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Odynophagia in Esophageal Cancer Patients Treated with High Dose Brachytherapy

Journal of Comprehensive Cancer Research

Research Article

Odynophagia in Esophageal Cancer Patients Treated with High Dose Brachytherapy (HDRBT) - Results from A Prospective Study of Fungal Infections

Emilia Timotin1, Lilian Doerwald-Munoz1, Crystal Hann2, Jim Wright2, and Ranjan Sur2*
1Department of Radiation Therapy, Juravinski Cancer Centre, Hamilton, Canada
2Division of Radiation Oncology, Department of Oncology, McMaster University, Juravinski Cancer Centre, Canada
*Corresponding author: Dr. Ranjan Sur, Department of Radiation Oncology, Juravinski cancer centre, 699 Concession Street, Hamilton, ON L8V 5C3, Canada; E-mail: sur@hhsc.ca
Received: November 08, 2017; Accepted: December 20, 2017; Published: December 27, 2017
Copyright: ©2017 Timotin E, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Citation: Timotin E, Doerwald-Munoz L, Hann C, Wright J, Sur R (2017) Odynophagia in Esophageal Cancer Patients Treated with High Dose Brachytherapy (Hdrbt) - Results from A Prospective Study of Fungal Infections. J Compr Cancer Res 1(1): 100006.

Abstract

In esophageal cancer patient’s fungal infections and esophagitis can be the cause of odynophagia. Seventy nine consecutive patients with biopsy proven locally advanced esophageal cancer receiving HDRBT were evaluated. All patients received a dose of 18 Gy in 3 fractions on alternate days. All patients had endoscopy performed before, during and after brachytherapy treatment. The endoscopic presence of white or yellow mucosal patches in the esophagus surrounded by erythema was considered to be consistent with underlying fungal infection (FI). Twenty nine patients (36.7%) complained of odynophagia between fractions or after brachytherapy treatments. Clinically proven fungal infection on esophagoscopy was observed in 13/29 (44.8%) patients. The mean time to odynophagia was 12 days (range: 1- 26) after the first brachytherapy fraction. Odynophagia improved in 11/13 (84.6%) of patients after oral Nystatin therapy. Only 2/13 (15.4%) patients required additional oral Fluconazole before odynophagia was relieved. In patients with esophageal cancer who have received brachytherapy and are complaining of odynophagia, Nystatin should be routinely used for treatment and prophylaxis.

Keywords: esophageal cancer, brachytherapy, fungal infection, candidiasis, odynophagia
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Introduction

The prevalence of Candida colonization in the esophagus is higher in patients with esophageal carcinoma than in those with benign disease [1]. This is attributed to impairment of both the nutritional and immunological status, and to delayed esophageal outflow caused by luminal obstruction. High Dose Rate Brachytherapy (HDRBT) is a form of radiation treatment where a radioactive isotope is placed in or around the tumor. In case of esophageal malignancies, the procedure is done by placing an intraoral catheter into the lumen of the esophagus across the tumor under fluoroscopic vision. Then programming an after loader, a pellet of 192Iridium is sent through the catheter to deliver a high dose of radiation to the luminal aspect of the tumor with minimal dose to surrounding normal tissues [2]. Brachytherapy is an effective modality of treatment for the palliation of symptoms resulting from luminal disease in esophageal cancer [2].

Various International Atomic Energy Agency Studies have demonstrated that brachytherapy improves dysphagia free survival and overall survival in patients with advanced esophageal cancer [3,4]. A dose of 18 Gy in 3 fractions delivered on three alternate days (i.e. Day 1, Day 3 and Day 5), provides effective palliation in more than 70% of cases and swallowing is usually restored in 3-4 weeks’ time [3]. Some patients complain of painful swallowing (odynophagia) during or soon after a course of brachytherapy treatment. Odynophagia can cause weight loss as a result of inadequate nutrition. Therefore, timely management of odynophagia symptoms is important. To date there are no reports in the literature that have examined the incidence and cause of pain in patients with locally advanced esophageal cancer treated with brachytherapy who have increasing odynophagia during or soon after treatment. The incidence of fungal infection (FI) as a cause of odynophagia after HDRBT has not been well documented in the literature (Medline search). In view of the lack of evidence we undertook a prospective study during 16-month time period to do an endoscopic evaluation of the incidence of esophageal candidiasis in patients with esophageal cancer treated with HDRBT.

Material and Methods

A total of 79 consecutive patients with locally advanced esophageal cancer who were treated with HDRBT for a 16-month period (2008-2009) were included in this prospective observational study. Approval from the local research ethics board was obtained to collect relevant patient data from our in-house medical record systems (MOSAIQ and Meditech). No consent was required because all the patients received standard care and assessments indicated for the treatment of esophageal cancer using HDRBT.

All patients received a dose of 18 Gy in 3 fractions, 6 Gy per fraction given on alternate days. The dose was prescribed at 1 cm from the center of the source axis with a 2 cm margin proximal and distal to the tumor visualized by endoscopy. As per the standard practice at our center an esophagoscopy was performed for each HDRBT fraction under conscious sedation using a Pentax ultra slim fibreoptic gastroscope. The entire esophagus was examined for FI prior to each HDRBT fraction. The diagnosis of an underlying FI was clinical and was determined by visual inspection (Figure 1). Fungal infection was suspected on scope findings on the basis that visible white patches could not be washed away [5]. All central white or yellow esophageal patches or plaques that were discrete or raised, surrounded by erythema and filamentous cloudy white growth were considered signs of an underlying fungal infection. Patients with positive findings were prescribed Nystatin liquid (suspension) 500,000 units p.o. q.i.d for a three-week period with instructions to swish and swallow. Following the 3 weeks of Nystatin treatment, patient underwent another esophagoscopy. If there was persistent visual evidence of underlying infection at the time of esophagoscopy, patients were treated with Fluconazole liquid 100mgs bid for a further two week period.

