Keywords
Carcinoma Esophagus - pathological complete response - preoperative chemoradiation
Introduction
Esophageal cancer is the fourth most common cause of cancer-related deaths in India.
Squamous cell carcinoma is the most common histology (80%) although there has been
a recent relative increase in the incidence of adenocarcinoma.[1]
In 2012, a multi-institutional Phase III study (CROSS trial) evaluated the benefit
of induction therapy using weekly carboplatin and paclitaxel with 41.4 Gy radiation
versus surgery alone.[2] The pathological complete response (pCR) rate was 28%, and overall survival was
much improved in the combined therapy arm. However, there is limited data regarding
the outcomes of preoperative chemoradiation in Indian scenario. Esophageal cancer
in India has a unique etiological basis (alternative forms of tobacco and tea drinking).[1] Most patients present in advanced stage and poor general health at diagnosis. This
retrospective study was conducted to determine the response to preoperative chemoradiation
at a tertiary care center in India.
Aims
Primary objective was to evaluate the rates of pCR and to determine the significance
of various factors affecting pCR. Secondary objective was to determine the recurrence
rate and patterns of recurrence.
Materials and Methods
We retrospectively reviewed patients with locally advanced esophageal cancer (middle
and lower third) and gastroesophageal junction (Siewert I and II) treated at our hospital
from September 2013 to July 2015. These patients were selected from a larger cohort
of operable esophageal cancer patients as they were planned for neoadjuvant chemoradiation
followed by surgery. Information on demographic data, initial investigations, and
treatment administered were recorded from our hospital database for 50 patients. The
pretreatment workup included a physical examination, esophagogastroscopy and biopsy,
chest and abdominal computed tomography (CT), and 18F-fluorodeoxyglucose-positron
emission tomography, if necessary. After completion of neoadjuvant chemoradiotherapy
and before surgery, all patients were imaged with CT abdomen and pelvis. Patients
who received preoperative radiotherapy dose of 41.4 Gy with chemotherapy (weekly paclitaxel-carboplatin
or cisplatin-5 FU or cisplatin-capecitabine) were included in this study. The outcomes
analyzed were pCR, recurrence rate, and recurrence patterns. An ethics committee approval
was taken before starting the study. An informed consent was taken from all study
participants.
Treatment
Radiotherapy
External beam radiotherapy was administered using LINAC 6MV or 15MV photons. Radiation
technique was based on the discretion of the radiation oncologist. Total dose delivered
was 41.4 Gy in 23 fractions of 1.8 Gy, 5 fractions per week. Thirty-nine patients
were treated by conventional technique, 4 patients by 3DCRT, and 7 patients by IMRT
technique. The gross tumor volume (GTV) was defined by the primary tumor and any enlarged
regional lymph nodes. The planning target volume was defined by giving a proximal
and distal margin of 4 cm. In case of tumor extension into the stomach, a distal margin
of 3 cm was chosen. A 2 cm radial margin around the GTV was provided to include the
area of subclinical involvement and to compensate for tumor motion and set up variations.
Chemotherapy
Chemotherapy was administered concurrently on the 1st day of radiotherapy (RT). Only
patients who received concurrent chemotherapy regimen of paclitaxel and carboplatin
or cisplatin and 5 fluorouracil or cisplatin and capecitabine were included in the
analysis.
Surgery
Surgery was scheduled for 6–8 weeks after preoperative chemoradiotherapy. Complete
resection (R0) was characterized by negative margins on microscopic examination. Incomplete
resection was determined by the presence of microscopic residual disease (R1) or gross
residual disease (R2).
Evaluation of response
Pathologic response evaluation was performed by analyzing surgical specimens. A pCR
was defined by the absence of histologically identifiable residual cancer in the tumor
and lymph nodes and fibrosis extending through the different layers of the esophagus.
Follow-up
The patients were followed up postsurgery at 1 month initially, then every 3 months
for first 2 years and every 6 months till 5 years and yearly thereafter, to determine
recurrence rates, recurrence patterns, and mortality.
Statistical analysis
Patients were followed up periodically until the last follow-up or death. Postoperative
mortality was defined as death on the day of surgery or within 30 days postsurgery.
The relationship of various prognostic factors with pCR was computed using Chi-square
test and Fischer's exact test SPSS is a statistical software (statistical package
for the social sciences). P < 0.05 was considered statistically significant.
Results
A total of 50 patients were included in the analysis (females – 32, males – 18). The
median age was 50 years (22–70 years). All patients had ECOG PS <2 at the time of
starting treatment. The clinico demographic characteristics are summarized in [Table 1].
