Update on Neoadjuvant Regimens for Patients with Operable Oesophageal/Gastrooesophageal Junction Adenocarcinomas and Squamous Cell Carcinomas
Curr Oncol Rep
Update on Neoadjuvant Regimens for Patients with Operable Oesophageal/Gastrooesophageal Junction Adenocarcinomas and Squamous Cell Carcinomas
Samantha J. Cox 0 1 2 3 4 5
Sean M. O'Cathail 0 1 2 3 4 5
Bernadette Coles 0 1 2 3 4 5
Tom Crosby 0 1 2 3 4 5
Somnath Mukherjee 0 1 2 3 4 5
0 Department of Clinical Oncology, Velindre Cancer Centre , Cardiff , UK
1 Cardiff University , Cardiff CF10 3XQ , UK
2 Samantha J. Cox, Sean M. O'Cathail, Tom Crosby and Somnath Mukherjee are joint authors
3 MRC/CRUK Oxford Institute for Radiation Oncology, University of Oxford , Oxford , UK
4 Library Services, Velindre NHS Trust , Cardiff , UK
5 Department of Clinical Oncology, Oxford University NHS Trust , Oxford , UK
Survival outcomes following multimodal treatment of operable oesophageal and gastrooesophageal cancer remain disappointingly poor. Although an appreciation of the impact of both tumour location and histological subtype is now shaping the design of clinical trials, there has been a lack of consensus of the optimal neoadjuvant treatment strategy. This update article will review recent advances in the use of both neoadjuvant chemotherapy and chemoradiotherapy. The emerging role of PET imaging to direct appropriate neoadjuvant treatment regimens and the additive benefit of biological agents are also discussed.
Neoadjuvant; Oesophagus; Gastrooesophageal junction; Adenocarcinoma; Squamous cell carcinoma; Chemotherapy; Chemoradiotherapy
Approximately 450,000 new cases of oesophageal cancer
are diagnosed each year worldwide, making it the eighth
most common cancer . Although squamous cell
carcinoma (SCC) is the most common variant, there is
geographical variation in the incidence of the two major
histological subtypes. The number of patients diagnosed with
adenocarcinoma has increased during the last few
decades, particularly in Western countries, and is felt to
reflect the rise in obesity rates and gastrooesophageal reflux
disease [2, 3]. Adenocarcinoma typically affects the lower
oesophagus and gastrooesophageal junction (GOJ) and
likely represents a separate disease entity to squamous
cell tumours, which are more common in the upper and
middle third of the oesophagus.
Long-term outcomes for oesophageal cancer remain poor
with 5-year overall survival (OS) rates of only around 20%,
and the majority of patients treated with curative intent
eventually succumb to their disease . Patients deemed to have
potentially resectable disease are offered a multimodal
approach with either neoadjuvant or perioperative chemotherapy
or neoadjuvant chemoradiotherapy. The rationale for
perioperative therapy is to treat occult micrometastases, and to
increase the likelihood of a complete surgical resection (R0
resection) and pathological complete response (pCR).
Historically studies have included oesophageal, GOJ and
gastric tumours of both SCC and adenocarcinoma subtypes.
These specific subgroups are important in the management of
oesophageal cancer, as reflected by the design of more recent
trials. This review will summarise the current evidence for
neoadjuvant chemotherapy in both histological subtypes,
perioperative chemotherapy in adenocarcinoma of the
oesophagus/GOJ, and neoadjuvant chemoradiotherapy (nCRT). The
role of PET imaging in guiding neoadjuvant treatment
strategies and the use of novel biological agents is also
discussed. Table 1 summarises ongoing neoadjuvant trials in
Neoadjuvant Chemotherapy in Oesophageal Cancer
(both Adenocarcinoma and SCC Histologies)
There has been a lack of international consensus regarding the
role of neoadjuvant chemotherapy for oesophageal cancer
following results from conflicting large randomised trials.
Practice in the UK was largely dictated by the outcomes of
the MRC OE02 trial, which compared 2 cycles of cisplatin
and 5-fluorouracil followed by surgery to surgery alone, with
a 6% improvement in 5-year OS rates (23 vs 17%) [5, 6].
Tumours were smaller, less locally invasive following
neoadjuvant chemotherapy, with lower rates of lymph node
positivity, and significantly higher rates of R0 resection compared to
those in the surgery-alone arm. Nine percent of patients in
both arms received neoadjuvant radiotherapy but this did not
influence outcomes in subgroup analysis.
In contrast, the RTOG 8911 trial failed to identify any
survival advantage or difference in R0 rates for neoadjuvant
cisplatin/5-fluorouracil versus surgery alone . Differences
with OE02 include the use of three neoadjuvant cycles with a
longer time to surgery, a higher dose of cisplatin and the use of
postoperative chemotherapy for stable disease/responders
(with 52% of patients receiving at least 1 cycle of adjuvant
chemotherapy) . Analysis for histological subtype did not
identify a difference in survival outcomes, but subsequent
analysis of the long-term results did confirm that an objective
response to neoadjuvant chemotherapy was associated with
significantly better OS than that of non-responders or patients
receiving surgery alone .
Two recent meta-analyses have confirmed the survival
benefit for neoadjuvant chemotherapy over surgery alone [9, 10 ].
The first meta-analysis of 17 trials found a survival benefit of
5.1% at 2 years (HR 0.87) (95% CI 0.79–0.96; P = 0.005) .
Analysis according to histological subtype showed only
patients with adenocarcinoma (HR 0.83; 95% CI 0.71–0.95;
P = 0.01) and not SCC (HR 0.92; 95% CI 0.81–1.04;
P = 0.18) had a statistically significant improvement in OS
with neoadjuvant chemotherapy. This is in contrast to the
OE02 trial which did not observe a survival difference
according to histological subtype, and neoadjuvant chemotherapy is
regarded as an option for both SCC and adenocarcinoma
tumours in the UK.
The Cochrane meta-analysis of over 2000 patients with
localised, potentially resectable thoracic oesophageal
carcinoma found that the use of cisplatin-based neoadjuvant
chemotherapy reduced the risk of death by 12% at 5 years (HR 0.88,
95% CI 0.80–0.96; P = 0.003) [10 ]. Furthermore, R0
resection rates were significantly higher in patients receiving
chemotherapy compared to surgery alone, although both local
and distant recurrence rates did not significantly differ
between the two groups. Whilst preoperative chemotherapy
was associated with mortality and toxicity, the authors did
not find that the latter equated to a higher rate of postsurgical
complications. They noted that significant study heterogeneity
exists in terms of the chemotherapy regimens used, provision
of adjuvant chemotherapy, and inclusion of patients with
tumours of both histological subtypes and also the quality of
included trials. The conclusion is that the evidence to date
for neoadjuvant chemotherapy is only of moderate quality
for thoracic oesophageal cancer.
