original article
Annals of Oncology 20: 231–238, 2009
doi:10.1093/annonc/mdn622
Published online 3 October 2008
Histological type of esophageal cancer might affect
response to neo-adjuvant radiochemotherapy and
subsequent prognosis
E. Bollschweiler1*, R. Metzger1, U. Drebber2, S. Baldus3, D. Vallböhmer1, M. Kocher4 &
A. H. Hölscher1
1
Department of General-, Visceral- and Cancer Surgery, University of Cologne; 2Institute of Pathology, University of Cologne, Cologne; 3Institute of Pathology, University
of Düsseldorf, Düsseldorf; 4Department of Radiation Oncology, University of Cologne, Cologne, Germany
Received 4 May 2008; revised 5 August 2008; accepted 6 August 2008
Background: This study investigates response and prognosis after neo-adjuvant chemoradiation (CTx/RTx) in
patients with advanced esophageal carcinoma, according to histological type.
esophagectomy from 1997 until 2006 were included in this retrospective analysis. Patients receiving preoperative CTx/
RTx (5-fluorouracil, cisplatin, 36 Gy) were compared with those with primary surgery for pT3 tumors. Therapy response
after CTx/RTx was evaluated using ‘Cologne Regression Grade’ (minor response: ‡10% vital residual tumor cells
(VRTCs), major response: <10% VRTC or pathologic complete response). Prognosis was evaluated for
adenocarcinoma (AC) and squamous cell carcinoma (SCC).
Results: Of 297 patients, 52% were SCC and 48% AC. In all, 192 patients underwent CTx/RTx, 100 (65%) SCC and
92 (64%) AC (nonsignificant). In SCC group 51% and in AC group 29% achieved major response (P < 0.01). Patients
with major response had a 2-year survival rate (2y-SR) of 78% versus those with minor response or without CTx/RTx,
with a 2y-SR of 45% (P = 0.001). Examining patients with major response exclusively, the prognosis of AC (2y-SR
85%) is better than that of SCC (2y-SR 54%) (P < 0.01).
Conclusion: This retrospective study concludes that in esophageal tumors, response to and prognosis after
neo-adjuvant CTx/RTx vary according to histology.
Key words: adenocarcinoma squamous cell carcinoma, esophageal cancer, lymph node metastases, neo-adjuvant
chemoradiation, prognosis
introduction
Increasingly, neo-adjuvant therapies are the standard of care in
the treatment of advanced esophageal carcinoma [1]. A number
of meta-analyses have been published investigating the effects
of preoperative chemo- or radiochemotherapy compared with
surgery alone [2–6]. Studies with neo-adjuvant chemotherapy
plus surgery compared with surgery alone did not demonstrate
a survival benefit for patients receiving neo-adjuvant therapy
[2, 7]. In contrast, neo-adjuvant chemoradiation plus surgery
improved 3-year survival and reduced local–regional cancer
recurrence. CTx/RTx was associated with a lower rate of
esophageal resection, but a higher rate of complete (R0)
resection. There was a (nonsignificant) trend toward increased
treatment mortality after neo-adjuvant chemoradiation [4].
*Correspondence to: Prof. E. Bollschweiler, Klinik und Poliklinik für Allgemein-, Visceralund Tumorchirurgie, der Universität zu Köln, Kerpener Str. 62, 50937 Köln, Germany.
Tel: +49-221-478 6273; Fax: +49-221-478 5076; E-mail: elfriede.bollschweiler@
uk-koeln.de
Similar results have been found by other authors [3, 5, 6]. In
these reviews, no differentiation of histological tumor type
[squamous cell carcinoma (SCC) or adenocarcinoma (AC)]
was made.
Radiation therapy plays an important role in the treatment of
esophageal SCC and is used for both definitive treatment and
the neo-adjuvant approach [8]. On the other hand, for patients
with AC of the esophagus or the gastroesophageal junction and
stomach, the clinical benefit of radiation remains a contentious
issue. Surgical resection still plays the decisive role in the
treatment of these tumor entities.
