Introduction: Esophageal carcinoma is the eight most common cancer in the world. The management of locally advancedcarcinoma esophagus is mainly palliative with chemoradiotherapy. The outcome data of such a modality along with oralmetronomic chemotherapy after treatment completion are sparse. Here, we present the outcomes of treatment of locally advancedunresectable esophageal cancer after palliative chemoradiotherapy and oral metronomic therapy from a rural setting in India.Methods: Retrospective analysis of all patients of locally advanced unresectable nonmetastatic esophageal carcinoma treatedwith short course of induction chemotherapy followed by radiotherapy/chemoradiotherapy and oral metronomic chemotherapywas performed. The primary aim was estimation of progression free-survival (PFS) and overall survival (OS). Results: A total of45 patients were analyzed. Mean age was 55 years (30-85 years). A total of 32 patients had tumors in upper and middle esophagus,with the most common histology being squamous cell carcinoma (N-41). The estimated 2 year PFS is 47.2% and the estimated2 years OS is 57.8%. Conclusion: Combined modality therapy with adjuvant oral metronomic therapy shows promising results inthe management and should be the basis of further trials

Banavali, S D

Chandrakanth, M V

Desai, A

Ghosh, Joydeep

Kulkarni, A

Mandhare, Amit

Pokharkar, Ashish

Sharma, Nandini

English

Atharva Scientific Publications (E-Jounals)