Perioperative Chemotherapy for Adenocarcinoma
of the Lower Oesophagus and GOJ
The efficacy of perioperative chemotherapy for resectable
adenocarcinoma of the lower third of the oesophagus, and GOJ
was established in the MAGIC trial . Six cycles of
epirubicin, cisplatin and 5-fluorouracil (ECF; 3 cycles
administered before and after surgery, qd21) improved both OS and
PFS in over 500 patients, with a 5-year survival rate of 36%
compared to 23% for surgery alone. Downstaging and R0
rates were also superior with ECF, as were local and failure
rates. This was despite 45% of patients in the perioperative
chemotherapy arm not receiving any postoperative treatment.
Initially only patients with operable gastric carcinoma were
eligible for inclusion; in light of the increasing incidence of
GOJ adenocarcinoma, patients with lower third oesophageal
tumours were later included but only constituted 26% of the
population which may limit the applicability of the results to
oesophageal cancer patients. Perioperative
cisplatin/5fluorouracil has also shown similar survival benefits and
improved R0 rates compared with surgery alone in a smaller trial
of predominantly gastrooesophageal adenocarcinoma .
Both regimens are now standard treatment options.
Several groups have investigated different combination
chemotherapy regimens in phase II studies in an attempt to
improve response rates and survival outcomes in locally
advanced resectable gastrooesophageal adenocarcinoma. Three
cycles of DCF (docetaxel, cisplatin, 5-fluorouracil) before and
after surgery resulted in all (n = 41) patients achieving a R0
resection with a 10% pCR rate, and 3-year survival of 60%
; docetaxel, cisplatin and capecitabine (DCX) has shown
similar response rates, with 60% of patients achieving T-stage
downstaging and 40% of node-positive patients converting to
N0 status . Only around half of patients completed
postoperative treatment with both of these taxane-based regimes,
most often due to patient choice or fitness.
In the German FLOT4 trial, 714 patients with locally
advanced resectable gastric and GOJ tumours were randomised
between perioperative FLOT (5-fluorouracil, leucovorin,
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oxaliplatin and docetaxel, 4 + 4 cycles, qd14) and ECF/ECX.
The study demonstrated a 10% increase in pCR rates in favour
of the FLOT arm (15.6% versus 5.8%, P = 0.015); survival
outcomes are awaited . FLOT is a feasible regimen in
patients over the age of 65 years, however caution is required
in selecting the patients most likely to benefit due to higher
toxicity rates compared to those seen with perioperative FLO
Concerns exist regarding increa sed grade 3/4
chemotherapy-related toxicities, namely neutropenia and
mucositis, with taxane-based treatment. However, it is
argued that these are manageable with appropriate
dose-reductions and prophylactic G-CSF, and may be
off-set by the early improvements in dysphagia with
such regimens and avoidance of anthracycline-induced
cardiotoxicity [13, 14]. Furthermore, postsurgical
complications (around 40%) and mortality rates do not
appear to be increased; further studies are warranted.
Neoadjuvant Chemotherapy for Adenocarcinoma
of the Lower Oesophagus and GOJ
Extended neoadjuvant chemotherapy as an alternative to
perioperative treatment has been proposed as a strategy to avoid
the need for postsurgical treatment. Four cycles of ECX
(epirubicin, cisplatin and capecitabine) was compared to 2
cycles of cisplatin/5-fluorouracil prior to surgery in the UK
OE05 trial which included over 800 patients. Three-year OS
rates did not significantly differ at 42 and 39%, respectively
(HR 0.92, 95% CI 0.79–1.08; P = 0.3017) [17 ]. There was a
suggestion that ECX improved R0 resection rates and the
likelihood of pCR, and although PFS and DFS were both
longer in the ECX arm, statistical significance was not met.
ECX caused more grade 3/4 chemotherapy-related toxicity,
however postsurgical complication and mortality rates did
not differ significantly between treatment arms.
The NeoFLOT was a single centre, non-randomised phase
II trial where 6 cycles FLOT were administered every 14 days
(n = 50) prior to surgery in T3/T4 or node positive tumours of
the GOJ or stomach . The regimen was well tolerated
(main grade 3/4 toxicities included neutropenia, diarrhoea
and mucositis), 86% of patients achieved a R0 resection and
a 1-year survival rate of 79% was observed. The authors
reported that in those achieving either a pCR or near pCR
(40%), the majority of patients had intestinal type tumours.
Neoadjuvant Chemotherapy for SCC
SCC is the predominate histological subtype in Asia
where the standard of care for stage II-III disease is
neoadjuvant chemotherapy followed by transthoracic
oesophagectomy and lymphadenectomy. The JCOG
9907 trial randomised patients to 2 cycles of cisplatin/
5-fluorouracil either before or after surgery; 5-year OS
rates were 55 versus 43%, respectively (HR 0.73, 95%
CI 0.54–0.99, P = 0.04), with no significant differences
in adverse events between the groups [19, 20].
Interest has recently developed in the potential
additive benefit of taxanes following promising Asian phase
II feasibility studies in oesophageal SCC and known
benefits in head and neck SCC. Perioperative weekly
nab-paclitaxel and cisplatin achieved 100% R0 rates
and both OS and DFS were significantly longer in
patients who were downstaged (63%) compared to those
not downstaged .
In a trial of 42 patients, impressive 2-year OS and PFS rates
of 88 and 75%, respectively were reported with DCF when
compared to standard cisplatin/5-fluorouracil [22 ]. Over 90%
of patients completed at least 2 cycles of neoadjuvant
treatment and achieved R0 resection, despite a large proportion of
patients (42%) requiring dose reductions after the first cycle.
The overall response rate was 64% according to RECIST
criteria with a pCR rate of 17%. Despite 83% of patients
developing grade 3–4 neutropenia, only 2% had febrile
neutropenia; all patients received prophylactic antibiotics but not
G-CSF as standard. There were no treatment-related deaths,
although overall perioperative complication rates were higher
compared to standard cisplatin/5-fluorouracil. A second
smaller feasibility study also showed DCF efficacy in this
setting ; 93% of patients achieved a curative oesophageal
resection with a similar toxicity profile, although higher rates
of febrile neutropenia were noted at 18%.
The Japanese JCOG1109 NExT three-arm phase III study
is comparing neoadjuvant cisplatin/5-fluorouracial to
neoadjvuant DCF and to neoadjvuant chemoradiotherapy
(concurrent cisplatin/5-fluorouracil, 41.4Gy in 23 fractions
over 5 weeks) in SCC of the thoracic oesophagus . The
primary end-point is OS, with secondary measures including
PFS, pCR/R0 resection rates and toxicities, with the aim of
identifying the optimal neoadjuvant treatment strategy in this
Neoadjuvant Chemoradiotherapy (nCRT)
Stage I and II oesophageal cancers are unlikely to
require neoadjuvant or perioperative treatment. Indeed,
outcomes may be worse because of the morbidity and
mortality associated with multimodality treatment [25 ].
