.023, odds ratio 2.215), although there was no increase of short-term
mortality [38]. Thus, the survival benefit of neoadjuvant chemoradiation in early stage cancers is
unestablished, and potential risk should be considered.
Two underpowered studies are of historical note. Walsh reported on a prospective, randomized trial
which compared preoperative chemoradiation with cisplatin/5-FU and radiation with surgery alone in
113 patients with adenocarcinoma in 1996 [39]. Pre-treatment staging was unavailable, and CT was
performed in selected patients only. At the time of surgery, 23 of 55 patients (42%) treated with che-
moradiation had positive nodes or metastases, as compared with 45 of the 55 patients (82%) in surgery
alone group (P < 0.001), which may reflect treatment effect or imbalance of disease stages between two
groups at time of randomization. Preoperative chemoradiation led to pCR rate of 25%. Median survival
was 16 versus 11 months, and 3-year survival rate was 32% versus 6%, respectively (p ¼ 0.01). The phase
III study that enrolled only 58 patients before it was closed for poor patient accrual (CALGB 9781)
compared oesophagectomy with node dissection alone with neoadjuvant chemoradiation followed by
surgery in resectable T1-4N0-1 M0 SCC or adenocarcinoma was reported in 2008 [40]. It showed
median survival of 4.48 versus 1.79 years in favour of trimodality therapy (P ¼ 0.002). Five-year survival
was 39% versus 16%. The chemotherapy regimen was cisplatin and fluorouracil, given concurrently with
radiation therapy followed by oesophagectomy with node dissection.
Recently, the multicenter randomized phase III CROSS study confirmed survival benefit of neo-
adjuvant chemoradiation to surgery in patients with resectable oesophageal or GOJ cancers (T2-3N0-
1M0) [41]. The study enrolled 368 patients, with 75% AC, 23% SCC and 2% with large-cell undifferen-
tiated carcinoma. In the chemoradiation group, five courses of weekly carboplatin (AUC2) and pacli-
taxel was given with radiation. R0 resection was achieved in 92% of patients in the
chemoradiationesurgery group versus 69% in the surgery group (P < 0.001), and chemoradiation led to
pathological complete response of 29%. Median OS was 49.4 months in the chemoradiationesurgery
group versus 24.0 months in the surgery group (hazard ratio (HR) 0.657, P ¼ 0.003). In addition, car-
boplatin/paclitaxel appeared to cause less toxicity compared to cisplatin/fluorouracil used in other
chemoradiation regimens. This study differed from the FFCD9901 study (which failed to show a benefit
of neoadjuvant chemoradiation) in that the majority of patients in the CROSS study had locally
advanced disease, T3 (approximately 80%) or N1 (approximately 64%) and the R0 resection rate in
surgery alone arm (69%) was much less compared with the FFCD9901 study (92.1%). For locally
advanced oesophageal cancer, pre-operative chemoradiation is currently a standard option, based on
this study (Fig. 1).
Alternative chemotherapy regimens other than cisplatin/5FU and Carboplatin/Paclitaxel have also
been explored in the preoperative chemoradiation setting. For example, the randomized phase II UK
study NeoSCOPE compares preoperative oxaliplatin/capecitabine with carboplatin/paclitaxel given
concurrently with radiotherapy after induction with two cycles of oxaliplatin and capecitabine in 85
patients with resectable oesophageal cancer [42]. ICORG 10-14, a study by All Ireland Co-operative
Oncology Group will compare MAGIC versus CROSS trial protocols (ECF or ECX versus carboplatin/
paclitaxel) concurrently with radiotherapy in patients with oesophageal or GOJ adenocarcinoma
(NCT01726452).
A recently updated meta-analysis for resectable oesophageal carcinoma (T0-3N0-1 disease)
included 12 randomized studies comparing neoadjuvant chemoradiation versus surgery alone
(n ¼ 1854), illustrating neoadjuvant chemoradiation conferred absolute 2-year survival benefit of 8.7%,
although analysis by tumour stage or location (lower oesophagus versus GOJ for adenocarcinoma) was
not performed [43]. The HR for all-cause mortality for neoadjuvant chemoradiation was 0$78 (95% CI
0$70e0$88; p < 0$0001), with HR for SCC only and adenocarcinoma only were 0$80 (95% CI 0$68-0$93;
p ¼ 0$004) and 0$75 (0$59e0$95; p ¼ 0$02), respectively, indicating the survival benefit of neo-
adjuvant chemoradiation was similar between these two histology types. In addition, the overall
survival advantage gained from neoadjuvant treatment is not offset by higher 30-day postoperative or
in-hospital mortality, suggesting that if neoadjuvant chemoradiation can be administered safely and
without increased mortality, it should be considered.
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Induction chemotherapy followed by preoperative chemoradiation

