This document summarizes key information about cancer of the esophagus: 1) The esophagus spans from the cricopharyngeus to the GE junction. Esophageal cancer risk factors include smoking, alcohol, caustic injury, HPV infection, obesity, and Barrett's esophagus. 2) The most common types of esophageal cancer are squamous cell carcinoma (SCC) in the upper two-thirds and adenocarcinoma in the lower third. Distant metastases are most common in the lung, liver, and bone. 3) Treatment options discussed include surgery, chemotherapy, radiation therapy, and their combinations in neoadjuvant and adjuvant settings. Several large randomized controlled trials

1. Ca Esophagus

2. • The esophagus spans from the cricopharyngeus
at the cricoid to the gastroesophageal (GE)
junction.
Relative to the incisors
The cervical esophagus spans from 15–18 cm
The upper thoracic from 18–24 cm
The midthoracic from 24–32 cm and
The lower thoracic from 32–40 cm.

7. • The esophagus has an adventitial layer but
does not have a serosal layer, thus reducing
the resistance against local spread of cancer.

8. • The proximal three-fourths of the esophagus (cervical to mid-
thoracic) are mostly SCCs (∼40%)
• Adenocarcinoma generally is found in the distal esophagus
(∼60%).
• Adenocystic, mucoepidermoid, small cell, and sarcomatous
(leiomyosarcoma) carcinomas (all typically 1% of cases).
• Extremely rare types are lymphoma, Kaposi sarcoma, and
melanoma.
• Lung, liver, and bone are the most common sites of distant Dz.

9.  Esophageal SCC risk factors:
 smoking/alcohol tylosis,
 Plummer-Vinson syndrome,
 caustic injury to the esophagus,
 Hx of H&N cancer, and achalasia.
 HPV infection has been associated in ∼20% cases in high-incidence
areas (China, Africa, Japan) but none in low-incidence areas
(Europe, U.S.).
 Esophageal adenocarcinoma risk factors:
 obesity/ GERD,
 Barrett esophagus,
 lack of fruits/ vegetables,
 low socioeconomic status

12. • The frequency of distant metastatis at presentation depends on the location and size of
the tumor.
• Disease at the middle and lower third of the esophagus tends to present with localized
Dz (25%–50%),
• upper thoracic Dz is less commonly localized (10%–25%).
• Tumors >5 cm also tend to have greater metastatic rate (~75%) than tumors <5 cm.
• DOI is the most important factor dictating nodal and distant spread. (Mariette C et al.,
Cancer 2003)

13. • Dysphagia and weight loss (>90%),
odynophagia, pain, cough, dyspnea, and
hoarseness.
• Tumors of the esophagus spread
locoregionally through the extensive
submucosal lymphatic plexus or distantly
through hematogenous routes.

19. surgery
• Surgical Resection
• Surgery is considered as the primary treatment for resectable esophageal
cancer, with the exception of cancer of the cervical esophagus.
• Surgery alone is usually indicated for stage I and IIA thoracic esophageal
cancer.
• The 5-year survival rates of less than 40% only after surgery alone for
locally advanced esophageal cancer suggested adjuvant treatment is
necessary (Hulscher et al. 2002; Kelsen et al. 1998).
• Esophagectomy can be accomplished by a transhiatal or transthoracic
approach.
• Results of a randomized trial comparing transhiatal versus transthoracic
approach in patients with adenocarcinoma of esophagus revealed no
significant differences in 5-year overall and disease-free survival rates,
• though transhiatal esophagectomy was associated with lower morbidity
(Hulscher et al. 2002).