More locally advanced tumours benefit from
neoadjuvant therapy compared to surgery alone . There have
been several trials comparing nCRT to surgery alone in
oesophageal cancer. However, most of these trials were
c o m m e n c e d i n t h e 1 9 8 0 s a n d 1 9 9 0 s , w e r e
underpowered, and there was significant heterogeneity
in chemotherapy, radiation doses and surgical technique
[26–31]. Unsurprisingly results have been mixed. A
2003 meta-analysis of these trials concluded that OS at
3 years was improved (OR 0.66, CI 0.47–0.92;
P = 0.016) in the nCRT arms but with the cost of
increased all treatment mortality (OR 1.63, CI 0.99–
2.68; P = 0.053) . A further meta-analysis including
trials from 1960 to 2007, concluded that in spite of the
significant heterogeneity, nCRT increases 3 year OS
versus surgery alone with a number needed to treat (NNT)
of 10. There was an increased morbidity and mortality
with a number needed to harm (NNH) of 25 .
Therefore, on balance, the benefit outweighs the risk
for appropriately selected patients.
The German POET study, which sought to establish
the superiority of chemoradiation over chemotherapy,
closed early due to poor accrual and was significantly
underpowered as a result . Patients with locally
advanced adenocarcinoma of the EGJ were randomised to
either neoadjuvant cisplatin/5-fluorouracil chemotherapy
over 15 weeks followed by surgery or 12.5 weeks of
induction chemotherapy (cisplatin/5-fluorouracil)
followed by nCRT (cisplatin and etoposide, 30Gy in 15
fractions over 3 weeks) and then surgery. Its results showed
a non-significant trend in favour of CRT improving
survival relative to chemotherapy, but postoperative
mortality was higher in the CRT arm.
In 2012, the randomised phase III trial CROSS, established
the modern precedent for chemoradiotherapy in the
preoperative treatment of oesophageal cancer . Patients were
randomly assigned to surgery alone or neoadjuvant treatment
with weekly carboplatin (AUC2) and paclitaxel (50 mg/m2)
given concurrently with 41.4 Gy in 23 fractions of radiation.
Median overall survival was more than doubled from 24 to
49 months in patients treated with tri-modality therapy, R0
resections improved as did pCR rates, a benefit which
persisted in long-term follow-up [36 ]. Adverse events were
low, with no increase in postoperative mortality.
The benefit of the CROSS protocol is most pronounced in
the squamous cell subgroup. Patients with SCC performed
significantly better with a median survival of 81 months
compared to 43 months for adenocarcinoma of the oesophagus.
Proponents of chemotherapy alone argue that for
adenocarcinoma these data are no more persuasive than the MAGIC trial.
In the adenocarcinoma subgroup of CROSS, the 5 year OS for
CRT and surgery was 47%, compared to 33% in the surgery
alone group [36 ]; this is similar to the 13% absolute benefit
for chemotherapy seen in MAGIC, although the OS rate for
surgery only patients in this study was lower at 23% . The
ongoing Neo-AEGIS trial, which is randomising patients with
operable oesophageal and GOJ adenocarcinoma between the
CROSS regimen and perioperative ECX (as in the MAGIC
trial), may provide the definitive answer of which regimen to
use , but until then recommendations are likely to vary.
Induction Chemotherapy prior to nCRT
Other attempts to improve response rates include
induction chemotherapy prior to neoadjuvant
chemoradiotherapy. Two cycles of induction oxaliplatin and S-1,
followed by concurrent CRT to 46 Gy with the same
agents did not improve pCR in a randomised phase II
study . Toxicity was significantly increased. These
results are supported by phase II trials where 2 cycles
of oxaliplatin and 5-fluorouracil were followed by
50.4 Gy using the same chemotherapy without any
significant benefit [39, 40].
In summary, induction chemotherapy is likely to only
increase toxicity with no discernible benefit, and the
choice of concurrent radiosensitizing chemotherapy is
likely to be more important.
The CROSS regimen chemotherapy used was a
deviation from the traditional cisplatin/5-fluorouracil regimen
. Weekly low dose carboplatin and paclitaxel were
novel choices which proved exceptionally well tolerated
in CROSS. Previous attempts to incorporate taxanes into
chemoradiotherapy regimes have had varying results.
Docetaxel and paclitaxel both show activity in phase
I/II settings but may increase toxicity, possibly
unacceptably [42–44]. The triple agent arm of the NExT
trial which includes docetaxel will likely answer the
question of whether additional taxanes are useful and
Oxaliplatin with capecitabine is more active in the
metastatic setting than cisplatin with 5-fluorouracil, has a
more favourable toxicity profile and is easier to
administer . Recent results from the NEOSCOPE study are
instructive here. This phase II trial randomised patients
following induction chemotherapy with oxaliplatin and
capecitabine to concurrent chemoradiation to 45 Gy, with
either two weekly oxaliplatin-capecitabine or weekly
carboplatin and paclitaxel . Only the carboplatin/
paclitaxel arm passed the prespecified threshold of pCR
of 35%, and will now be used in a phase III setting in
comparison with neoadjuvant chemotherapy.
A retrospective comparison of 215 patients treated in
a single institution showed that carboplatin/paclitaxel
was associated with a better overall survival when
compared to cisplatin/irinotecan, cisplatin/5-fluorouracil or
cisplatin/5-fluorouracil/cetuximab . On balance,
where nCRT is to be used, current data favours the use
of weekly carboplatin and paclitaxel based regimen,
based on its efficacy and toxicity profile.
Toxicity of Neoadjuvant Therapy
Concerns over the added acute toxicity of nCRT
compared to chemotherapy alone are legitimate. As such
factors including patient age, performance status and
comorbidities should be carefully considered when
selecting neoadjuvant therapy. Rigorous radiotherapy
quality assurance is now a standard feature in trials
which together with advances in the management of
treatment-related toxicities, improvements in
postoperative care and the centralisation of surgery to
highvolume centres, have improved the outlook for cancer
patients treated with multimodality therapy . Data
from the Netherlands pre- and postcentralisation of
surgery showed that R0 rates improved by 5%, mortality
fell from 12 to 4% and overall survival at 2 years
increased from 38 to 54% . The complicated,
multidisciplinary care of the patient group means that
institutional differences in surgical technique, wound
management and intensive care protocols make comparisons
between patient groups within trials difficult. However,
this highlights that perhaps the severity of complications
should be reported as well as overall incidence.
A Scandinavian study randomised 181 patients to
either neoadjuvant CRT or chemotherapy alone (cisplatin/
5-fluorouracil +/− 40 Gy concomitant radiotherapy) with
the purpose of comparing postresection morbidity and
mortality [50 ]. They concluded that CRT did not
increase the chances of complication, but any
complication was more likely to be severe. CROSS showed no
increase in incidence of complications in the CRT
group, but they did not comment on severity .
A small substudy of 40 patients enrolled in a
randomised phase III trial comparing chemotherapy
and CRT examined cardiac function. They found
evidence of acute negative effects on systolic and diastolic
function, as recorded on echocardiography and
N-terminal Pro-B-Type Natriuretic peptide, in patients
undergoing CRT . The clinical relevance of this needs
prospective evaluation but shows clear physiological
differences between both regimes.