Ajani and colleagues randomized 126 patients with T2-3N0/þM0 oesophageal cancer (predomi-
nantly adenocarcinoma) to receive no induction or induction with oxaliplatin/5-FU before oxaliplatin/
FU/radiation and surgery. Addition of induction chemotherapy failed to significantly increase pCR rate
(26% versus 13%, P ¼ 0.094) or prolong median OS (43.68 versus 45.62 months, P ¼ 0.69), though
without an increase in grade 3 or 4 toxicity [44].
Similarly, RTOG 0113 tested the hypothesis that addition of induction chemotherapy would improve
outcome of definitive chemoradiation [45]. Eighty-four patients with oesophageal SCC or ADC were
randomized to either induction with fluorouracil, cisplatin, and paclitaxel and then fluorouracil plus
paclitaxel with radiation or induction with paclitaxel plus cisplatin and then the same chemotherapy
with radiation. The median survival was 28.7 months for three drug induction group and 14.9 months
for two drug induction group. The 1-year survival rate of 75.7% in three drug induction group was close
to, but did not meet or surpass, the 77.5% goal for either induction regimen. The 2-year survival rate was
56% versus 37%. Both groups experienced significant toxicities (Grade 3 toxicities 54% versus 43%;
grade 4 toxicities 27% versus 40%), and treatment-related death (3% versus 6%). Thus, the addition of
induction chemotherapy does not seem to improve outcome of preoperative or definitive
chemoradiation.
In a phase 2 study of 55 patients with resectable SCC or adenocarcinoma of oesophagus or GOJ, 69%
underwent R0 resection after induction with weekly cisplatin and irinotecan prior to concurrent
chemoradiation with the same regimen [46] The pCR rate of 16% and median OS of 31.7 months were
either comparable to a contemporary study using concurrent chemoradiation with cisplatin and iri-
notecan without induction chemotherapy [47]. However, 26% and 50% of patients who had baseline
dysphagia reported improvement or resolution of symptoms, respectively, after induction
chemoradiation.
Taken together, addition of induction chemotherapy to preoperative chemoradiation does not
improve pCR rate or OS, but may be considered in patients with significant dysphagia at diagnosis.
Generally, induction chemotherapy can be administered safely without added toxicity.