20. Pre-op chemo vs surgery

21. • Kelsen et al. 1998, 2007).
• An Intergroup randomized trial of 440 patients with local and operable esophageal cancer
(squamous cell carcinoma or adenocarcinoma)
• surgery only or surgery with three cycles of pre- and two cycles of postoperative
chemotherapy (cisplatin + 5 FU).
• The rate of CR after neoadjuvant chemotherapy was merely 2.5%.
• 2-year local control (32% vs. 31%) or overall survival rates (23% vs. 26%).
• Results from long-term follow-ups were also negative. In addition, there were no differences
in survival between patients with squamous cell carcinoma or adenocarcinoma.
• MRC Oesophageal Cancer Working Group 2002)
• 802 patients with resectable esophageal cancer of any cell type
• two cycles of chemotherapy (cisplatin + 5-FU) followed by surgery or surgery alone.
• patients receiving neoadjuvant chemo had improved 2-year survival rate(43% vs 34%).
• However, the benefit of neoadjuvant chemotherapy on survival was questionable because
clinicians could choose to give preoperative radiotherapy to patients irrespective of
randomization. In addition, preoperative CT scan was not required for staging.
• Gebski et al. (2007)
• meta-analysis of eight randomized controlled trials
• neoadjuvant chemotherapy with surgery versus surgery alone
• more than 1700 patients with local and operable esophageal cancer.
• The results revealed that neoadjuvant chemotherapy did not have a survival benefi t [hazard
ratio for mortality 0.88 (0.75–1.03)] for squamous cell carcinoma, but may be benefi cial for
adenocarcinoma, although only one of the eight trials reported treatment effects of
neoadjuvant chemotherapy.

22. US
Intergroup
trial
Kelsen DP et al.,
NEJM 1998
467 pts
-53% adeno
-47% SCC
3 × 5-FU/ cisplatin
preop and 2 × 5-FU/
cisplatin postop vs
immediate surgical
resection alone.
No differences in
resectability or
survival
-4-yr OS 26% vs.
23%, respectively
-MS 16 mos vs. 15
mos, respectively)
Pts with complete
resection had a 5-yr
DFS of 32% vs. 5%
with R1-R2
resection.
MRC
randomized
trial of preop
chemo
MRC,Lancet 2002 802 pts
-66% adeno
-31% SCC
-3% undifferentiated
2 × cisplatin/5-FU
preop vs immediate
surgery.
-
There was a
significant benefit of
neoadj chemo.
-MS was 13.3 m vs.
16.8 m respectively
-2-yr OS was 34% vs.
43%, respectively.
The complete
resection rate was
also improved by
chemo (54% vs.
60%, respectively).
MRC
Adjuvant
Gastric
Cancer
Infusional
Chemo
(MAGIC) trial
(Cunningham D et
al., Lancet 2008):
503 PTS
-250 for preop
chemo vs 253 for
only surgery.
pts randomized with
gastric, GE junction,
and distal
esophageal
adenocarcinoma
(26%) to preop
epirubicin/cisplatin/
5-FU (ECF) × 3 and
postop ECF × 3 vs
surgery alone
Showed a survival
benefit for chemo.
5-yr OS was 36% vs.
23%, respectively
(p = 0.009).

23. Preoperative Radiation Therapy
• Results from numerous randomized trials of various sizes
comparing esophagectomy with or without preoperative
radiotherapy
• No improvement in respectability or overall survival rates
from the addition of preoperative radiation (Arnott et al.
1992; Gignoux et al. 1987; Launois et al. 1981; Wang et al.
1989).
• Results from a meta-analysis including samples from five
randomized studies showed no significance between
patients treated with preoperative radiotherapy followed
by surgery as compared to surgery alone, although a trend
of reduction of risk of death (11% at 5 years) was noticed
(Oesophageal Cancer Collaborative Group meta-analysis)
(Arnott et al. 2005).

24. Pre-op CRT vs surgery

26. Post op rt

27. • Postoperative Radiation Therapy
• Radiation given after complete resection does not improve survival,
but may reduce locoregional recurrence in locally advanced
diseases.
• Results from three randomized trials comparing esophagectomy
alone or esophagectomy followed by radiation therapy reported no
survival advantage with the addition of adjuvant radiotherapy (
o Fok et al. 1993
o Ténière et al. 1991
o Zieren et al. 1995
• Completely resected stages II–III adenocarcinoma of the GE
junction should receive postop CRT based on the Intergroup gastric
trial. (MacDonald JS et al., NEJM 2001)