SCC and AC of the esophagus are assumed to have differing
biological behavior and this influences treatment choices. Some
authors have classified AC as a primarily systemic disease [9,
10]. They propose different treatment approaches for each
tumor entity, especially when neo-adjuvant therapy strategies
are discussed [11]. In studies comparing the effectiveness of
neo-adjuvant radiochemotherapy with that of surgery alone for
esophageal cancer, the investigators generally include either
ª The Author 2008. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: [email protected]
original
article
Patients and methods: Patients with uT3 carcinoma of the esophagus treated with curative-intention
original article
SCC patients alone or both histological types. Very few groups
have investigated patients with AC exclusively. In the first such
study, treatment was not carried out using current standards of
optimal fractionation and dosage and yet neo-adjuvant
radiochemotherapy still achieved a complete response (CR)
rate of 25% [12]. Gebski et al. [13] analyzed the treatment
effects by tumor type, showing more benefits of
radiochemotherapy in patients with AC compared with SCC.
Randomized studies like the MAGIC trial [14] and the SWOG
trial [15] have given new impetus to the debate regarding the
value of chemotherapy and radiotherapy in these patients.
The aim of the current retrospective study was to analyze
response and prognosis after neo-adjuvant radiochemotherapy,
comparing patients with advanced SCC and AC of the
esophagus.
patients and methods
patients
In all, 523 patients with esophageal cancer were treated at the Department
of Surgery between 1 January 1997 and 31 December 2006. Sixty-four
patients received nonsurgical palliative treatment due to advanced disease
or functional inoperability. A total of 459 patients were treated with surgical
resection. Of these, 297 patients had uT3 or uT4 tumors according to
endosonography (154 SCC and 143 AC) and were included in the study.
Written informed consent was obtained from all patients.
staging
Tumor–node–metastasis (TNM) staging was carried out according to the
criteria of the International Union Against Cancer [16]. Clinical staging was
on the basis of the results from barium swallow examination, endoscopy,
endoscopic ultrasound, and computed tomography (CT) of chest and
abdomen (4 mm sections). Endoscopy and endoscopic ultrasound were
carried out in a standardized manner for all patients.
therapy
Treatment of choice was subtotal en bloc esophagectomy using a right
transthoracic approach including two-field lymphadenectomy of
mediastinal and abdominal lymph nodes [17]. In 34 cases, a transhiatal
subtotal esophagectomy was carried out because of poor physical condition
or special situations [18]. The specimens were removed en bloc, including
the lymph nodes. To ensure primary tumor integrity, the lymph nodes were
dissected partially in the operating theater and partially by pathologists
according to a standardized protocol. The examined lymph nodes were
documented according to the sixth edition of the TNM classification [16].
The median number of examined lymph nodes was 27 (minimum 2 to
maximum 58) for SCC and 28 (minimum 11 to maximum 74) for AC
(difference not significant).
Standard reconstruction for patients receiving transthoracic
esophagectomy was done by stomach interposition with high intrathoracic
esophagogastrostomy [17]. After January 2004, laparoscopic mobilization
of the stomach including the cardia and preparation of the gastric conduit
was done with esophagectomy and reconstruction by gastric pull-up and
intrathoracic esophagogastrostomy in a two-time setting (see [19]). Two
patients underwent esophagogastrectomy, with colon interposition. The R0
resection rate was 93% (n = 276); R1, n = 20 and R2, n = 1.
Locally advanced tumors (uT2–4) were included in this study unless
documented systemic metastases or bronchoscopically proven invasion of
the tracheobronchial tree was present. Preoperative risk factors of all
patients were monitored with standardized criteria: a composite risk score
to evaluate the pulmonary, cardiovascular, hepatic, renal, and endocrine
232 | Bollschweiler et al.