Neoadjuvant and perioperative chemotherapy

Of note, chemoradiation is not the only option for oesophageal and GOJ patients; pre- or peri-
operative chemotherapy has improved outcome over surgery alone, especially in patients with
lower oesophageal and GOJ cancer (Table 4). This modality, extensively studied, is widely adopted in
the UK, much of Europe, and parts of the US. The phase III MRC MAGIC trial randomized 503 gastro-
oesophageal cancer patients to either surgery alone or perioperative chemotherapy of epirubicin,
cisplatin, and fluorouracil [48]. Twenty-five percent of patients had lower oesophageal (14%) or GOJ
(11%) cancer. Local recurrence was confirmed in 14.4% of patients in perioperative-chemotherapy group
and 20.6% in the surgery group, while distant metastases were 24.4% and 36.8%, respectively. The OS
rate for perioperative chemotherapy was significantly higher than with surgery alone, 36% and 23%,
respectively. Among all patients undergoing resection, there was a greater proportion of stage T1 and
T2 tumours in the perioperative-chemotherapy group than in the surgery group (51.7% versus 36.8%,
P ¼ 0.002), which likely reflects down-staging with pre-operative chemotherapy.
In another trial, FNCLCC/FFCD, 224 patients were randomized to either surgery alone or perioper-
ative chemotherapy [49]. Sixty-four percent of patients had GOJ cancer, 11% had lower oesophageal
adenocarcinoma, and 25% had gastric cancer. R0 resection rate of 87% in the perioperative chemo-
therapy group was also significantly improved compared to the rate of 74% in the surgery alone group
(P ¼ 0.04). Five-year year DFS rates were significantly higher in the perioperative group versus the
surgery group (34% versus 19%). Recurrence occurred in 55% and 64% patients in perioperative
chemotherapy group and surgery only group, respectively, possibly with a reduced rate of distant only
recurrence (30% versus 38%). The 5-year OS was higher for patients treated with perioperative
chemotherapy and surgery versus surgery only (38% versus 24%).
The randomized UK MRC OEO2 study evaluated the utility of adding preoperative of chemotherapy
to surgery, and the impact of R0 versus R1/R2 resection on survival in 840 patients with SCC or ADC of
 T. Dai, M.A. Shah / Best Practice & Research Clinical Gastroenterology 29 (2015) 193e209
Table 4
Selected studies of surgery with or without pre- or peri-operative chemotherapy.

Study Histology N Radiation dose Chemotherapy Resection rate Local Distant 5-year Survival P
recurrence recurrence rate (%)

OEO2 Allum [6] SCC 30.8%, Adeno 66.3% 400 9% both arm Cisplatin/5-FU 92% (R0: 60%) 11.5% 17.0% 23% 0.03
SCC 30.8%, Adeno 66.7% 440 received, 25 None 97% (R0: 54%) 12.2% 14.9% 17%
Gy/1 wk, or 32.5
Gy/2 wks
MAGIC Cunningham [48] ADC 100% 250 NA Epirubicin/Cisplatin/5-FU 91.6% (R0: 69.3%) 14.4% 24.4% 36.3% 0.01
253 None 96.4% (R0: 66.4%) 20.6% 36.8% 23.0%
FNCLCC/FFCD Ychou [49] ADC 100% 113 NA Cisplatin/5-FU 94% (R0: 87%) 12% 30% 38% 0.02
111 none 90% (R0: 74) 8% 38% 24%
RTOG 8991 Kelsen [50] SCC 46.80%, ADC 53.2% 216 NA Cisplatin/5-FU (~50% 78% (R0: 59%) 25% 34% SCC 19.4%, NS
received post-op chemo) ADC 20.70%
SCC 46.70%, ADC 53.30% 227 none 89% (R0: 63%) 19% 38% 3-yr: SCC 23.6%,
ADC 26%

203
204 T. Dai, M.A. Shah / Best Practice & Research Clinical Gastroenterology 29 (2015) 193e209

Table 5
Selected studies of definitive chemoradiation with targeted therapy.

Study N Clinical SCC ADC Radiation dose Chemotherapy Median OS 2-year P

N1 (months) Survival
disease rate (%)

ACOSOG 70 80% e 100% 50.4 Gy/5.5e6 wks Cisplatin/docetaxel/panitumumab 19.4 3-year: NA