PET-Directed Neoadjuvant Strategies
As well as the obvious need to stratify future
oesophageal studies by tumour subtype, there is a need for
other predictive markers to assess response to treatment.
To date the most studied, for both aspects, has been
MUNICON-I trial showed that PET response can be used
to direct further treatment in distal adenocarcinoma of the
oesophagus . A >35% decrease in SUV indicated
metabolic response and assessment was done 14 days after day 1 of
cisplatin/5-fluorouracil. Responders continued with treatment
but non-responders proceeded directly to surgery. The results
showed that metabolic responders had not reached median OS
at the time of reporting, whereas non-responders had a median
OS of 25.8 months. This implies that patients who are not
responding to standard induction chemotherapy, according
to PET criteria, can discontinue neoadjuvant therapy and
proceed to surgery without compromise.
The follow-up trial, MUNICON-II, attempted to clarify the
role of salvage nCRT for patients failing to demonstrate a
PET-response following 14 days of cisplatin/5-fluorouracil
based induction chemotherapy. Metabolic responders
(n = 33) continued on 3 months of neoadjuvant chemotherapy
prior to surgical resection whilst the non-responders (n = 23)
received 32 Gy in twice daily 1.6 Gy fractions, 10 fractions
per week, with either concurrent cisplatin or 5-fluorouracil
. The R0 resection rate was 82% in the PET responders
but a lower than expected rate of 70% was observed in the
non-responders, resulting in this primary study endpoint not
being met. One-year PFS rate was significantly higher in
responders (74 vs 57%, P = 0.035) although overall survival
was similar at around 80%. The authors argue that although
salvage nCRT resulted in a major histopathological response
rate in 26% of PET non-responders, long-term clinical
outcomes were not improved. They suggest the aggressive
tumour biology of this group is responsible for these results
and that studies exploring alternative approaches, including
the addition of systemically active drugs, are warranted .
A reduction in the metabolic activity of a tumour, defined by a
35% decrease in FDG uptake compared to baseline, at day 14
of neoadjuvant chemotherapy has been prospectively
validated as prognostic biomarker . PET responders had a 3-year
survival of 70% compared to 35% for non-responders. In an
exploratory substudy within a phase II study of induction
cisplatin and irinotecan, an SUV reduction of >35% again
predicted for improved outcomes; higher pCR, increased R0,
longer PFS and improved OS (40.2 versus 25.5 months) .
Data supporting the use of PET during nCRT is less
convincing, potentially due to false positive results as a
consequence of treatment-induced inflammation or false
negatives due to small volume occult disease .
Within the CROSS trial, a substudy of 100 patients
had a repeat PET scan 14 days after commencing
nCRT, the results of which were correlated to the
histopathological response as defined by the Mandard score
(no or <10% viable tumour) on the resection specimen.
A median SUV decrease of 30.9% was observed in
histopathological responders (n = 64) versus 1.7% for
non-responders (n = 36) (P = 0.001). Although the
sensitivity of PET in correctly identifying patients with a
h i s t o p a t h o l o g i c a l r e s p o n s e w a s 9 1 % u s i n g t h e
predefined cut-off SUV value of 0% (signifying any
decrease in SUV as a positive test result), the specificity
was only 50% . On the basis of these results,
FDGPET cannot currently be recommended to accurately
identify patients who are not responding nCRT after
2 weeks of treatment. An excellent overview of the
literature by Omloo et al. points out that standardisation
of protocols and minimising inter-institutional
differences is needed before PET-guided treatment can be
routinely adopted for chemoradiation patients .
Biological Agents with Chemotherapy
The use of targeted therapies in combination with
chemotherapy in locally advanced gastrooesophageal
adenocarcinoma remains investigational. Perioperative cetuximab/
5-fluorouracil did not demonstrate efficacy with 71% of
patients (n = 64) classified as non-responders .
Similarly, the addition of neoadjuvant panitumumab to
ECX did not improve the rates of downstaging or pCR
in an AIO phase II study . Bevacizumab and
perioperative ECX (ECX-B) chemotherapy did not improve
survival outcomes in patients with resectable lower
oesophageal or GOJ adenocarcinoma [62 ]. Recently published
in abstract form, the phase III ST03 trial showed similar
rates in both response to preoperative therapy, R0
resections and 3-year OS (48.9% ECX vs 47.6% ECX + B; OS
HR 1.067) but an increased rate of anastomotic leak
following oesophago-gastrectomy in patients receiving
ECXB (23 vs 9%).
Trastuzumab with cisplatin/5-fluorouracil chemotherapy is
known to improve OS in advanced HER-2 positive gastric and
GOJ tumours , and phase II studies have assessed its
efficacy in locally advanced gastrooesophageal adenocarcinoma.
pCR rates of more than 20% were achieved using
perioperative trastuzumab in combination with FLOT, with 93% of
patients (n = 45) achieving a R0 resection; adverse events
were as expected with this regimen . Perioperative
trastuzumab and XELOX may also have activity with a
reported 18 month DFS of 71% .
Further modification of chemoradiotherapy with
biological agents appears attractive given their success in
the neighbouring anatomical site of head and neck ,
in particular agents that target the epidermal growth
factor receptor (EGFR). A phase Ib/II trial of induction
cisplatin, docetaxel and cetuximab followed by 45 Gy
with cisplatin and cetuximab showed acceptable toxicity
with 86% of patient completing therapy and a pCR rate
of 68% and a phase III trial is ongoing . A novel
EGFR inhibitor, nimotuzumab, has been trialled with
cisplatin and CRT (cisplatin and 5-fluorouracil) .
In an almost exclusive SCC population, it did not meet
its primary endpoint of endoscopic CR but the addition
of nimotuzumab did significantly improve a secondary
endpoint of combined endoscopic CR and pCR (62.3 vs
33.3%). This regimen may be taken forward for phase
III testing. The addition of panitumumab to cisplatin
and docetaxel augmented radiation resulted in a pCR
rate of 32.8% however, the toxicity profile was
significant with 23% having grade 4 + toxicity . A small
phase II study of 33 patients adding bevacizumab to
cisplatin and irinotecan modified radiation given in the
neoadjuvant setting found that although the regime was
tolerable there was no suggestion of improvement in
PFS, OS or pCR . The regimen was deemed
unsuitable for taking forward to the phase III setting.
Rapid developments over the last 15 years in the
management of oesophageal cancer have left many
clinicians uncertain in how best to proceed. Ongoing trials,
organised according to histological subtype and
anatomical location, will help to unravel the uncertainty caused
by the significant heterogeneity of older data.