Annals of Oncology
function as well as the general health status of patients using objective and
subjective parameters [20, 21]. Patients with higher risk received no
preoperative therapy (risk score >21 points according to risk analysis).
Limits for neo-adjuvant chemoradiation were set for ages 75 years or
younger, and creatinine clearance at least 60 ml/min. Patients with liver
cirrhosis were also excluded. Patients with previous malignancies were
disallowed, with the exception of surgically cured basal cell skin cancer and
carcinoma in situ of the cervix.
One hundred and ninety-two patients (65%) received preoperative
radiochemotherapy according to a standardized protocol, which is
described in detail elsewhere [22]. Patients with uT2 tumors were offered
this treatment protocol when CT showed a tumor mass compatible with
a T3 category while endoscopic ultrasound showed complete invasion of
the muscularis propria without clear invasion of the adventitia (so-called
‘near T-3 categories’). Cisplatin (20 mg/m2/day) was administered
as a short-term infusion on days 1–5 and 5-fluorouracil (5-FU)
(1000 mg/m2/day) as a continuous infusion over 24 hours on days 1–5.
Radiation therapy was administered by linear accelerators with 10–15 MV
photons. Radiation therapy was planned to encompass the tumor volume
with 5 cm cephalocaudal margins and 2 cm radial margins, and the
planning target volume included enlarged regional nodes based on CT
evaluation and endoscopic ultrasound. Radiation was delivered in daily
fractions of 1.8 Gy (days 1–5, 8–12, 15–19, and 22–26) to a total dose of 36
Gy using a multiple field technique. Surgical resection was carried out 4–5
weeks following completion of chemoradiation, after clinical restaging.
The control group consisted of 105 patients with resected esophageal
cancer who were staged as pT3 tumor but received no preoperative
chemoradiation. The reasons for primary surgical resection were
exclusion criteria for chemoradiation like comorbidity, age, lack of
patient consent, etc.
pathology
Histopathologic examination of all resected specimens consisted of
thorough evaluations of tumor stage, residual tumor (R) category, grading,
and number of examined and involved lymph nodes.
The lymph nodes were counted and the maximum diameter of each node
was measured with a slide gauge. A series of sections from each node was
selected and stained with hematoxylin and eosin as well as with periodic
acid-Schiff. All dissected lymph nodes were microscopically analyzed for
metastatic disease. The ratio of the number of involved to examined
regional lymph nodes was termed the ‘lymph node ratio’ [18]. The ratio of
0.2 was used as a cut-off point to differentiate advanced lymph node
infiltration [23]. According to the sixth edition of the TNM classification
for tumors of the lower thoracic esophagus, metastasis in the celiac lymph
node group (LNG 9) was classified as M1a and in other nonregional
locations as M1b [16]. After neo-adjuvant therapy, the pathological
assessment is difficult because of possible tumor regression. Thus, such
a classification is identified with the prefix ‘y’ to indicate decreased
reliability compared with the pTNM classification after surgery alone.
histopathologic response classification
The degree of histomorphologic regression was classified into four
categories (Cologne Regression Grade): grade I >50% vital residual tumor
cells (VRTCs), grade II 10%–50% VRTC, grade III nearly complete
response with <10% VRTC, and grade IV CR [22, 24]. This analysis was
carried out by two independent staff pathologists who were blinded to all
other clinical data. Due to prognostic implications, regression grades III
and IV were classified as major histomorphologic response compared with
grades I and II, which constituted minor histopathologic response.
Histopathologic tumor regression is the most significant independent
prognostic indicator [22].
Volume 20 | No. 2 | February 2009
original article
Annals of Oncology
statistics
Beginning in 1997, data were collected prospectively according to
a standardized protocol. The median, with the lower (LQ) and upper (UQ)
quartiles, was used for descriptive statistics. Chi-square statistics were
calculated for frequencies of factors with a significance level of P < 0.05.
