Carcinoma of the esophagus is the seventh most common cancer worldwide, the sixth most common cause of cancer-related deaths worldwide [1], and fourth most common cause of cancer-related deaths in India [2]. In India, every year more than 47,000 new cases are reported of which around 90% of patients die [2].

The two major sub-types of esophageal carcinoma are esophageal squamous cell carcinoma (SCC) and adenocarcinoma. The history and incidence of these two types differ considerably. The predominant factors responsible for esophageal carcinoma are age, gender, race, environmental toxins, nutritional deficiency, alcohol consumption etc [3-6]. SCC affects the stratified squamous epithelial lining of the organ whereas adenocarcinoma affects columnar glandular cells that replace the squamous epithelium. Esophageal carcinoma is the most frequently occurring type having features like late presentation, late diagnosis, rapid progression, and low survival rates. An overall survival at 5 years ranged between 0% to 12% for patients treated with radiotherapy and 1% to 7% for patients treated with surgery [7-9].

Esophageal cancer is staged using the TNM system that implies the extent and presence of primary tumor, spread to lymph nodes and organs beyond lymph nodes. Common imaging modalities used in staging include computed tomography (CT), endoscopic ultrasound and positron emission tomography scans [10]. Studies suggest esophageal tumor length and diameter as important prognostic factors for nonsurgical T staging in SCC patients undergoing definitive chemo-radiotherapy [11]. The treatment of esophageal carcinoma may demand multiple approaches including combination of radiotherapy and chemotherapy, particularly cases which are considered unresectable, such as upper third esophageal cancers, locally advanced middle and lower third cancers [2].

Diagnosis reveals majority of patients with advanced stage of SCC, hence surgery is not feasible. So, a non- surgical treatment modality like radiotherapy combined with chemotherapy is preferred but has poor response and survival rates [12, 13]. Few recent meta-analyses have demonstrated that the use of chemo-radiotherapy has significant survival benefits in patients with esophageal carcinoma.

≥4000/mm³, platelet count ≥100,000/mm³, serum creatinine ≤1.6 mg/dL, and serum bilirubin ≤1 mg/dL.

Exclusion criteria: Patients with adenocarcinoma, second primary neoplasm, and with recurrent disease were excluded from the study.

Ethical considerations: The institutional review board reviewed and approved the study protocol.

The study was conducted in accordance with the approved protocol, International Conference on Harmonization Good Clinical Practice (ICH-GCP) guidelines, and the ethical principles laid down in the Declaration of Helsinki 2013.

Each study participant provided written informed consent before participation in the study.

Response assessment and follow-up: Response criteria included dysphasia free survival (DySF), disease free survival (DFS), and overall survival (OS).

A patient was considered locally disease free only if the barium swallow at one month after completion of radiotherapy or at subsequent follow-up was smooth.

A local recurrence was scored if there was a positive pathological diagnosis (on endoscopic biopsy), evidence to suggest recurrence on a barium swallow, or signs and symptoms of mediastinal disease.

Dysphasia scores were recorded pre-and post-treatment and at every follow-up. Patients was considered dysphasia free only if solids or soft solids could be consumed without appreciable difficulty during or after treatment.

The dysphasia free status was terminated when patient reported any sustained inability to swallow solids or soft solids in spite of repeated attempts at dilatation when feasible.

Adverse events were recorded throughout the study duration using WHO criteria for acute and sub-acute toxicities. During follow-up period, ulcers, strictures and trachea-esophageal fistula were recorded along with recurrences, distant metastasis and second primaries.

Statistical analysis: There was no formal sample size calculation employed for this study. Statistical significance was computed using Chi square test, t test and log rank test.

A univariate analysis that assessed factors influencing DyFS, DFS, and OS is summarized in Table 2, which showed generally comparable results between the groups.

There were no significant differences in both the groups in EBRT, total treatment duration and duration of EBRT (Table 3). Seven patients received 6-7 cycles of chemotherapy, of which, two patients discontinued the treatment, one died due to disease progression and four patients reported grade 2-3 neutropenia. No patient reported thrombocytopenia or nephrotoxicity.

Among patients from chemo-radiotherapy group, seven patients reported anemia (grade 1, n=3; grade 2, n=2 and grade 3, n=1); six patients reported leucopenia (grade 1, n=4; grade 2, n=2); and 12 patients reported emesis (grade 1, n=4; grade 2, n=3; grade 3, n=5).