In summary, the authors would recommend several
key principles of management. Early stage I do tumours
do not benefit from neoadjuvant therapy and should
proceed directly to surgery; locally advanced tumours
will benefit. In SCC, both definitive CRT as well as
tri-modality therapy consisting of nCRT and surgery
are considered as standard options. Both neoadjuvant
chemotherapy and neoadjuvant CRT are treatment
options for oesophageal adenocarcinoma, however, it may
be particularly useful to consider tri-modality treatment
for bulky adenocarcinomas where there is a priori
concern about the ability to achieve an R0 margin. In other
situations, neoadjuvant chemotherapy alone can be
considered an acceptable alternative. Decision making may
also not purely be about tumour factors. Baseline
patient factors may also favour one form of neoadjuvant
therapy over another, for example previous “in field”
radiotherapy for another condition may persuade a
clinician to use chemotherapy alone. Given the complex
nature of care leading to any given outcome, in
particular survival, we would also recommend institutions
regularly audit their practice to ensure a patient-centred,
Compliance with Ethical Standards
Conflict of Interest Samantha J. Cox, Sean M. O’Cathail, Bernadette
Coles, Tom Crosby, and Somnath Mukherjee declare that they have no
conflict of interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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Papers of particular interest, published recently, have been
Of major importance
1. Cancer Incidence and Mortality Worldwide: IARC CancerBase No . 11 [Internet] [database on the Internet] . International Agency for Research on Cancer; 2013 . 2013 . Available from: http://globocan. iarc.fr. Accessed Dec 2013 .
2. Pohl H , Sirovich B , Welch HG . Esophageal adenocarcinoma incidence: are we reaching the peak? Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology . 2010 ; 19 ( 6 ): 1468 - 70 . doi:10.1158/ 1055 - 9965 . EPI-10-0012.
3. Vizcaino AP , Moreno V , Lambert R , Parkin DM . Time trends incidence of both major histologic types of esophageal carcinomas in selected countries , 1973 - 1995 . Int J Cancer . 2002 ; 99 ( 6 ): 860 - 8 . doi:10.1002/ijc.10427.
4. Oesophageal Cancer Statistics. Cancer Research UK . http://www. c a n c e r r e s e a r c h u k . o r g / h e a l t h - p r o f e s s i o n a l / c a n c e r - statistics/statistics-by-cancer-type/oesophageal-cancer . Accessed 26 May 2016 .
5. Medical Research Council Oesophageal Cancer Working G . Surgical resection with or without preoperative chemotherapy in oesophageal cancer: a randomised controlled trial . Lancet . 2002 ; 359 ( 9319 ): 1727 - 33 . doi:10.1016/S0140-6736(02)08651- 8 .
6. Allum WH , Stenning SP , Bancewicz J , Clark PI , Langley RE . Long-term results of a randomized trial of surgery with or without preoperative chemotherapy in esophageal cancer . J Clin Oncol . 2009 ; 27 ( 30 ): 5062 - 7 . doi:10.1200/JCO. 2009 .22. 2083 .
7. Kelsen DP , Winter KA , Gunderson LL , Mortimer J , Estes NC , Haller DG , et al. Long-term results of RTOG trial 8911 (USA Intergroup 113): a random assignment trial comparison of chemotherapy followed by surgery compared with surgery alone for esophageal cancer . J Clin Oncol . 2007 ; 25 ( 24 ): 3719 - 25 . doi:10.1200/JCO. 2006 .10.4760.
8. Kelsen DP , Ginsberg R , Pajak TF , Sheahan DG , Gunderson L , Mortimer J , et al. Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer . N E n g l J M e d . 1 9 9 8 ; 3 3 9 ( 2 7 ) : 1 9 7 9 - 8 4 . d o i : 1 0 . 1 0 5 6 /NEJM199812313392704.
9. Sjoquist KM , Burmeister BH , Smithers BM , Zalcberg JR , Simes RJ , Barbour A , et al. Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis . Lancet Oncol . 2011 ; 12 ( 7 ): 681 - 92 . doi:10.1016/ S1470-2045(11)70142-5.
10. Kidane B , Coughlin S , Vogt K , Malthaner R. Preoperative chemotherapy for resectable thoracic esophageal cancer . Cochrane Database Syst Rev . 2015 ; doi:10.1002/14651858.CD001556. pub3. Cisplatin-based neoadjuvant chemotherapy improves survival and R0 resection rates in patients with potentially resectable thoracic esophageal carcinoma however the evidence to date is only of modest quality
11. Cunningham D , Allum WH , Stenning SP , Thompson JN , Van de Velde CJ , Nicolson M , et al. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer . N Engl J Med . 2006 ; 355 ( 1 ): 11 - 20 . doi:10.1056/NEJMoa055531.
12. Ychou M , Boige V , Pignon JP , Conroy T , Bouché O , Lebreton G , et al. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial . Journal of clinical oncology : official journal of the American Society of Clinical Oncology . 2011 ; doi:10.1200/JCO. 2010 .33.0597.
13. Ferri LE , Ades S , Alcindor T , Chasen M , Marcus V , Hickeson M , et al. Perioperative docetaxel, cisplatin, and 5-fluorouracil (DCF) for locally advanced esophageal and gastric adenocarcinoma: a multicenter phase II trial . Ann Oncol . 2012 ; 23 ( 6 ): 1512 - 7 . doi:10.1093/annonc/mdr465.
14. Thuss-Patience PC , Hofheinz RD , Arnold D , Florschutz A , Daum S , Kretzschmar A , et al. Perioperative chemotherapy with docetaxel, cisplatin and capecitabine (DCX) in gastro-oesophageal adenocarcinoma: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)† . Ann Oncol . 2012 ; 23 ( 11 ): 2827 - 34 . doi:10.1093/annonc/mds129.
15. Pauligk C , Tannapfel A , Meiler J , Luley KB , Kopp HG , Homann N et al. Pathological response to neoadjuvant 5-FU, oxaliplatin, and docetaxel (FLOT) versus epirubicin, cisplatin, and 5-FU (ECF) in patients with locally advanced, resectable gastric/esophagogastric junction (EGJ) cancer: Data from the phase II part of the FLOT4 phase III study of the AIO . J Clin Oncol . 2015 .
16. Lorenzen S , Pauligk C , Homann N , Schmalenberg H , Tauchert F , Jager E et al. Feasibility of perioperative chemotherapy with infusional 5-FU, leucovorin, and oxaliplatin with or without docetaxel, in elderly patients with locally advanced esophagogastric cancer . J Clin Oncol Conf . 2012 ; 30 ( 15 SUPPL. 1).
17. Cunningham D , Langley R , Nankivell M , Blazeby J , Griffin M , Crellin A , et al. Neoadjuvant chemotherapy for resectable oesophageal and junctional adenocarcinoma: Results from the UK medical research council randomised OEO5 trial (ISRCTN 01852072) . Ann Oncol. 2015 ; 26 : iv117 - iv8 . doi:10.1093/annonc/mdv262.3. Increasing the amount of neoadjvuant chemotherapy for lower esophageal/GOJ adenocarcinoma does not improve overall survival and is associated with higher rates of chemotherapy toxicity (four cycles of ECX compared to the standard two cycles of cisplatin-fluouracil)
18. Schulz C , Kullmann F , Kunzmann V , Fuchs M , Geissler M , Vehling-Kaiser U , et al. NeoFLOT: Multicenter phase II study of perioperative chemotherapy in resectable adenocarcinoma of the gastroesophageal junction or gastric adenocarcinoma-Very good response predominantly in patients with intestinal type tumors . Int J Cancer . 2015 ; 137 ( 3 ): 678 - 85 . doi:10.1002/ijc.29403.