Results

Twenty-nine out of the 79 patients (36.7%) included in the study complained of odynophagia between or after brachytherapy treatments. Out of the 29 patients, 13 were found to have a fungal infection on esophagoscopy during or after last HDRBT, which gives an overall incidence of 44.8% (13/29). Details of all 13 patients with locally advanced esophageal cancer were found to have fungal infection are shown in Table 1.

The majority of the patients were men with ages ranging from 47 to 92 years old. Tumor location and the presence of fungal infection were examined for possible correlation, but it was not found to be statistically significant (p>0.05). Most often the primary tumor was located in the lower third of the esophagus and the GE junction (9/13 or 69.2%). Fungal infection (FI) was not suspected before esophagoscopy although 1 out of 13 patients was seen to have oral evidence of FI at the time of endoscopy for the first HDRBT fraction.

No correlation was found between the length of treatment field and the number of days after the first fraction when fungal infection was first seen (Figure 2). The mean time to odynophagia based on fungal infection was 12 days (range: 1- 26) after the first brachytherapy fraction.

The number of days to fungal infection diagnosis and the tumor location were also compared for possible correlation. This is illustrated in Figure 3. The mean number of days to fungal infection for the upper and mid esophagus cancer patients grouped together was 11 days (range 2-20 days), and for the lower and GEJ tumors the mean value was 12.2 days (range 0-26 days). This result is also not statistically significant.

Twenty nine out of 79 patients (36.7%) complained of odynophagia between fractions or after brachytherapy treatments. Clinically proven fungal infection on esophagoscopy was observed in 13/79 patients (16.5%) (Table2).

Approximately 85% (11/13) of patients with esophageal carcinoma had good response to Nystatin as first line therapy (Table 3).

The incidence of fungal infections in relation to the number of days after the first HDRBT fraction that a fungal infection was detected is shown in Table 4.

For all cancer treatments, the weighted prevalence of clinical fungal infection by time of first visual assessment was 7.7% pre-HDRBT treatment, 7.7% after first treatment, 38.5% after second treatment, 30.7% after third treatment and 15.4% at 3-week post treatment follow-up.

The mean time to odynophagia when there was clinical evidence of an underlying fungal infection was 12 days (range: 2- 26) after the first brachytherapy fraction.

Odynophagia improved in 11/13 (84.6%) patients after oral Nystatin therapy; only 2 out of 13 patients required additional medication before the odynophagia was controlled (Table 5). Statistical testing yielded a statistically significant result.

Discussion

Fungal infections are a major cause of odynophagia in locally advanced esophageal cancer patients specially if undergoing for radiation or chemotherapy. Established risk factors are previous fungal infection, neutropenia exceeding 10 days, older age, active cancer [6]. The incidence of FI following esophageal brachytherapy has not been well described previously in literature. With external beam radiation using conventional fractionation, acute esophagitis usually begins in the second or third week of treatment after a dose of 20 to 30 Gy has been delivered [7]. Dosimetric parameters like maximal esophageal point dose, mean and median esophageal dose, esophageal surface area receiving >55 Gy or volume >50 Gy and >60 Gy have been reported to be predictive for occurrence of acute esophagitis >2 [8-10]. Histopathologically, a wide range of acute reactions may occur from mild symptoms to total necrosis [11,12]. Initially the mitotic activity of the basal germinal dividing epithelial cell layer maybe reduced, which leads to atrophy and epitheliolysis. This may promote opportunistic infections reflected in inflammatory infiltrations of the submucosa. Vascular alterations including necrosis and endarteritis obliterans of small blood vessels with fibrin thrombi following inflammation can lead to mucosal necrosis. Reepithelization of the denuded areas begins during a course of radiation treatment, and complete regeneration of the mucosa is possible, provided the mucosal cell loss has not been too extensive.

Hirota et al. performed an esophagoscopy during or just after thoracic radiation therapy and concurrent chemo-radiotherapy in 82 patients [13]. Endoscopic findings were graded into four grades. (0-normaly appearing mucosa, 1-erythema, 2-errosion or epitheliolysis, 3-thickly coated ulcer, hemorrhage and/or stricture). In 16 percent of patients a candida infection was found with a comparable incidence in both groups. Soffer et al. reported that 31 percent patients showed Candida infection at the end of thoracic radiotherapy when treatments in the range of 30 to 50Gy were delivered [12].

The oral cavity, pharynx, and esophagus are all lined with stratified squamous epithelium. Candidiasis is an often observed side effect during radiation treatment for head and neck and thoracic cancers. Antimycotic prophylaxis is described and often used [13]. Findings in the study by Endod Raminez show an increase in positive FI in 46 patients on radiotherapy with a median external radiation dose of 22.5Gy [14]. FI was seen during 2nd and 3rd week of radiotherapy. In our study, 16% of patients treated with brachytherapy developed candidal infection. This finding is in keeping with the findings of Hirota et.al [13] who observed a similar incidence amongst patients receiving fractionated thoracic radiotherapy.

The Infectious Disease Society of America (IDSA) recommends Nystatin either as a suspension or pastilles to be used as a start in cancer patients with signs of FI [15]. As mentioned in one of the study done by Epstein et.al demonstrated that Nystatin rinse, swish and swallow has more advantages in terms of affordability and ease of use. The IDSA guidelines [15] further recommends Fluconazole as the next step for management of superficial fungus or as a first line for moderate to severe cases.

In conclusion, in patients receiving treatment with HDRBT for relief of dysphagia in esophageal cancer, routine Nystatin therapy may improve odynophagia and quality of life.

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