Table 1
Clinico demographic characteristics of the study population (n=50)
|
Parameter
|
Subsite
|
|
3D CRT – Three-dimensional conformal radiotherapy; IMRT – Intensity-modulated radiation
therapy; GE – Gastroesophageal
|
|
Tumor site (%)
|
|
Middle third
|
18 (36)
|
|
Lower third
|
22 (44)
|
|
GE junction
|
10 (20)
|
|
Histology (%)
|
|
Squamous cell carcinoma
|
38 (76)
|
|
Adenocarcinoma
|
12 (24)
|
|
Grade (%)
|
|
Well differentiated
|
6 (12)
|
|
Moderately differentiated
|
16 (32)
|
|
Poorly differentiated
|
28 (56)
|
|
Technique (%)
|
|
Conventional
|
39 (78)
|
|
3D CRT
|
4 (8)
|
|
IMRT
|
7 (14)
|
|
Chemotherapy (%)
|
|
Paclitaxel-carboplatin
|
30 (60)
|
|
Cisplatin-5-fluorouracil
|
16 (32)
|
|
Cisplatin-capecitabine
|
4 (8)
|
All patients received 41.4 Gy preoperative radiotherapy in 23 fractions. About 60%
of the patients (30/50) received weekly paclitaxel and carboplatin (CROSS protocol),
32% (16/50) patients received cisplatin and 5 fluorouracil, and 8% (4/50) received
cisplatin and capecitabine combination chemotherapy. The neoadjuvant chemotherapy
details are described in [Table 2].
Table 2
Details of preoperative chemotherapy regimens
|
Chemotherapy
|
Dose and schedule
|
5 cycles
|
4 cycles
|
3 cycles
|
2 cycles
|
1 cycles
|
pCR
|
|
AUC – Area under the curve; pCR – Pathological complete response
|
|
Paclitaxel
|
26
|
3
|
1
|
-
|
-
|
14 (48.3%)
|
|
Carboplatin
|
50 mg/m2 AUC=2 (weekly)
|
|
Cisplatin
|
75 mg/m2 (D1)
|
-
|
1
|
6
|
7
|
2
|
4 (25%)
|
|
5 fluorouracil
|
1000 mg/m2 (D1-D4)
|
|
Cisplatin
|
40 mg/m2 (D1)
|
3
|
1
|
-
|
-
|
-
|
1 (33.3%)
|
|
Capecitabine
|
40 mg/m2 (D1) 1000 mg (D1-D14)
|
After receiving preoperative chemoradiotherapy, two patients progressed on treatment
and did not undergo surgery. These patients were censored at the time of analysis.
The remaining 48 patients underwent surgery at a median time of 8-week postchemo radiation
(4–18 weeks). All patients (100%) achieved R0 resection. pCR (ypT0N0) was achieved
in 19 patients (39.6%). When histology was analyzed separately, 44.7% of the resected
squamous cell carcinoma achieved a pCR whereas only 20% of adenocarcinomas achieved
a pCR. About 48.3% (14 out of 29) of patients who received preoperative radiotherapy
along with weekly carboplatin–paclitaxel achieved a pCR as compared to 25% pCR rate
for cisplatin-5 FU and 33.3% pCR rate for cisplatin–capecitabine. When the impact
of age, gender, histology, tumor site, radiation technique, and chemotherapy was analyzed,
none of the factors were significant [Table 3].
Table 3
Factors associated with pathological complete response in patients with esophageal
carcinoma treated with preoperative chemoradiation and surgery (n=48)
|
Study characteristics
|
Total
(n)
|
Pathological complete
response achieved, n (%)
|
P
|
|
3D CRT – Three-dimensional conformal radiotherapy; IMRT – Intensity-modulated radiation
therapy; GE – Gastroesophageal; CDDP – Cis diamminedichloridoplatinum
|
|
Age (years)
|
|
<50
|
23
|
11 (47.8)
|
0.263
|
|
≥50
|
25
|
8 (32.0)
|
|
Gender
|
|
Male
|
18
|
5 (27.8)
|
0.195
|
|
Female
|
30
|
14 (46.7)
|
|
Histopathology
|
|
Squamous cell
|
38
|
17 (44.7)
|
0.276
|
|
carcinoma
|
|
Adenocarcinoma
|
10
|
2 (20%)
|
|
Tumor site
|
|
Middle third
|
17
|
9 (52.9)
|
0.311
|
|
Lower third
|
21
|
6 (28.6)
|
|
GE junction
|
10
|
4 (40.0)
|
|
Radiation therapy
|
|
Conventional
|
37
|
14 (37.8)
|
0.732
|
|
3D CRT/IMRT
|
11
|
5 (45.5)
|
|
Chemotherapy
|
|
Carboplatin-paclitaxel
|
29
|
14 (48.3)
|
0.303
|
|
CDDP-5-fluorouracil
|
16
|
04 (25.0)
|
|
CDDP-capecitabine
|
3
|
1 (33.3)
|
At a median follow-up of 12 months, 38 patients were alive, 8 dead, and 4 lost to
follow-up. All patients who achieved a pCR were alive and disease free at the time
of final analysis.
Out of the 8 patients who died, 7 deaths were related to cancer. One patient died
due to cerebrovascular accident. The postoperative mortality rate was 0% as none of
the patients died within 30 days of surgery. Isolated locoregional failure was developed
in 1 patient. Synchronous local and distant failure occurred in 1 patient. Eight patients
(80% of all recurrences) developed distant metastases as the first site of recurrence.