Vol 1 | Issue 2 | Oct - Dec 2016 Eastern J Medical Sciences 50
Original Article
Outcomes of treatment of unresectable esophageal carcinoma treated with 
chemoradiotherapy and oral metronomic chemotherapy: An experience from a 
rural cancer center
Joydeep Ghosh1, Nandini Sharma2, A Kulkarni3, S D Banavali1, Ashish Pokharkar4, A Desai5, 
Amit Mandhare6, M V Chandrakanth1
Departments of 1Medical Oncology, and 4Surgical Oncology, Tata Memorial Hospital, Mumbai, Departments of 2Medical Oncology, 3Radiation 
Oncology, and 5Surgical Oncology, BKL Walawalkar Hospital, Derwan, Chiplun, Maharashtra, India
Correspondence to: Dr. Joydeep Ghosh, Deparment of Medical Oncology, Tata Memorial Hospital, Parel, Mumbai, India. 
E-mail: dr.joydeep.ghosh@gmail.com
Received – 03 November 2016 Initial Review – 20 November 206 Published Online – 18 December 2016
Esophageal carcinoma is the world’s eighth most common cancer. In developing countries, the estimated incidence in 282,000 cases/year, of which 223,000 patients die [1]. The 
outcome of esophageal cancer is poor, with only 18% of patients 
surviving at 5 years [2]. The survival depends on the stage. Most 
of the esophageal cancers are locally advanced at presentation, 
with stage II and III comprising 80% of cases [3].
In unresectable tumors, the treatment is largely palliative. The 
commonly used palliative measures are stenting, radiotherapy, 
chemotherapy, and combined modality chemoradiotherapy. 
Chemoradiotherapy has shown better survival compared to 
radiotherapy alone [4,5]. Even with combined modality treatment, 
the median survival is in the range of 9-12 months in major 
studies [4]. Severe toxicities occur in 40-50% of cases treated 
with concurrent chemoradiotherapy. It is the most common cause 
of stoppage of treatment before completion.
Taxanes have demonstrated significant activity in esophageal 
cancer. The commonly used taxanes are paclitaxel and docetaxel. 
Platinum agents such as cisplatin and carboplatin have traditionally 
being efficacious in esophageal cancers. The combination of 
paclitaxel with carboplatin is a moderately active and tolerable 
regimen in advanced esophageal cancer, when used in a 3 weekly 
regimen [6]. This combination has produced response rates of 
60% [7].
In a study by Noronha et al., where metronomic weekly 
paclitaxel was used, median progression free survival (PFS) was 
4.7 months and median overall survival (OS) was 7.5 months [8]. 
There is no data till now on the outcomes of esophageal cancer 
from the rural setting. Here, in this study, we analyzed the outcomes 
of treatment of locally advanced unresectable esophageal cancer 
from a rural hospital.
MATERIALS AND METHODS
This is a retrospective analysis from the Oncology Department 
of BKL Walawalkar Hospital, Derwan, Chiplun, Maharashtra, 
India. Patients with advanced cancer of the esophagus or 
gastroesophageal junction, both adenocarcinoma and squamous 
cell carcinoma, who were treated with curative intent, were 
included in the study. All patients were evaluated at baseline, 
including history and physical examination, laboratory 
parameters, upper endoscopy (if indicated), and imaging studies.
ABSTRACT
Introduction: Esophageal carcinoma is the eight most common cancer in the world. The management of locally advanced 
carcinoma esophagus is mainly palliative with chemoradiotherapy. The outcome data of such a modality along with oral 
metronomic chemotherapy after treatment completion are sparse. Here, we present the outcomes of treatment of locally advanced 
unresectable esophageal cancer after palliative chemoradiotherapy and oral metronomic therapy from a rural setting in India. 
Methods: Retrospective analysis of all patients of locally advanced unresectable nonmetastatic esophageal carcinoma treated 
with short course of induction chemotherapy followed by radiotherapy/chemoradiotherapy and oral metronomic chemotherapy 
was performed. The primary aim was estimation of progression free-survival (PFS) and overall survival (OS). Results: A total of 
45 patients were analyzed. Mean age was 55 years (30-85 years). A total of 32 patients had tumors in upper and middle esophagus, 
with the most common histology being squamous cell carcinoma (N-41). The estimated 2 year PFS is 47.2% and the estimated 
2 years OS is 57.8%. Conclusion: Combined modality therapy with adjuvant oral metronomic therapy shows promising results in 
the management and should be the basis of further trials.
Key words: Esophageal cancer, Chamoradiotherapy, Metronomic Chemotherapy
Vol 1 | Issue 2 | Oct - Dec 2016 Eastern J Medical Sciences 51
Ghosh et al. Chemoradiotherapy followed by metronomic chemotherapy in locally advanced esophageal cancer
The common treatment protocol followed in this hospital is 
8 cycles of weekly combination chemotherapy with paclitaxel 
80 mg/m2 intravenous as a 1 h infusion given weekly with 
standard pre-medications, including antihistamines, antiemetics, 
H2 antagonists and steroids, along with carboplatin area under 
curve (AUC) 2 or cisplatin 30 mg/m2 as a 1 h infusion with 
standard hydration preceding and following cisplatin. Each dose 
of chemotherapy was considered one cycle. Similar regimen was 
used in the chemoradiotherapy setting except that the dose of 
paclitaxel was reduced to 50 mg/m2. Complete blood count was 
checked weekly and patients were evaluated by a physician weekly 
before chemotherapy. Serum biochemistry (including fasting 
blood glucose, liver functions, and renal functions) and serum 
electrolytes were checked once a month. After the completion 
of radiation, the patients were started on oral metronomic 
chemotherapy for 18 months that include oral methotrexate at 
12.5 mg/m2 weekly with celecoxib 200 mg twice a day. Follow-up 
comprised history and physical examination every monthly along 
with complete blood counts, liver function tests, and chest X-ray. 
Endoscopy was done when clinically indicated.
Response assessment with contrast-enhanced computerized 
tomographic scan was performed after 8 weeks. If there was 
response to chemotherapy in the form of stable disease or 
partial response (based on response evaluation criteria in solid 
tumors 1.1), the patients proceeded to concurrent chemo radiation 
with paclitaxel 50 mg/m2 and cisplatin 30 mg/m2 or carboplatin 
AUC 2. Single agent platinum was used in case of poor tolerance 
to chemotherapy.
PFS was calculated from the date of receiving the first dose 
of paclitaxel chemotherapy to the date of radiologic progression, 
symptomatic deterioration in the absence of progressive disease 
on scan, start of next line of therapy due to any reason (logistic 
reasons, financial constraints, or unacceptable toxicity) or 
death from any cause. OS was calculated from the date of first 
chemotherapy to the date of death from any cause. Survival 
analysis was performed by Kaplan–Meier method using SPSS 
version 20.
RESULTS
Between January 2011 and February 2016, a total of 45 patients 
for whom survival data were available and were analyzed. The 
cut-off date for last follow-up was June 2016. Patient details are 