28. Crt vs rt

29. RTOG 85-01 (Herskovic A et al., NEJM 1992; Cooper JS et al., JAMA 1999):
-130 pts (82% SCC, 18% adenocarcinoma)
-64 Gy RT alone vs. 50 Gy RT + cis/5-FU × 2 during RT and 2 cycles after RT.
-There was SCC in 88% pts.
- The 2-year overall survival and local recurrence rates were 38% versus 10%, and 16%
versus 24%, respectively, both in favor of the chemoradiation arm
-5-yr OS was 27% vs. 0% for RT alone.
-10-yr OS was 20% for CRT.
-There was no difference between adenocarcinoma and SCC.
RT technique used in this trial: initial RT field was the whole esophagus to 50 Gy (RT alone)
or 30 Gy (CRT) → CD to 14 Gy (RT) or 20 Gy (CRT) to tumor + 5-cm sup/inf margin.
Benefit of escalating the RT dose during CRT for esophageal cancer
Minsky BD et al., JCO 2002 (phase III study)
-Randomized pts to 50.4 Gy vs. 64.8 Gy with cisplatin + 5-FU × 2 → adj cisplatin/5-FU × 2.
-There was no difference in LC (44% vs. 48%).
-Excessive deaths in 64.8-Gy arm (11 vs. 2) were seen even before the 50.4-Gy dose (7 of 11
deaths).
-However, separate analysis excluding the early deaths still did not find a benefit to a higher
dose.

30. Pre op crt vs crt only

31. Bedenne L et al. (JCO 2007): French randomized trial
-444 patients with T3 N0-1 M0 potentially resectable thoracic esophageal cancer
-Concurrent chemotherapy (cisplatin + 5-FU) and radiation therapy (two split courses of 15 Gy given at 3
Gy per fraction, 2 weeks apart, or 46 Gy given in 23 fractions).
-230 responding pts (88% SCC) were randomized to surgery or no surgery.
-LC was better with surgery (66% vs. 57%).
-There was no difference in survival (34% vs. 40%) (17.7 months vs 19.3 months).
-The 3 month mortality rate was higher in the surgery group (9.3% vs. 0.8%).
-Surgery after chemoradiotherapy offered no improvement in outcome in locally advanced esophageal
cancer, at least in responders to chemoradiation
Stahl M et al. (JCO 2005):
-172 pts with resectable SCC
-Induction chemo + 40 Gy/chemo + surgery vs. induction chemo + 65 Gy/chemo alone.
-PFS was better with surgery (64% vs. 41%).
-The median survival and 3-year overall survival rates were 16 months versus 15 months and 31% versus
24%, respectively, without significant difference.
-However,2-year progression-free survival was 64.3% vs 40.7%,with the addition of surgery (p=0.003).
-It is interesting to note that the subgroup of patients who achieved pathologic CR after chemoradiation
had an improved survival rate (50% at 5 years after treatment)
SCOPE1 trial (Crosby et al., 2013 ).
-Patients with squamous or adenocarcinoma
-cisplatin/capecitabine-based CRT regimen with or without the cetuximab (anti-EGFR)
-Although no benefit was seen with the addition of the anti-EGFR therapy, the 2-year survival seen in the
standard treatment arm was impressive at 56% (versus 41.3% in the cetuximab arm).
-Median overall survival was significantly worse in the experimental group, 22.1 months versus 25.4
months

32. POST OP CHEMO / RT

33. • Postoperative Chemotherapy
• Chemotherapy alone given postoperatively is not routinely indicated after
complete resection of esophageal cancer (Grade B).
• Japanese Esophageal Oncology Group 1993(resectable squamous cell
carcinoma of esophagus)
-Surgery alone or surgery followed by adjuvant cisplatin and vindesine.
-The results showed no benefit in 5-year overall survival from the addition of
postoperative chemotherapy (Japanese Esophageal Oncology Group, Level I)
(Japanese Esophageal Oncology Group 1993).
• Japanese Clinical Oncology Group, 242 patients with esophageal
squamous cell carcinoma.
-Surgery alone or surgery followed by cisplatin and 5-FU.
-Although the 5-yeardisease-free survival (primary end point) was
significantly improved with adjuvant chemotherapyin patients with nodal
involvement, the study failed to demonstrate an overall survival
benefit(JCOG9204, Level I) (Ando et al. 2003).