19. Hirao M , Ando N , Tsujinaka T , Udagawa H , Yano M , Yamana H , et al. Influence of preoperative chemotherapy for advanced thoracic oesophageal squamous cell carcinoma on perioperative complications . Br J Surg . 2011 ; 98 ( 12 ): 1735 - 41 . doi:10.1002/bjs.7683.
20. Ando N , Kato H , Igaki H , Shinoda M , Ozawa S , Shimizu H , et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907) . Ann Surg Oncol . 2012 ; 19 ( 1 ): 68 - 74 . doi:10.1245/s10434- 011 - 2049 -9.
21. Yun F , Jiang Y , Chen Q , Zhou X , Huang Z , Mao W. Survival outcomes in patients with locally advanced esophageal squamous cell carcinoma treated with nab-paclitaxel and cisplatin as neoadjuvant chemotherapy . European journal of cancer (Oxford , England : 1990 ). 2015 ; 51 (Supplement 3): S411 .
22. Hara H , Tahara M , Daiko H , Kato K , Igaki H , Kadowaki S , et al. Phase II feasibility study of preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for esophageal squamous cell carcinoma . Cancer Sci . 2013 ; 104 ( 11 ): 1455 - 60 . doi:10.1111 /cas.12274. Neoadjuvant DCF chemotherapy for SCC appears to have activity in the phase II setting. The imminent JCOG1109 NExT trial will compare this regimen to neoadjvuant cisplatin-5-fluorouracil and neoadjuvant cisplatin-based CRT
23. Yokota T , Hatooka S , Ura T , Abe T , Takahari D , Shitara K , et al. Docetaxel plus 5-fluorouracil and cisplatin (DCF) induction chemotherapy for locally advanced borderline-resectable T4 esophageal cancer . Anticancer Res . 2011 ; 31 ( 10 ): 3535 - 41 .
24. Nakamura K , Kato K , Igaki H , Ito Y , Mizusawa J , Ando N , et al. Three-arm phase III trial comparing cisplatin plus 5-FU (CF) versus docetaxel, cisplatin plus 5-FU (DCF) versus radiotherapy with CF (CF-RT) as preoperative therapy for locally advanced esophageal cancer (JCOG1109, NExT study) . Jpn J Clin Oncol . 2013 ; doi:10.1093/jjco/hyt061.
25. Mariette C , Dahan L , Mornex F , Maillard E , Thomas PA , Meunier B , et al. Surgery alone versus chemoradiotherapy followed by surgery for stage I and II esophageal cancer: final analysis of randomized controlled phase III trial FFCD 9901 . Journal of clinical oncology : official journal of the American Society of Clinical Oncology . 2014 ; doi:10.1200/JCO. 2013 .53.6532. nCRT does not improve resection rates or survival in patients with early-stage (I-II) esophageal cancer and is associated with a significant 7.7 % increase in the postoperative mortality rate
26. Apinop C , Puttisak P , Preecha N. A prospective study of combined therapy in esophageal cancer . Hepato-Gastroenterology . 1994 ; 41 ( 4 ): 391 - 3 .
27. Walsh TN , Grennell M , Mansoor S , Kelly A. Neoadjuvant treatment of advanced stage esophageal adenocarcinoma increases survival . Dis Esophagus . 2002 ; 15 ( 2 ): 121 - 4 .
28. Bosset JF , Gignoux M , Triboulet JP , Tiret E , Mantion G , Elias D , et al. Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus . N Engl J Med . 1997 ; 337 ( 3 ): 161 - 7 . doi:10.1056/NEJM199707173370304.
29. Lee JL , Park SI , Kim SB , Jung HY , Lee GH , Kim JH , et al. A single institutional phase III trial of preoperative chemotherapy with hyperfractionation radiotherapy plus surgery versus surgery alone for resectable esophageal squamous cell carcinoma . Ann Oncol . 2004 ; 15 ( 6 ): 947 - 54 .
30. Burmeister BH , Smithers BM , Gebski V , Fitzgerald L , Simes RJ , Devitt P , et al. Surgery alone versus chemoradiotherapy followed by surgery for resectable cancer of the oesophagus: a randomised controlled phase III trial . Lancet Oncol . 2005 ; 6 ( 9 ): 659 - 68 . doi:10.1016 / S1470-2045(05)70288-6.
31. Urba SG , Orringer MB , Turrisi A , Iannettoni M , Forastiere A , Strawderman M. Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma . J Clin Oncol . 2001 ; 19 ( 2 ): 305 - 13 .
32. Urschel JD , Vasan H. A meta-analysis of randomized controlled trials that compared neoadjuvant chemoradiation and surgery to surgery alone for resectable esophageal cancer . Am J Surg . 2003 ; 185 ( 6 ): 538 - 43 .
33. Wijnhoven BP , van Lanschot JJ , Tilanus HW , Steyerberg EW , van der Gaast A. Neoadjuvant chemoradiotherapy for esophageal cancer: a review of meta-analyses . World J Surg . 2009 ; 33 ( 12 ): 2606 - 14 . doi:10.1007/s00268- 009 - 0223 -z.
34. Stahl M , Walz MK , Stuschke M , Lehmann N , Meyer HJ , RieraKnorrenschild J , et al. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction . J Clin Oncol . 2009 ; 27 ( 6 ): 851 - 6 . doi:10.1200/JCO. 2008 .17.0506.
35. Van Hagen P , Huls hof MCCM , Van Lan schot JJB , Steyerberg EW , Van Berge Henegouwen MI , Wijnhoven BPL , et al. Preoperative chemoradiotherapy for esophageal or junctional cancer . N Engl J Med . 2012 ; 366 ( 22 ): 2074 - 84 . doi:10.1056/NEJMoa1112088.
36. Shapiro J , Lanschot JJ , Hulshof MC , Hagen P , Berge Henegouwen MI , Wijnhoven BP , et al. Neoadjuvant chemoradiotherapy plus surgery versus surgery alone for oesophageal or junctional cancer (CROSS): long-term results of a randomised controlled trial . The Lancet Oncology. 2015 ; doi:10.1016/ S1470-2045(15)00040-6. nCRT with weekly carboplatin and paclitaxel offers a survival advantage to surgery alone and should be considered a s t a n d a r d o f c a r e f o r l o c a l l y a d v a n c e d r e s e c t a b l e esophageal/ GOJ cancer of both histological subtypes
37. Keegan N , Keane F , Cuffe S , Cunningham M , Ravi N , Lee G , et al. ICORG 10-14: Neo-AEGIS: A randomized clinical trial of neoadjuvant and adjuvant chemotherapy (modified MAGIC regimen) versus neoadjuvant chemoradiation (CROSS protocol) in adenocarcinoma of the esophagus and esophagogastric junction . J Clin Oncol Conf . 2014 ; 32 ( 15 SUPPL. 1).