Lockhart [70] 38.60%
Safran [74] 19 95% 0 100% 50.4 Gy/5.6 wks Cisplatin/paclitaxel/trastuzumab 24 50% NA
SCOPE1 129 III 69% 71% 26% 50 Gy/5 wks Cisplatin/Capecitabine/cetuximab 22.1 41.30% 0.04
Crosby [71] 129 74% 25% Cisplatin/Capecitabine 25.4 56.00%
RTOG 0436 [72] 169 65% 39% 61% 50.4 Gy/5.6 wks Cisplatin/paclitaxel e 41.70% 0.7
159 66% 37% 63% Cisplatin/paclitaxel/cetuximab e 44.00%

oesophagus [6]. Chemotherapy was administered as two cycles of cisplatin and fluorouracil. R0 versus
R1/R2 resection rate was similar in the two treatment groups. The 5-year survival was better in the
chemotherapy group versus surgery alone, 23% versus 17.1% respectively, although the rate of local and
distant recurrence were similar between the two groups (11.5% versus 12.2%, and 17.0% versus 14.9%,
respectively). In contrast, the US RTOG 8991 yielded different results in terms of OS [50]. This study
randomized 443 patients with SCC or adenocarcinoma to receive preoperative chemotherapy with
cisplatin and fluorouracil or surgery alone, but approximately 50% of patients in preoperative group
also received postoperative chemotherapy [50]. R0 resection rate was similar between the two groups
(63% and 59%, respectively). Both of these studies comparing preoperative chemotherapy versus sur-
gery alone showed R0 resection predicts prolonged survival.
An updated meta-analysis included 2062 patients from ten randomized trials comparing neo-
adjuvant chemotherapy followed by surgery with surgery alone [43]. The FNCLCC/FFCD study using
perioperative chemotherapy was also included. The pooled HR for all-cause mortality was 0.87
(0.79e0.96; p ¼ 0.005), corresponding to an absolute survival difference at two years of 5.1%. This
analysis supports a small but significant survival benefit from addition of preoperative chemotherapy
for oesophageal cancer.

Neoadjuvant chemotherapy with and without chemoradiation prior to surgery

A phase III study compared preoperative chemotherapy followed by surgery with induction
chemotherapy followed by concurrent chemoradiation and surgery in total of 126 patients with locally
advanced (uT3-4NxM0) adenocarcinoma of the lower oesophagus or gastric cardia [51]. Similar por-
tions of patients between two groups underwent complete tumour resection (69.5% versus 71.5%).
Significantly more patients treated with neoadjuvant chemotherapy followed by concurrent chemo-
radiation achieved pathologic complete response (15.6% versus 2.0%) or tumour-free lymph nodes
(64.4% versus 37.7%) at resection. These patients also had improved 3-year survival rate compared to
those treated with neoadjuvant chemotherapy alone (47.4% versus 27.7%, HR: 0.67, log-rank P ¼ .07).
Although underpowered, this is one of the few studies suggesting superiority of preoperative che-
moradiotherapy over chemotherapy alone for localized oesophageal cancer. The caveat is post-operate
morbidity, as previously discussed.

Can we improve on chemoradiation in oesophageal cancer?

Despite advances in chemoradiation, 5-year survival rate remains only 20e30%. Follow-up report of
the CROSS trial showed neoadjuvant chemoradiation reduced locoregional recurrence from 34% to 14%,
and peritoneal carcinomatosis from 14% to 4% at median follow-up of 45 months, although there was
no significant difference in recurrence rate at the supraclavicular or celiac axis level [52]. Thus, systemic
effect of chemotherapy rather than indirect effect of reducing locoregional recurrence is more likely to
be responsible for the survival benefit of neoadjuvant chemoradiation [41]. Combination of chemo-
radiation with novel targeted agents modulating radiosensitivity and inhibiting oncogenic pathway
may improve both locoregional and systemic control, ultimately resulting in prolonged survival.
 T. Dai, M.A. Shah / Best Practice & Research Clinical Gastroenterology 29 (2015) 193e209 205