34. • Postoperative Chemoradiotherapy
• The effects of postoperative chemoradiotherapy have not
been thoroughly examined for locally advanced squamous
cell carcinoma; however, adjuvant chemoradiation may
improve treatment outcome in patients with
adenocarcinoma of the esophagus.
• Macdonald et al. 2001 (Intergroup 0116 trial )
• Approximately 20% of patients treated in the had primary
adenocarcinoma of the GE junction or proximal stomach
with involvement of the GE junction. The subgroup analysis
of patients with gastroesophageal disease of the trial
revealed a significant survival advantage in the adjuvantly
treated group

35. THANK YOU

39. US Intergroup trial (Kelsen DP et al., NEJM 1998): 467 pts (53% adeno, 47% SCC)
-randomized to 3 × 5-FU/cisplatin preop and 2 × 5-FU/cisplatin postop or immediate
surgical resection alone.
-There were no differences in resectability or survival (4-yr OS 26% vs. 23%, respectively;
MS 16 mos vs. 15 mos, respectively). pCR was 2.5%.
-Pts with complete resection had a 5-yr DFS of 32% vs. 5% with R1-R2 resection.
MRC randomized trial of preop chemo (MRC,Lancet 2002): 802 pts (66% adeno, 31% SCC,
3% undifferentiated)
-randomized to (a) 2 × cisplatin/5-FU preop or (b) immediate surgery.
-There was a significant benefit of neoadj chemo.
-MS was 13.3 mos vs. 16.8 mos, respectively, and 2-yr OS was 34% vs. 43%, respectively.
-The complete resection rate was also improved by chemo (54% vs. 60%, respectively).
MRC Adjuvant Gastric Cancer Infusional Chemo (MAGIC) trial (Cunningham D et al., Lancet
2008):
-pts randomized with gastric, GE junction, and distal esophageal adenocarcinoma (26%) to
(a) preop epirubicin/cisplatin/5-FU (ECF) × 3 and postop ECF × 3 or (b) surgery alone
-showed a survival benefit for chemo.
-5-yr OS was 36% vs. 23%, respectively (p = 0.009).
German Esophageal Cancer Study Group trial (Stahl M et al., JCO 2009): randomized phase
III in pts with T3-4NXM0 adenocarcinoma of the GE junction or gastric cardia. The study
closed early due to poor accrual (126 of 354 Intended). Randomization: (a) induction
chemo → surgery or (b) induction chemo → preop CRT → surgery. Chemo was cisplatin/5-
FU/ leucovorin. RT was 30 Gy in 15 fx. pCR was better in the preop CRT group (15.6% vs.
2%) and in tumorfree LNs (64% vs. 38%). 3-yr OS trended better in the CRT group (47% vs.

40. • What is the randomized trial evidence to support preop CRT over surgery alone?
• This had been controversial until the recent publication of the CROSS trial.
• Urba SG et al. (JCO 2007): 100 pts (75% adenocarcinoma, 25% SCC) randomized to
cisplatin/vinblastine/5-FU + RT to 45 Gy bid vs. surgery alone. 3-yr OS was 30% vs.
16%, respectively (p = 0.18). DM was the same in both arms (60%).
• Bosset JF et al. (NEJM 1997, EORTC): SCC only, stages I–II. Cisplatin was given 0–2
days prior to RT, and RT was a split course of 18.5 Gy (3.7 Gy × 5) given on days 1
and 22. There was higher postop mortality in the trimodality approach (12% vs.
4%). There was no improvement in DFS or OS.
• Burmeister B et al. (Lancet 2007, TTROG): 256 pts (67% adenocarcinoma, 33%
SCC) randomized to cisplatin + 5-FU with RT to 35 Gy/15 fx. Less intensive chemo
(5-FU 800 mg/m2 vs. 1,000 mg/m2 in other studies) was used. There was no
difference in OS, but there was a trend to improved survival in SCC.
• CALGB 9781 (Tepper J et al., JCO 2008): 56 pts (75% adenocarcinoma, 25% SCC)
randomized (closed due to poor accrual) to cisplatin + 5-FU with RT to 50.4 Gy. pCR
rate was 40%. 5-yr OS was 39% vs. 16% (p = 0.005). MS was 48 mos vs. 22 mos.
• CROSS (van Hagen P et al., NEJM 2012): 368 pts (75% adenocarcinoma, 23% SCC,
2% undifferentiated) were randomized to surgery alone or CRT followed by
surgery. CRT arm was 41.4 Gy in 23 fx with concurrent carboplatin (AUC 2
mg/mL/min) and paclitaxel (50 mg/m2) for 5 wks followed by surgery. MS was 49.4
mos with CRT vs. 24.0 mos. Nonhematologic side effects were comparable in the 2
groups