The median follow-up time was calculated using the time between the
date of surgery and the date for patients reaching the end point and the
time between surgery and the date of censoring for censored patients [25].
The median follow-up time of the patients was 4.5 years (range 1.0–11.2
years).
Kaplan–Meier plots were used to describe survival distribution [26]. The
log-rank test was used to evaluate for survival differences [27]. For multiple
comparisons, the Holm–Sidak method was used. In addition, 95%
confidence intervals (CIs) for the different survival curves were calculated.
Postoperative mortality was not included in the calculation of prognosis.
The 30-day postoperative mortality was 3.0%. The multivariate analysis of
survival used Cox regression analysis to identify independent prognostic
variables. The level of significance was set to P < 0.05.
All statistical analyses were carried out using the statistic program
SPSS for Windows version 15.0. For graphic presentation of the results,
MedCalc version 9.3 was used.
results
In all, 297 patients were included in the study. Gender
distribution was 235 (79%) males and 62 females. The median
age was 61 years: the youngest patient was 21 and the oldest
81 years old. Table 1 compares the demographics and tumor
characterization of the different histological types.
response evaluation
In all, 192 of the patients with advanced esophageal carcinoma
received preoperative chemoradiation. The frequency of neoadjuvant therapy use did not differ according to histologic
tumor type (Table 1). Patients with SCC showed significantly
more frequent tumor size reduction characterized by ypT
category than those with AC (Table 2). Comparing
histomorphologic tumor regression, only one-third of 92
AC patients showed major histomorphologic response
(CR or <10% vital tumor cells) after neo-adjuvant
radiochemotherapy. In contrast, 50% of patients with
SCC were major responders (P < 0.01) (Table 3).
The median number of lymph node metastases (LNM) in all
patients was 1 (LQ = 1; UQ = 2). The rate of pN0 cases differed
significantly (P < 0.001) for patients without neo-adjuvant
therapy (25% pN0), compared with those with minor response
(39% ypN0) and with major response (71% ypN0). In addition,
the number of LNM in pN1 cases differed according to
therapeutic procedure and response rate (Figure 1). There were
no differences between the two histologic types regarding the
frequency of pN0/pN1 cases or ypN0/ypN1 cases for the
different procedures (Table 4), but patients without RTx/CTx
or those with minor response had significantly higher rates of
LNM in AC tumors compared with SCC (Table 4).
prognosis
The median survival time for all patients was 1.7 years (95% CI
1.3–2.1 years) and the 5-year survival rate was 23.4% (95%
CI 17% to 30%). There was no significant difference in the
survival of patients with esophageal AC (median survival 1.9
years, 95% CI 1.1–2.3 years) versus SCC (median survival 1.7
years, 95% CI 1.2–2.1 years). Patients with major response
had significantly better prognosis, with a 2-year survival rate
(2y-SR) of 78%, versus those with minor response or without
CTx/RTx, with a 2y-SR of 45% (P = 0.001).
The univariate survival analysis for cases with R0 resection
showed significant prognostic impact only for major response
after neo-adjuvant therapy (Figure 2) and pN/pM category.
In the multivariate analysis, only age, presence of lymph node
Table 1. Demographic and survival data of 297 patients with advanced esophageal carcinoma
SCC (n = 154)
n (%)
Gender
Male
Female
Age, median (minimum–maximum)
Neo-adjuvant therapy
No
Yes
R0 resection
No. of resected lymph node, median (LQ–UQ)
pM/ypM
M0
M1a
M1b
Transthoracic esophagectomy
30-day mortality
2-y SR for R0 cases; rate (95% CI)
5-y SR for R0 cases; rate (95% CI)
AC (n = 143)
n (%)
Significance
P < 0.0001
105 (68)
49 (32)
60 (29–80) years
130 (91)
13 (9)
63 (21–81) years
54
100
145
27
51
92
131
28
132
16
7
142
5/154
46%
19%
(35)
(65)
(94)
(19–35)
(85.1)
(10.4)
(4.5)
(92.2)
(3.2)
(36% to 53%)
(12% to 28%)
109
21
13
124
4/143
48%
30%
(36)
(64)
(92)
(22–35)
(76.2)
(14.7)
(9.1)
(86.7)
(2.8)
(37% to 56%)
(13% to 37%)
n.s.
n.s.
n.s.
n.s.