Mechanism of radioresistance and potential radiosensitizing Agents

Several mechanisms contribute to radioresistance in oesophageal cancer. Radiotherapy kills ma-

lignant cells by generating free oxygen radicals, inducing DNA damage. Hypoxia-inducible factor 1a
(HIF-1a) plays a critical role in the response to hypoxia and upregulation of genes such as vascular
endothelial growth factor (VEGF) to promote the resistance of cancer cells to radiotherapy [53]. In
oesophageal cancer cell lines and xenograft models, STAT3 inhibitor NSC74859 confers radiosensitivity
in SCC via the inhibition of STAT3 activation and the down-regulation of HIF-1a and VEGF expression
[54]. In oesophageal cancer cell line Eca109, mTOR inhibitor suppressed radiation-induced expression
of DNA damage-repair proteins including Ku70, Ku80, while promoting radiation-induced apoptosis
[55]. Similarly, Wnt/b-catenin pathway can be activated by irradiation exposure, resulting in the
accumulation of b-catenin in the cytoplasm and subsequent translocation into the nucleus, and
transcription of b-catenin target genes including Myc [56]. The overexpression of a recently discovered
target gene of b-catenin, WISP-1, is associated with radioresistance in oesophageal cancer cell lines.
Depletion of extracellular WISP-1 by neutralizing antibody reversed radioresistance [57].
In response to DNA damage, the polycomb group (PcG) protein Bmi-1 accumulates very early at DNA
double-strand breaks (DSB) foci and promotes DSB repair by homologous recombination. A recent
study found Bmi-1 is required for DNA damage-induced ubiquitination of histone H2A at lysine 119,
and the loss of Bmi-1 leads to impaired DNA repair [58]. Histone deacetylase (HDAC) may also play a
role in regulating radiosensitivity by exerting epigenetic control of gene expression. A novel HDAC
inhibitor OBP-801/YM753 was found to enhance the effects of 5-FU with radiation on SCC cell line
KYSE170 cells [59]. It was proposed that HDAC inhibitors reverse acquired radioresistance by inhibiting
Bmi-1 expression [60]. A recently completed Phase I trial showed chemoradiation with capecitabine
and the HDAC inhibitor vorinostat was feasible and did not cause unexpected toxicity in patients with
pancreatic cancer [61]. However, at this time there is no evidence supporting the addition of HDAC
inhibitor or other agents targeting other cellular pathways to chemoradiation in treating oesophageal
cancer.

Targeted therapy in chemoradiation (Table 5)

HER family of tyrosine kinase receptors (RTKs) epidermal growth factor (EGFR) (or HER1), HER2,
HER3 and HER4 are encoded by the erbB oncogenes and play important role in cell-cycle progression,
cell division, motility, and survival [62]. They are also implicated in tumour invasion and metastasis.
Activation of these RTKs involves binding of ligands EGF, transforming growth factor a (TGF-a) and
amphiregulin to EGFR, subsequent homodimerization or heterodimerization between these RTKs, and
autophosphorylation of the intracellular tyrosine kinase domain, which leads to activation of down-
stream signalling cascade [63].
EGFR amplification has been reported in 21% of adenocarcinomas, 12e28% of oesophageal SCC in
small series, and activating EGFR mutations have also been identified in oesophageal adenocarcinomas
[64e67]. EGFR overexpression is detected in approximately 30e50% of early stage oesophageal ade-
nocarcinomas and is associated with shorter DFS and OS [68,69]. Strategies of incorporating anti-EGFR
antibodies to chemoradiation have been explored. Phase II study ACOSOG Z4051 treated 65 patients
with locally advanced but resectable (T2-3N0-1M0-1a) distal oesophageal adenocarcinoma with
docetaxel, cisplatin, and panitumumab with radiation prior to planned surgery [70]. Fifty-four patients
underwent resection, with PCR rate 33.3% and near-pCR rate 20.4%. At median follow-up of 26.3
months, median OS was 19.4 months and 3-year OS was 38.6%.
In the definitive chemoradiation setting, the randomized Phase II/III study SCOPE1 showed the
addition of cetuximab to cisplatin and capecitabine with radiotherapy was associated with a shortened
median OS (22.1 versus 25.4 months; adjusted HR:1.53, p ¼ 0.035), and increased non-haematological
grade 3 or 4 toxicities (79% versus 63%, p ¼ 0.004) in 258 patients with stage I-III oesophageal cancer
[71]. RTOG 0436 randomized 344 patients with locally advanced SCC or ADC to concurrent chemo-
radiation with cisplatin and paclitaxel with or without cetuximab [72]. Similarly, the addition of
cetuximab did not improve 2-year OS (44.0% versus 41.7%) or clinical CR rate (56% versus 59%),
206 T. Dai, M.A. Shah / Best Practice & Research Clinical Gastroenterology 29 (2015) 193e209