included in Table 1. All the patients had loco-regionally advanced 
unresectable esophageal carcinoma with no distant metastasis. 
Median age was 55 years with a range of 30-85 years. There 
were 28 females and 17 males. Only 6 patients had hypertension, 
rest all did not have any comorbidities. The epicenter for the 
tumor was upper in 13 points, middle in 19 points and lower 
in 13 points. Adenocarcinoma was present in 4 patients, rest all 
were squamous cell carcinoma. Node was positive in baseline 
computed tomography scan in 18.7% of patients. Upfront 
radiotherapy without neoadjuvant chemotherapy was started in 
10 points. Weekly regimen was given in 34 patients; however, 
rest of the patients received 3 weekly regimen with paclitaxel 
and platinum. Median radiation therapy (RT) dose delivered 
was 50 Gy. Median duration of follow-up was 5 months with a 
range of 1-54 months. The estimated 2 year PFS is 47.2% and the 
estimated 2 years OS is 57.8%. Results are shown in Tables 1 and 
2, and Figures 1a and b.
DISCUSSION
The disappointing rates of survival and local control associated 
with single-modality therapy and the need for effective 
nonsurgical management led to the development of definitive 
chemoradiotherapy paradigms for esophageal cancer. The 
use of chemoradiotherapy was reported as early as 1968 [9]. 
In the study by Cooper et al., 5 years of follow-up the OS for 
combined therapy was 26% (95% confidence interval [CI], 
15-37%) compared with 0% following RT. In the succeeding 
nonrandomized part, combined therapy produced a 5-year OS 
of 14% (95% CI, 6%-23%). Acute adverse effects were more 
in combined modality group [10]. In another meta-analysis of 
chemoradiation, overall response rate (complete remission and 
partial remission) was 93.4% for concurrent chemoradiotherapy 
and 83.7% for radiotherapy alone. The relative risk values 
of 1-, 3-, and 5-year survival rates were 1.14 (95% CI: 1.04-1.24, 
p = 0.006), 1.66 (95% CI: 1.34-2.06, p < 0.001), and 2.43 (95% 
Table 1: Patient demographics
Total number of patients 45
Age Range 30-85 years Median 55 years
Sex Male: 17 Female: 28
Comorbidties Hypertension: 6
ECOG performance status 1 8
2 37
Epicenter of tumor Upper 13
Middle 19
Lower 13
Histopathology SCC 41
Adenocarcinoma 4
Tumor stage T2 7
T3 10
T4 27
Nodal stage Node positive 8
Neoadjuvant chemotherapy Received 35
Not received 10
Median number of cycles 4
Median RT dose 50 Gy
ECOG: Eastern Cooperative Oncologic Group, RT: Radiation therapy
Table 2: Response to NACT
Partial response 29
Stable disease 3
Progressive disease 4
Treatment ongoing 6
Data not available 4
NACT: Neo-adjuvant chemotherapy
Vol 1 | Issue 2 | Oct - Dec 2016 Eastern J Medical Sciences 52
Ghosh et al. Chemoradiotherapy followed by metronomic chemotherapy in locally advanced esophageal cancer
CI: 1.63-3.63, p < 0.001), respectively, which proves that 
combination therapy is better than radiation alone. In our study, 
the definite treatment was chemoradiotherapy in the majority of 
patients. A phase II randomized trial was undertaken to clarify 
the role of chemotherapy before chemoradiation. However, 
both the arms utilized induction chemotherapy. Both the arms 
were associated with significant morbidity and did not meet the 
1 year survival endpoint of 77.5% [11]. There is a phase III trial 
currently recruiting patients with locally advanced unresectable 
tumors, who will be randomized to induction chemotherapy 
followed by chemoradiotherapy versus chemoradiotherapy 
alone.
The tumor location in outpatients is consistent with the most 
common site for esophageal cancers in India, that is, upper and 
middle third [12]. The most common histology in this region 
is squamous cell carcinoma. In our study, 90% of patients had 
squamous cell carcinoma. This is consistent with the feeding 
habits, smoking prevalence and alcohol usage in the rural areas. 
A majority of our patients were T3 and T4 disease, which rendered 
them unresectable at baseline either due to enroachement on 
surrounding structures or due to their location. Tumors in the 
upper esophagus are usually not resectable, sometime even in early 
T-stages. The nodal involvement is less in our patient population. 
The reasons for this finding are possibly two. First, many of our 
patients had upper esophageal disease for which they presented 
to us before nodal involvement, due to the location of the tumor 
which made them symptomatic earlier. Second, due to financial 
constraints and logistic issues, we could not do positron emission 
tomography scan or endoscopic ultrasound for assessment of 
nodal status, which is the standard diagnostic modality. The usage 
of the above may nave nodally upstages many of our patients. The 
majority of our patients were started on induction chemotherapy 
as a part of the departmental protocol. However, 10 patients were 
deemed unfit for chemotherapy. Hence, chemo radiation alone 
was given to them. The survival in our study is comparable to the 
other publications of similar patients. This underlies the fact that 
with proper supportive care, standard management is possible in 
rural cancer centers. There is accumulating data on the use of low 
dose non-toxic metronomic chemotherapy after primary disease 
control as an adjuvant. As shown by Patil et al., metronomic 
chemotherapy has a promising role in oral cancers [13]. There 
is not much data for esophageal cancer. Our study can for the 
basis of further research into the role of adjuvant metronomic 
in these patients. A large proportion of our patients were lost to 
follow-up, so they could not be used in the survival analysis. 
A major reason is severe financial and logistic constrains. Most 
of the patients are elderly, and there is a lack motivation from the 
family members to continue treatment. The occurrence of toxicity 
with slow symptom control and the lack of awareness about the 
disease outcomes are one of the causes.
CONCLUSION
Locally advanced unresectable esophageal cancer remains as one 
of the most fatal malignancy. Combined modality has proven 
benefit in palliation of symptoms. This treatment is possible in the 
rural setting, in a measure to debulk the tertiary cancer centers.
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Funding: None; Conflict of Interest: None Stated.
How to cite this article: Ghosh J, Sharma N, Kulkarni A, Banavali SD, 
Pokharkar A, Desai A, Mandhare A, Chandrakanth MV. Outcomes of treatment 
of unresectable esophageal carcinoma treated with chemoradiotherapy and 
oral metronomic chemotherapy: An experience from a rural cancer center. 
East J Med Sci. 2016; 1(2):50-53.


Outcomes of treatment of unresectable esophageal carcinoma treated with chemoradiotherapy and oral metronomic chemotherapy: An experience from a rural cancer center

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Outcomes of treatment of unresectable esophageal carcinoma treated with chemoradiotherapy and oral metronomic chemotherapy: An experience from a rural cancer center

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