41. • Preoperative chemoradiotherapy
• In the UK there is now increasing interest in neoadjuvant CRT. The rate of CRM positivity aft er radical resection
alone is high (> 50% in T3 cancers) and this correlates with poor survival (Reid et al ., 2012; O’Neill et al ., 2013).
Previous concerns about the safety of such an approach had all but stopped use in the UK, although CRT remains a
standard preoperative treatment in the US. These concerns have been alleviated to some extent following the
recent publication of the CROSS trial, a Dutch phase III trial of surgery alone versus neoadjuvant CRT prior to
surgery. Th e results showed an almost doubling of overall survival (OS) in favour of the CRT-S arm (OS = 49 versus
26 months, HR = 0.67), a pathological complete response (pCR) rate of 32%, and additionally no increase in
surgical mortality (3.8% (S) versus 3.4% (CRT-S); van Hagen et al. , 2012 ). Although adenocarcinomas made up the
majority of the patients in this trial, the benefit was seen in both tumour types and was most marked in squamous
cancers. Previous studies of preoperative CRT had been heterogeneous in design and findings (Walsh et al. , 1996 ;
Bosset et al. , 1997 ; Urba et al. , 2001 ). It is important to note that the radiotherapy techniques used in these
older trials would now be considered outdated and staging less robust, which would partly explain both the poor
outcomes and excessive toxicities seen. A meta-analysis from 2007 gave further weight to the role of neoadjuvant
CRT, as it included both neoadjuvant chemotherapy versus surgery alone trials and neoadjuvant CRT versus
surgery trials (Gebski et al. , 2007 ). It concluded that the hazard ratio for neoadjuvant CRT was 0.81
(corresponding to a 13% absolute difference in 2-year survival) and for neoadjuvant chemotherapy was 0.9
(corresponding to a 7% difference at 2 years), and this was seen in both adenocarcinoma and squamous cancers.
• Recently this multimodality approach has been further investigated in the UK within the NEOSCOPE trial, a phase
II study of preoperative CRT in adenocarcinoma of the oesophagus, comparing two CRT regimens. In order to
determine the gold standard preoperative treatment, these ongoing trials will help to define the optimum
preoperative chemotherapy and CRT schedules which could then be compared in a future randomised study .
NeoAEGIS is one such study currently recruiting.

42. • Preoperative Chemoradiotherapy
• Preoperative chemotherapy given concurrently with radiation should be considered in potentially resectable locally advanced [stage IIA
(T3 N0 M0) to IVA] cancer of the thoracic esophagus (Grade A). Radiation therapy techniques including simulation, fi eld arrangement,
and dose/fractionation are similar to those used in defi nitive treatment for unresectable esophageal cancer. Chemotherapy regimens
consisting of cisplatin and 5-FU [e.g., two cycles of cisplatin (100 mg/m2, day 1) and 5-FU (1000 mg/m2/d, 4 days) spaced 4 weeks
apart, as used in the CALGB9781 trial] with current external-beam radiation therapy to 50.4 Gy can be considered. (Tepper et al. 2006).
• Neoadjuvant concurrent radiation and cisplatin and 5-FU-based chemotherapy can produce a pathological complete response (pCR)
rate of approximately 25%, and patients who achieved pCR had improved treatment outcome (Level I) (Stahl et al. 2005; Walsh et al.
1996).
• In a randomized trial from Ireland, Walsh et al. (1996) randomly assigned 113 patients with adenocarcinoma of the esophagus to
surgery alone or neoadjuvant chemotherapy (cisplatin + 5-FU) and radiation therapy (40 Gy in 15 fractions over 3 weeks) followed by
surgery. The results revealed that approximately 25% of patients achieved pCR after concurrent chemoradiation. A signifi cantly
improved 3-year overall survival rate after preoperative chemoradiation plus surgery was demonstrated, as compared to surgery alone
(32% versus 6%); however, these results were criticized because of the lower than expected survival of patients treated with surgery
alone (Level I) (Walsh et al. 1996). Bosset et al. (1997) randomly assigned 282 patients with squamous cell carcinoma of the esophagus
to surgery alone or concurrent cisplatinbased chemotherapy and radiation therapy (split course) followed by surgery. Although median
survival after either treatment regimen showed no difference (18.6 months for both groups), patients receiving neoadjuvant
chemoradiotherapy had a signifi cantly higher rate of curative resection, local control and disease-free survival. However, the
postoperative mortality in the combined treatment arm was signifi cantly higher as compared to surgery alone (12% vs. 4%) (Level I)
(Bosset et al. 1997).
• In the recently reported meta-analysis by Gebski et al. (2007), ten randomized controlled trials comparing neoadjuvant
chemoradiotherapy plus surgery versus surgery alone, comprising more than 1200 patients with local and operable esophageal cancer,
were included. The results revealed that neoadjuvant combined chemoradiation signifi cantly improved 2-year overall survival [hazard
ratio for mortality 0.81 (0.70– 0.93, p=0.002)]. The benefi t of neoadjuvant chemoradiation was found in both squamous cell carcinoma
or adenocarcinoma. In addition, no benefi t was demonstrated in patients who received sequential preoperative chemotherapy and
radiotherapy (Level I) ( Gebski et al. 2007).
• The advantage of neoadjuvant chemoradiation was also reported in an earlier meta-analysis of nine randomized trials comprising more
than 1100 patients (Level I) (Urshel and Vasan 2003).