regardless of histology. The addition of EGFR antibody inhibitor therapy to definitive chemoradiation
does not appear to be a promising targeted approach in oesophageal cancer.
In a cohort of 381 metastatic gastric/GOJ cancer patients, 20% were found to be HER2 positive, either
by HER2 immunohistochemistry (IHC) 3þ or HER2/chromosome 17 ratio >2.0 by in-situ hybridization
(ISH) [73]. A phase I/II study added trastuzumab to chemoradiation using cisplatin and paclitaxel in
patients with locally advanced adenocarcinoma of the oesophagus with HER2 positivity defined as
HER2 2þ/3þ expression by IHC [74]. The majority (95%) of patients had T3N1 disease, and many pa-
tients did not undergo surgery due to extensive adenopathy or medical morbidities. 74% had either IHC
3þ, or increased HER2 gene copy number, determined by HER2 gene amplification or high polysomy by
fluorescence in-situ hybridization (FISH). The median survival of all patients was 24 months and the 2-
year survival was 50%. The complete clinical response for HER2 positive patients was 57%. Addition of
trastuzumab did not increase adverse events. These encouraging results led to the RTOG 1010 study,
which will test chemoradiation and weekly carboplatin (AUC2) and paclitaxel with or without con-
current and maintenance trastuzumab in localized HER2 positive oesophageal and GOJ cancer.

Discussion

Oesophageal cancer confers poor overall survival, and remains a challenge to patients, physicians,
scientists and clinical investigators. Chemoradiation is a critical treatment strategy for oesophageal
cancer. Definitive therapy is considered for squamous cell oesophageal cancer and for adenocarcinoma
in patients who are not surgical candidates. Neoadjuvant chemoradiation is critical in managing locally
advanced disease. The role of neoadjuvant chemoradiation in early stage disease is less clear, and is
associated with increased morbidity and mortality in large randomized studies. Further studies with
whole-exome and whole-genome sequencing may help us further understand the pathogenesis of
oesophageal cancer and identify potential therapeutic targets unique to both SCC and ADC. Dissecting
the complex molecular pathways regulating radiosensitivity and mechanisms of radioresistance is
essential to discover new targeted agents and improve outcome of chemoradiation. The overlapping or
differential effects of cytotoxic chemotherapy and targeted agents on cell cycle progression, apoptosis
and cellular survival, change of tumour microenvironment, local immune response, and the ultimate
tumour response and normal tissue toxicity should be carefully examined.

Practice Points

 Definitive therapy is considered for squamous cell oesophageal cancer and for adenocarci-
noma in patients who are not surgical candidates.
 Neoadjuvant chemoradiation is critical in managing locally advanced disease.
 The role of neoadjuvant chemoradiation in early stage disease is less clear.

Research agenda

 Further studies with whole-exome and whole-genome sequencing are critical in elucidating
pathogenesis of oesophageal cancer and identify potential therapeutic targets unique to both
SCC and adenocarcinoma.
 The molecular mechanism of radioresistance in oesophageal cancer needs to be defined.
 Further studies are necessary to explore the role of novel targeted therapy given concurrently
or sequentially with chemoradiation.
 T. Dai, M.A. Shah / Best Practice & Research Clinical Gastroenterology 29 (2015) 193e209 207

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