Distant sites of metastasis included the lung (n = 4), liver (n = 2), and cervical
lymph nodes (n = 2). Overall recurrence rate (ORR) of patients who underwent surgery
was 23%.
Discussion
Preoperative CRT has been used in the treatment of carcinoma esophagus and gastroesophageal
junction for decades and has shown good curative effects in local control and prolonged
overall survival. In the multi-institutional Phase III study (CROSS trial)[2] which evaluated the benefit of induction therapy using weekly carboplatin and paclitaxel
along with 41.4 Gy radiation versus surgery alone, only a quarter of the patients
had squamous histology. Median survival was 49 months in the combined therapy arm
compared to 24 months in the surgery arm (P = 0.003). The overall 5-year survival
was much improved in the combined therapy arm (47% vs. 34%, P = 0.003). Patients with
squamous histology derived a larger benefit.
Achieving a pCR has been known to be a powerful prognostic factor in patients treated
with trimodality therapy. Scheer et al.[3] reported that patients with a pCR after neoadjuvant chemoradiotherapy (NCRT) survived
at a rate two times higher than that of other patients. Rohatgi et al.[4] suggested that failure patterns were correlated with the proportion of residual
carcinoma after NCRT, implying worse survival of patients who had more residual disease
after NCRT. In the CROSS trial, 29% patients had a pCR (ypT0N0) after neoadjuvant
chemoradiotherapy. One or more pathologically positive lymph nodes were found in 74%
of patients in the surgery arm and in 31% of those in the CRT plus surgery arm (P
= 0.001). The pCR rate in our study was 39.6% in the entire patient cohort, which
was higher than that of the patients in the CROSS trial. However, the pCR rate of
squamous cell carcinoma patients in our study was 44.7% whereas only 20% patients
with adenocarcinoma achieved a pCR, which was comparable to the pCR rates achieved
in the CROSS trial squamous cell carcinoma and adenocarcinoma patients (49% and 23%,
respectively). Among the patients who received 41.4 Gy preoperative radiotherapy with
weekly paclitaxel and carboplatin (CROSS regimen), the pCR rate was 48.3%. The complete
resection rate (R0) in our study was 100%, which was comparable to the 92% reported
by the randomized controlled CROSS trial. Schneider et al.[5] performed a study evaluating the response to trimodality therapy and found that
the 3-year survival rate of R0 patients was 54%, while all non-R0 resection patients
died within 3 years.
An updated analysis of the CROSS trial group [6] showed a lower local recurrence rate (34% vs. 14%, P < 0.001) and lower risk of
peritoneal carcinomatosis (14% vs. 4%, P < 0.001) following neoadjuvant chemoradiation
and that squamous cell carcinoma was an independent prognostic variable in the surgery
alone group. Most patients diagnosed with locoregional recurrences (LRRs) also developed
synchronous distant metastases. Of the patients undergoing resection, 24% and 11%
had concurrent LRRs and distant relapses and only 9.3% and 3.3% had an isolated LRR
in the surgery and CRT plus surgery arms, respectively. Another meta-analysis by Sjoquist
et al.[7] on survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable esophageal
carcinoma concluded that there was a 13% absolute difference in survival at 2 years
neoadjuvant chemoradiotherapy versus surgery alone, with similar results for different
histological tumor subtypes (squamous cell carcinoma vs. adenocarcinoma). An update
of this meta-analysis [8] provided strong evidence for a survival benefit of neoadjuvant chemoradiotherapy
or chemotherapy over surgery alone in patients with esophageal carcinoma.
In our study, ORR was 23%. Of the ten patients that recurred, 1 (10%) patient had
isolated loco regional failure, 8 patients (80% of all recurrences) developed distant
metastases, and 1 (10%) patient had concurrent loco regional and distant failure.
At a median follow-up of 9.5 months, 8 patients were dead. Since the median follow-up
is short, it was not possible to comment on survival. Future prospective studies with
planned preoperative chemoradiation plus surgery involving a more consistent treatment
policy across a homogeneous patient cohort and longer follow-up are required.
Our study has certain limitations. First, the concurrent chemotherapy protocols are
not uniform in the group of patients treated. Second, the short median duration of
follow-up makes any interpretation of recurrences and survival premature. However,
this study provides important insights into the pathological responses and recurrence
patterns which are indirect predictors of overall survival. We believe that this study
is the first study from India reporting outcomes after administration of preoperative
chemoradiation as per CROSS trial regimen (41.4 Gy radiotherapy along with weekly
paclitaxel and carboplatin).
Conclusion
In our study, preoperative chemoradiotherapy in carcinoma esophagus was associated
with encouraging pCR rates (39.6%) and high rates of R0 resection. pCR rates were
higher among patients receiving CROSS protocol regimen and in squamous cell carcinomas.
Most of the recurrences were distant recurrences.