P < 0.01
n.s.
n.s.
n.s.
n.s.
SCC, squamous cell carcinoma; AC, adenocarcinoma; LQ, lower quartile; UQ, upper quartile; 2y-SR, 2-year survival rate; CI, confidence interval.
Volume 20 | No. 2 | February 2009
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Annals of Oncology
metastasis, and distant metastasis were independent prognostic
factors (Table 5).
Analyzing both histologic types separately, the prognosis was
not significantly different for SCC patients without neo-
Table 2. Frequency of downsizing of the tumor and patient survival
after neo-adjuvant radiochemotherapy for SCC or AC of the esophagus
(P < 0.02)
ypT category
SCC (n = 100)
n (%)
2y-SR (%)
AC (n = 92)
n (%)
2y-SR (%)
ypT0
ypT1
ypT2
ypT3
ypT4
27
5
23
45
0
10
8
16
57
1
(27)
(5)
(23)
(45)
73
38
49
38
(11)
(9)
(17)
(62)
(1)
76
73
53
52
adjuvant therapy compared with those with minor or major
responses (Figure 3). Only patients with path CR showed
a relevant survival benefit compared with the other groups
(Table 3). Of patients showing a major response, the prognosis
of AC (2y-SR 85%) was better than that of SCC (2y-SR 54%).
With multivariate analysis, the pN category was the only
significant prognostic factor (P < 0.01). In contrast, AC patients
with major response showed a 5-year survival rate of 71%,
a significant improvement over those with minor response or
without RTx/CTx (Table 3 and Figure 4). In addition,
compared with surgery-only patients, major response (P =
0.001), as well as pN (P < 0.001) and pM (P < 0.001) categories,
was significant in multivariate analysis.
discussion
The results of this study confirm the findings of previous
studies that the use of appropriate neo-adjuvant therapies in
patients with esophageal carcinoma can lead to reductions in
both tumor size and stage according to the pN category [3–6].
SCC, squamous cell carcinoma; AC, adenocarcinoma; 2y-SR, 2-year
survival rate.
Table 3. Results of therapy in patients with SCC or AC of the esophagus
SCC (n = 154)
n (%)
Neo-adjuvant therapy
No
Yes
Response rate after RTx/CTx
Minor response
Major response
Response rate after RTx/CTx
VRTC
Grade I >50%
Grade II 10%–50%
Grade III <10%
Grade IV path CR
R0 resection
No RTx/CTx
Minor response
Major response
2y-SR (95% CI) for R0 resection
No RTx/CTx
Minor response
Major response
2y-SR (95% CI) for R0 resection
No RTx/CTx
Grade I >50% VRTC
Grade II 10%–50% VRTC
Grade III <10% VRTC
Grade IV path CR (no VRTC)
5y-SR (95% CI) for R0 resection
No RTx/CTx
Minor response
Major response
AC (n = 143)
n (%)
Significance
n.s.
54 (35)
100 (65)
100
49 (49)
51 (51)
100
11
38
29
22
51
92
92
65
27
92
(11)
(38)
(29)
(22)
21
44
20
7
49/54 (91)
46/49 (95)
49/51 (96)
(30%
(15%
(19%
(26%
(50%
P < 0.01
(71)
(29)
P < 0.01
(23)
(48)
(22)
(7)
47/51 (92)
58/65 (89)
26/27 (96)
46% (30% to 58%)
39% (24% to 52%)
54% (36% to 66%)
46%
39%
39%
45%
81%
n.sa
23%
15%
20%
(36)
(64)
to
to
to
to
to
58%)
68%)
50%)
61%)
89%)
(11% to 35%)
(5% to 29%)
(7% to 40%)
n.s.
n.s.
n.s.