38. Yoon DH , Jang G , Kim JH , Kim YH , Kim JY , Kim HR , et al. Randomized phase 2 trial of S1 and oxaliplatin-based chemoradiotherapy with or without induction chemotherapy for esophageal cancer . Int J Radiat Oncol Biol Phys . 2015 ; 91 ( 3 ): 489 - 96 . doi:10.1016/j.ijrobp. 2014 .11.019.
39. Ajani JA , Xiao L , Roth JA , Hofstetter WL , Walsh G , Komaki R , et al. A phase II randomized trial of induction chemotherapy versus no induction chemotherapy followed by preoperative chemoradiation in patients with esophageal cancer . Annals of oncology : official journal of the European Society for Medical Oncology / ESMO . 2013 ; doi:10.1093/annonc/mdt339.
40. Alberts SR , Soori GS , Shi Q , Wigle DA , Sticca RP , Miller RC et al. Randomized phase II trial of extended versus standard neoadjuvant therapy for esophageal cancer, NCCTG (Alliance) trial N0849 . J Clin Oncol Conf . 2013 ; 31 ( 15 SUPPL. 1).
41. Tran Vuong TN , Le Prise E , Vauleon E , Boucher E , Audrain O , Raoul JL . Chemoradiotherapy for cancer of the esophagus: contribution of the leucovorin, 5-fluorouracil bolus, and infusioncisplatin-radiotherapy schedule starting with two neoadjuvant chemotherapy cycles: results from a pilot study . Dis Esophagus . 2010 ; 23 ( 4 ): 324 - 8 . doi:10.1111/j.1442- 2050 . 2009 .01016.x.
42. Ma HB , Di ZL , Wen J , Ke Y , Sun X , Ren J. Prospective , open, multicentre Phase I/ II trial to assess safety and efficacy of neoadjuvant radiochemotherapy with docetaxel and cisplatin for esophageal carcinoma . Jpn J Clin Oncol . 2015 ; 45 ( 2 ): 169 - 75 . doi:10.1093 /jjco/hyu181.
43. Wu S , Chen MY , Luo JC , Wei L , Chen Z. [ Comparison between docetaxel plus cisplatin and cisplatin plus fluorouracil in the neoadjuvant chemoradiotherapy for local advanced esophageal squamous cell carcinoma] . Zhonghua Zhong Liu Za Zhi [Chinese J Oncol] . 2012 .
44. Spigel DR , Greco FA , Meluch AA , Lane CM , Farley C , Gray JR , et al. Phase I/ II trial of preoperative oxaliplatin, docetaxel, and capecitabine with concurrent radiation therapy in localized carcinoma of the esophagus or gastroesophageal junction . J Clin Oncol . 2010 ; 28 ( 13 ): 2213 - 9 . doi:10.1200/JCO. 2009 .24.8773.
45. Cunningham D , Okines AF , Ashley S. Capecitabine and oxaliplatin for advanced esophagogastric cancer . N Engl J Med . 2010 ; 362 ( 9 ): 858 - 9 . doi:10.1056/NEJMc0911925.
46. Mukherjee S , Hurt C , Gwynne S , Bateman A , Gollins S , Radhakrishna R , Canham J , Ray R , Grabsch HI , Sharma RA , Maggs R , Hawkins MA , Sebag-Montefiore D , Maughan T , Griffiths G , Crosby T. NEOSCOPE : A randomised Phase II study of induction chemotherapy followed by either oxaliplatin/ capecitabine (OXCAP) or carboplatin/paclitaxel (CarPac) based chemoradiation (CRT) as pre-operative regimen for resectable oesophageal adenocarcinoma . Journal of clinical oncology : official journal of the American Society of Clinical Oncology . 2016 ; 34 (Suppl 4S):Abstract 3.
47. Niu NN , Catalano PJ , Enzinger PC , Bueno R , King BL , Martin NE , et al. A retrospective comparison of neoadjuvant chemoradiation therapy regimens for locally advanced esophageal cancer . International Journal of Radiation Oncology Biology Physics . 2015 ; 1 : E139 .
48. Chowdhury MM , Dagash H , Pierro A. A systematic review of the impact of volume of surgery and specialization on patient outcome . Br J Surg . 2007 ; 94 ( 2 ): 145 - 61 . doi:10.1002/bjs.5714.
49. Wouters MW , Karim-Kos HE , le Cessie S , Wijnhoven BP , Stassen LP , Steup WH , et al. Centralization of esophageal cancer surgery: does it improve clinical outcome? Ann Surg Oncol . 2009 ; 16 ( 7 ): 1789 - 98 . doi:10.1245/s10434- 009 - 0458 -9.
50. Klevebro F , Johnsen G , Johnson E , Viste A , Myrnas T , Szabo E , et al. Morbidity and mortality after surgery for cancer of the oesophagus and gastro-oesophageal junction: A randomized clinical trial of neoadjuvant chemotherapy vs . neoadjuvant chemoradiation. E u r J S u rg O n c o l . 2 0 1 5 ; 4 1 ( 7 ) : 9 2 0 - 6 . d o i : 1 0 . 1 0 1 6 / j . ejso. 2015 .03.226. The addition of radiotherapy to neoadjuvant cisplatin/5-fluorouracil increases the severity of treatmentrelated toxicities but not overall (surgical or non-surgical) complication rates
51. Lund M , Alexandersson von Dobeln G , Nilsson M , Winter R , Lundell L , Tsai JA , et al. Effects on heart function of neoadjuvant chemotherapy and chemoradiotherapy in patients with cancer in the esophagus or gastroesophageal junction-prospective cohort pilot study within a randomized clinical trial . Radiat . 2015 ; 10 ( 1 ): 16 . doi:10.1186/s13 014 - 0310 -7.
52. Lordick F , Ott K , Krause BJ , Weber WA , Becker K , Stein HJ , et al. PET to assess early metabolic response and to guide treatment of adenocarcinoma of the oesophagogastric junction: the MUNICON phase II trial . Lancet Oncol . 2007 ; 8 ( 9 ): 797 - 805 . doi:10.1016 / S1470-2045(07)70244-9.
53. zum Buschenfelde CM , Herrmann K , Schuster T , Geinitz H , Langer R , Becker K , et al. ( 18 ) F-FDG PET-guided salvage neoadjuvant radiochemotherapy of adenocarcinoma of the esophagogastric junction: the MUNICON II trial . J Nucl Med . 2011 ; 52 ( 8 ): 1189 - 96 . doi:10.2967/jnumed.110.085803.