43. • In a randomized trial from Germany, 172 patients with locally advanced but potentially resectable
squamous cell carcinoma (SCC) of esophagus were treated with three cycles of induction
chemotherapy (cisplatin, etoposide, 5-FU, leucovorin) followed by concurrent chemotherapy
(cisplatin + etoposide) and external beam radiotherapy (40 Gy). Patients were then randomized to
receive either further concurrent chemoradiation (to 60–65 Gy) or surgery. No survival benefit was
observed with the addition of surgery to combined chemoradiation: The median survival and 3-
year overall survival rates were 16 months versus 15 months and 31% versus 24%, respectively,
without significant difference. However, 2-year progression-free survival was 64.3% versus 40.7%,
signifi cantly improved with the addition of surgery (p=0.003). It is interesting to note that the
subgroup of patients who achieved pathologic CR after chemoradiation had an improved survival
rate (50% at 5 years after treatment) (Level I) (Stahl et al. 2005).
• A recently published French randomized trial treated 444 patients with T3 N0-1 M0 potentially
resectable thoracic esophageal cancer with concurrent chemotherapy (cisplatin + 5-FU) and
radiation therapy (two split courses of 15 Gy given at 3 Gy per fraction, 2 weeks apart, or 46 Gy
given in 23 fractions). A total of 259 patients with clinical partial or CR were subsequently
randomized to receive further combined chemoradiation or surgery. The median survival and
overall survival rates were 19.3 months versus 17.7 month and 40% versus 34%, respectively, for
the two groups, without signifi cant differences. However, the 3-month mortality rates were 9.3%
and 0.8%, respectively, signifi cantly worse in patients who received surgery after chemoradiation.
Surgery after chemoradiotherapy offered no improvement in outcome in locally advanced
esophageal cancer, at least in responders to chemoradiation (FFCD9102, Level I) (Bedenne et al.
2007).

44. In the CROSS trial, 92% had an R0 resection in the CRT arm vs. 69% in the surgery alone
arm. 29% (23% of adenocarcinoma and 49% of SCC) had a pCR to CRT (typical CR average
of randomized trials 25%–30%). (van Hagen P et al., NEJM 2012)

47. • Postoperative adjuvant therapy
• Despite improvements in perioperative care, the outcome from
surgery for patients with esophageal cancer remains poor and only
10–30% are alive 5 years after diagnosis. In an attempt to improve
these results, trials of adjuvant therapy have been undertaken.
There is no evidence that chemotherapy given after surgical
resection improves overall survival. In addition, neither pre- nor
postoperative radiotherapy, when used alone, improves survival
and neither is routinely recommended.
• Adjuvant therapy may improve local control in patients with R1
(microscopic residual) and patients with circumferential margin
involvement with low nodal involvement (e.g. fewer than three
nodes involved), although the evidence for this is not strong.