34% (19% to 46%)
43% (27% to 53%)
85% (60% to 95%)
n.s.
n.s.
P < 0.05
34% (19% to 46%)
37% (14% to 60%)
47% (30% to 63%)
80% (48% to 93%)
86% (53% to 98%)
P < 0.001a
14% (4% to 25%)
26% (11% to 45%)
73% (37% to 90%)
n.s.
n.s.
n.s
P = 0.001
n.s.
n.s.
n.s.
P < 0.04
a
Log-rank test for differences between survival in cases without RTx/CTx compared with cases with minor response and major response.
SCC, squamous cell carcinoma; AC, adenocarcinoma; VRTC, vital residual tumor cells after neo-adjuvant chemoradiation (RTx/CTx) according the Cologne
Regression Grade; SR, survival rate
234 | Bollschweiler et al.
Volume 20 | No. 2 | February 2009
original article
Annals of Oncology
After induction therapy, SCCs showed significantly more
frequent tumor regression (50% major response) than ACs
(33% major response). This was true not only for major
regression but also for the frequency of path CRs, which in this
Figure 1. Number of lymph node metastases in 192 patients with cT2–4
esophageal cancer posttransthoracic esophagectomy with minor or major
response after neo-adjuvant RTx/CTx, compared with 105 patients with
pT3 tumor without neo-adjuvant RTx/CTx.
cohort was 22% of SCC and 7% of AC patients. This appears
to confirm the prevailing opinion that AC responds less than
SCC to radiation [28]. Geh et al. systematically reviewed the
benefits of radiation as well as response rates from neoadjuvant chemoradiation with 5-FU, including studies
published between 1983 and 1997. Of 1012 patients included,
only 367 had esophageal AC. Studies including SCC exclusively
have shown an average CR rate of 25% and those with AC
17% [29]. Similar results have been reported from Ireland
with a path CR of 19% for AC and 33% for SCC [30].
However, in many studies investigating the use of neo-adjuvant
radiochemotherapy for esophageal carcinoma, no
differentiation between histological tumor types and efficacy
of treatment has been made.
The differences in histomorphologic response to treatment
could be a result of the type of therapy for one and of the
quality of pathologic findings for another. The review of Geh
et al. reported a dose–response relationship between increasing
protocol prescribed radiotherapy, 5-FU and cisplatin doses, and
path CR. Another significant factor was radiotherapy treatment
time [29]. This review showed that the probability of path
CR improved with increasing doses of radiotherapy (P = 0.006),
5-FU (P = 0.003), and cisplatin (P = 0.018). In contrast,
increasing radiotherapy treatment time (P = 0.035) and
increasing median age (P = 0.019) reduced the probability of
Table 4. Downstaging of pN category after neo-adjuvant chemoradiation in patients with SCC and AC of the esophagus
pN1
No RTx/CTx
Minor response
Major response
No. of lymph node metastasis in pN1 cases (median, LQ–UQ)
No RTx/CTx
Minor response
Major response
Lymph node ratio (LNR)
No RTx/CTx
pN0
LNR <0.2
LNR ‡0.2
Minor response
pN0
LNR <0.2
LNR ‡0.2
Major response
pN0
LNR <0.2
LNR ‡0.2
SCC (n = 154)
n (%)
AC (n = 143)
n (%)
Significance
39/54 (72)
33/49 (69)a
17/51 (33)c
P = 0.058e
3.0 (1.0–7.0)
3.0 (1.0–4.0)
2.0 (1.0–2.8)
40/51 (78)
36/65 (55)b
6/27 (22)d
P = 0.04e
6.0 (3.0–14.8)
4.0 (2.0–9.0)
2.0 (1.8–4.3)
n.s.
n.s.
n.s.