54. Lordick F. Molecular imaging for response monitoring in esophageal cancer . Eur J Cancer . 2011 ; 47 : S55 - S6 . doi:10.1016/S0959- 8049%2811% 2970450 - 6 .
55. Ott K , Weber WA , Lordick F , Becker K , Busch R , Herrmann K , et al. Metabolic imaging predicts response, survival, and recurrence in adenocarcinomas of the esophagogastric junction . J Clin Oncol . 2006 ; 24 ( 29 ): 4692 - 8 . doi:10.1200/JCO. 2006 .06.7801.
56. Ilson DH , Minsky BD , Ku GY , Rusch V , Rizk N , Shah M , et al. Phase 2 trial of induction and concurrent chemoradiotherapy with weekly irinotecan and cisplatin followed by surgery for esophageal cancer . Cancer . 2012 ; 118 ( 11 ): 2820 - 7 . doi:10.1002/cncr.26591.
57. Wu AJ , Goodman KA . Positron emission tomography imaging for gastroesophageal junction tumors . Semin Radiat Oncol . 2013 ; 23 ( 1 ): 10 - 5 . doi:10.1016/j.semradonc. 2012 .09.001.
58. van Heijl M , Omloo JM , van Berge Henegouwen MI , Hoekstra OS , Boellaard R , Bossuyt PM , et al. Fluorodeoxyglucose positron emission tomography for evaluating early response during neoadjuvant chemoradiotherapy in patients with potentially curable esophageal cancer . Ann Surg . 2011 ; 253 ( 1 ): 56 - 63 . doi:10.1097 /SLA.0b013e3181f66596.
59. O m l o o J M , v a n H e i j l M , H o e k s t r a O S , v a n B e r g e Henegouwen MI , van Lanschot JJ , Sloof GW . FDG-PET parameters as prognostic factor in esophageal cancer patients: a review . Ann Surg Oncol . 2011 ; 18 ( 12 ): 3338 - 52 . doi:10.1245 /s10434- 011 - 1732 -1.
60. Mariette C , Piessen G , Monterymard C , Pezet D , Ferru A , Baconnier M , Adhoute X , Tavan D , Lepage C , Bouche O. Efficacy and safety of perioperative chemotherapy with 5FUcisplatin-cetuximab in gastric and gastroeosphageal junction Adenocarcionmas (GGOJA): a single arm multicentre phase II trial (FFCD 0901) . Annals of oncology : official journal of the European Society for Medical Oncology / ESMO . 2014 ; 25 (Supplement 4) : iv216-iv . doi:10.1093/annonc/mdu334.17.
61. Stahl M , Mihaljevic AL , Moehler M , Kanzler S , Hoehler T , ThussPatience PC et al. Perioperative chemotherapy with ECX +/− panitumumab in locally advanced gastroesophageal adenocarcinomas (GEA): A randomized study of the Arbeitsgemeinschaft internistische onkologie and the chirurgische arbeitsgemeinschaft onkologie of the German cancer society . J Clin Oncol Conf . 2015 ; 33 ( 3 SUPPL. 1).
62. Cunningham D , Smyth E , Stenning S , Stevenson L , Robb C , Allum W , et al. Peri-operative chemotherapy ± bevacizumab for resectable gastro-oesophageal adenocarcinoma: Results from the UK Medical Research Council randomised ST03 trial . European journal of cancer (Oxford , England : 1990 ). 2015;51(Supplement 3):S400. Bevacizumab in combination with neoadjuvant ECX chemotherapy does not improve survival outcomes and is associated with higher rates of anatomotic leak following esoghagogastrectomy
63. Bang YJ , Van Cutsem E , Feyereislova A , Chung HC , Shen L , Sawaki A , et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial . Lancet . 2010 ; 376 ( 9742 ): 687 - 97 . doi:10.1016/S0140-6736(10) 61121 - X .
64. Hofeinz R , Hegewisch-Becker S , Thuss-Patience P , Kunzmann V , Fuchs M , Graeven U , Homann N , Heinemann V , Pohl M , Tannapfel A , Al-Batran S. HER-FLOT: trastuzumab in combination with FLOT as perioperative treatment for patients with HER2- positive locally advanced esophagogastric adenocarcinoma: a phase II trial of the AIO gastric cancer study group . journal of clinical oncology : official journal of the American Society of Clinical Oncology . 2014 ; 32 ( 5 s):abstr 4073.
65. Rivera F , Jimenez-Fonseca P , Alfonso P , Gallego J , Limon M , Alsina M , Lopez-Gomez L , Galan M , Falco E , Manzano J , Gonzalez E , Aranda E , Fernandez E , Jorge M. NEOHX study: Perioperative treatment with trastuzumab in combination with capecitabine and oxaliplatin (XELOX-T) in patients with HER-2 resectable stomach or esophagogastric junction (EGJ) adenocarcinoma-18 m DFS analysis . Journal of clinical oncology : official journal of the American Society of Clinical Oncology . 2015 ; 33 (s3):abstr 107.
66. Bonner JA , Harari PM , Giralt J , Azarnia N , Shin DM , Cohen RB , et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck . N Engl J Med . 2006 ; 354 ( 6 ): 567 - 78 . doi:10.1056/NEJMoa053422.
67. Ruhstaller T , Pless M , Dietrich D , Kranzbuehler H , von Moos R , Moosmann P , et al. Cetuximab in combination with chemoradiotherapy before surgery in patients with resectable, locally advanced esophageal carcinoma: a prospective, multicenter phase IB/II trial (SAKK 75/06) . J Clin Oncol . 2011 ; 29 ( 6 ): 626 - 31 . doi:10.1200 /JCO. 2010 .31.9715.
68. Castro G , Skare NG , Andrade CJC , Segalla LGM , De Azevedo SJ , Silva I , Filho FM , Del Grossi Neusquen LP, de Oliveira Berto CR . Chemoradiation with or without nimotuzumab in locally advanced esophageal cancer (LAEC): A randomized phase II study (NICE trial) . Journal of clinical oncology : official journal of the American Society of Clinical Oncology . 2014 ; 32 ( 5 s):abstr 4078.
69. Reed CE , Decker PA , Schefter TE , Meyers BF , Ferguson MK , Oeltjen AR , Putnam JB , Cassivi SD , Lockhart AC. A phase II study of neoadjuvant therapy with cisplatin, docetaxel, panitumumab plus radiation therapy followed by surgery in patients with locally advanced adenocarcinoma of the distal esophagus . Journal of clinical oncology : official journal of the American Society of Clinical Oncology . 2012 ; 30 (Supplement):abstr 4062.
70. Ilson D , Goodman KA , Janjigian YY , Shah MA , Kelsen DP , Rizk NP , Rusch VW , Jing-Ching Wu A , Campbell J , Capanu M , Bains MS . Phase II trial of bevacizumab, irinotecan, cisplatin, and radiation as preoperative therapy in esophageal adenocarcinoma . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2012 ; 30 (Supplement):abstr 4061.