Table-1: Demographics and baseline characteristics.

DFS, disease free survival; DyFS, dysphasia free survival; KPS, Karnofsky performance status; NR, not reached; OS, overall survival.

Table-3: Summary of study treatment and duration

Data shown as n (%), unless otherwise specified. EBRT, external beam radiation therapy; SD, standard deviation.

(ulcerations [n=6 vs. n=4]; strictures [n=6 vs. n=10]; fistulae [n=2 vs. n=1]; and retrosternal pain/epigastric discomfort [n=5 vs. n=2]; dilatation/stunting procedure [n=3 vs. n=2]; respectively for chemo-radiotherapy and radiotherapy alone group).

Table 4 summarizes survival outcomes for patients who completed the treatment, which demonstrates no significant difference between the groups. However, the outcomes were slightly higher in chemo-radiotherapy group than radiotherapy alone group.

Esophageal carcinoma can be managed by endoscopic mucosal resection, surgery, chemotherapy, radiotherapy, palliative therapy or a combination of these modalities depending on the stage and extent of the disease. Concurrent chemo-radiotherapy or radiotherapy alone are generally recommended in patients with upper or middle third carcinomas, inoperable cases, and in locally advanced cases. A meta-analysis by Ma et al, stated that concurrent chemo-radiotherapy significantly improves progression-free survival and OS in patients with esophageal cancer compared to surgery [19].

Another meta-analysis by Sun et al, investigated the safety and efficacy of treatment modalities used in concurrent radiotherapy. It revealed that concurrent therapy increased adverse reactions rather than patient survival [20]. In this prospective randomized study, we aimed to compare the efficacy of chemo-radiotherapy with radiotherapy alone in the treatment of locally advanced esophageal squamous cell carcinoma.

The present study was conducted in a teaching hospital in India, where patients are treated using concurrent chemo-radiotherapy or radiotherapy alone based on physicians’ preference and disease condition. This study was a part of postgraduate thesis at a single center and hence was limited by the study period that could have resulted in smaller sample size.

Both the groups showed male preponderance and comparable mean age. Smith et al, conducted a study to determine the efficacy of chemo-radiation in comparison to radiation alone that showed male predominance and a longer median survival with chemoradiation (14.8 months) compared to patients with radiation therapy alone (9.2 months) [21].

however, to our knowledge limited data is available regarding its relief. In a previous study, patients receiving fluorouracil and cisplatin showed improvement from baseline to week 15 (37.6 versus 29.9, p=0.047) [25].

Another retrospective study that included patients (N=66) with esophageal carcinoma and treated with chemoradiotherapy (carboplatin and paclitaxel) demonstrated that around 70% of patients had relief of dysphagia [26]. In the present study, dysphasia relief was achieved in 64% and 48% of patients from chemo-radiotherapy and radiotherapy alone group, respectively. The median DFS was 12 months and 5 months for chemo-radiotherapy and radiotherapy alone group, respectively.

Chemotherapy compliance was observed in 76% of patients. Overall, both treatments were generally tolerable with no new safety signals. Chemotherapy associated acute toxicities were also consistent with the previous study [24]. There were no reports of thrombocytopenia or nephrotoxicity. None of the patients from chemo-radiotherapy group reported grade 4 toxicity. The worst chemotherapy toxicities observed were grade 3 neutropenia and grade 3 emesis.

Previous studies suggest that preoperative chemo-radiotherapy for esophageal SCC significantly increased patients’ risk of cardiopulmonary complication [27]. As per European Society for Medical Oncology (ESMO) recommendations, the patients unable or unwilling to undergo surgery, a combined chemo-radiotherapy is superior to radiation therapy alone and four courses of cisplatin/5-Flourouracil combined with radiation doses of 50.4 Gy in fractions of 1.8 Gy are regarded as standard for definitive chemo-radiotherapy [28].

Intensity modified radiotherapy (IMRT) with concurrent chemotherapy has demonstrated reduction inradiation-induced toxicities, enhanced local control and improved long-term survival combining [29]. Literature has documented studies that have confirmed patient outcomes favoring chemoradiation compared to radiation alone [30].

This study with a small sample size showed concurrent chemo-radiotherapy with cisplatin can improve dysphasia and OS in patients with esophageal carcinoma; however, the difference was not statistically significant. Future research may be needed to corroborate these outcomes.