54
15 (28)
34 (55)
9 (17)
49
16 (33)
24 (49)
9 (18)
51
33 (65)
17 (33)
1 (2)
51
11 (22)
21 (41)
19 (37)
65
29 (45)
20 (31)
16 (24)
27
21 (78)
6 (22)
0
P < 0.01
P < 0.01
n.s.
P < 0.05
n.s.
n.s.
a
Comparison between SCC without RTx/CTx and SCC with minor response: P = 0.56
Comparison between AC without RTx/CTx and ACC with minor response: P < 0.02
c
Comparison between SCC with minor response after RTx/CTx and major response: P < 0.002
d
Comparison between AC with minor response after RTx/CTx and major response: P < 0.01
e
Kruskal–Wallis analysis for comparison of number of lymph node metastases in cases without RTx/CTx compared with cases with minor response and
major response.
SCC, squamous cell carcinoma; AC, adenocarcinoma; LQ, lower quartile; UP, upper quartile; LNR, lymph node ratio.
b
Volume 20 | No. 2 | February 2009
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Annals of Oncology
path CR. However, low dosage of radiation reduced the risks of
postoperative morbidity and mortality. Our study protocol,
with 36 Gy and one cycle chemotherapy (100 mg/m2 and 5000
mg/m2 5-FU), is in the median range of published study
protocols [13, 29]. The advantage of the current study is that all
patients were treated with the same protocol regardless of
histologic tumor type, so that varying therapies could not
affect the results.
Figure 2. Kaplan–Meier survival curve for patients with R0-resected
cT2–4 esophageal cancer after neo-adjuvant RTx/CTx with minor or major
response, compared with patients with pT3 tumor without RTx/CTx
(P = 0.005).
Various systems and classifications have been developed to
evaluate histopathologic response. According to the World
Health Organization (WHO), clinical response is graded as
complete, partial (>50% tumor regression), minor/no change
(<50% tumor regression), or progressive disease [31]. In an
effort to evaluate response to neo-adjuvant therapy objectively,
morphologic criteria have been defined for several cancers,
including lung, [32] stomach [33], and esophagus [34, 35].
In the current study, we used the Cologne Regression
Classification System [22, 24], a modified system based on
Junker et al. [32], that also considers clinical response
evaluation according to WHO [31]. This type of classification
has been used by other authors [33, 36]. Wu et al. [37]
evaluated the quality of grading for the extent of residual
carcinoma after preoperative chemoradiation in esophageal
and esophagogastric junction carcinoma and reported that
interobserver variability, particularly for the determination of
path CR, is very small.Similar results were reported by Chang
et al. [38]. They reanalyzed archived tumor blocks of
esophageal carcinoma classified by routine pathology as path
CR. They concluded that inadequate pathologic examination is
likely not a major factor in the suboptimal survival of patients
with path CR. One can conclude, therefore, that interstudy
comparisons of path CR rates are reliable.
Currently, it is less well recognized that patients with
esophageal AC benefit from this neo-adjuvant therapy regimen.
In a meta-analysis, Gebski compared patients with AC and SCC
and found no difference in survival. The hazard ratio for
all-cause mortality with neo-adjuvant radiochemotherapy
versus surgery alone was 0.81, with similar results for different
Table 5. Univariate and multivariate survival analysis for patients with R0-resected esophageal cancer after transthoracic esophagectomy (n = 275)
Factor
Gender
Male
Female
Age
<50 years
50–70 years
>70 years
Histology
SCC
AC
Response
Only surgery
Minor
Major
pN category
pN0
pN1
pM category
pM0
pM1a
pM1b
Univariate analysis
Survival time
median (95% CI)
Significance
Multivariate analysis
Hazard
ratio
95% CI
n.s.
2.0 (1.5–2.4) years
2.3 (1.7–2.9) years
n.s.
1 (ref)
0.8
0.5–1.3
P = 0.051
4.8 (0.8–8.7) years
2.0 (1.6–2.3) years
1.6 (1.0–2.3) years
P = 0.04
1 (ref)
1.7
2.4
1.1–3.0
1.2–4.6
n.s.
1.9 (1.4–2.4) years
2.1 (1.2–3.0) years
n.s.
1 (ref)
0.8
0.6–1.3
P = 0.005
1.7 (1.2–2.3) years
1.8 (1.0–2.7) years
3.8 (2.7–4.9) years
n.s.
1 (ref)
1.2
0.8
0.8–1.8
0.5–1.3
P < 0.001
3.6 (2.5–4.7) years
1.3 (0.9–1.7) years
P < 0.01
1 (ref)
1.8
1.2–2.6
P < 0.001
2.3 (1.9–2.7) years
1.1 (1.0–1.2) years
0.7 (0.2–1.2) years
Significance
P < 0.01
1 (ref)
1.2
2.9
0.8–1.9
1.6–5.6
CI, confidence interval; ref = reference value; SCC, squamous cell carcinoma; AC, adenocarcinoma.
236 | Bollschweiler et al.
Volume 20 | No. 2 | February 2009
original article
Annals of Oncology
Figure 3. Kaplan–Meier survival curve for patients with R0-resected cT2–
4 squamous cell carcinoma of the esophagus after neo-adjuvant RTx/CTx
with minor or major response, compared with patients with pT3 tumor
without RTx/CTx (no significance).
We compared the data of patients receiving neo-adjuvant
therapy with that of patients treated with primary
esophagectomy and histologically diagnosed as pT3 category.
Surprisingly, the surgery-only patients had no worse prognosis
than patients having a minor response to neo-adjuvant therapy.
Of course, this comparison shows some selection bias.
However, one can assume that the non-neo-adjuvant patients
show more negative selection bias. In a population-based study
evaluating neo-adjuvant therapy for esophageal carcinoma in
Sweden, patients having a minor response to pretreatment had
worse prognoses than patients treated with surgery alone [44].
Prospective studies with multivariate analysis considering
previous medical history and age have shown that after primary
surgery, histology of the tumor has no particular impact on
prognosis [23]. For this reason, the differing prognoses for
patients with path CR after neo-adjuvant radiochemotherapy
can be attributed to that therapy. Rohatgi et al. reported
comparable results in a study of 235 patients receiving neoadjuvant radiochemotherapy. The majority of patients (82%)
had esophageal AC. The authors analyzed survival as a function
of histological type with adjustment of exit variables. In the
SCC patient group, the prognosis after path CR was not
significantly different than that of patients with minor response
to neo-adjuvant radiochemotherapy. In contrast, AC patients
with path CR had a significantly better survival rate than minor
responders and a 5-year survival >60% [45].
conclusion
This retrospective study concludes that patients with uT3
esophageal AC have less frequent complete or major response
to neo-adjuvant therapy with 5-FU, cisplatin, and 36-Gy
radiation compared with patients with esophageal SCC.
However, AC patients showing major response have a markedly
better prognosis than those with SCC. The reasons for this
difference require further evaluation.
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Figure 4. Kaplan–Meier survival curve for patients with R0-resected cT2–
4 adenocarcinoma of the esophagus after neo-adjuvant RTx/CTx with
minor or major response, compared with patients with pT3 tumor without
RTx/CTx (P < 0.001).
histological tumor types [13]. In the current study, there was
no significant difference in the overall prognosis of AC and
SCC patients. However, AC patients with a major histologic
response to neo-adjuvant therapy had a significantly better
prognosis than those with SCC. The 73% 5-year survival rate in
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For SCC patients, only a path CR to neo-adjuvant therapy
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