In the current study, the risk factors of esophageal fistula for T4b ESCC were total circumferential lesion and CRP ≥1.00 mg/dL. To the best of our knowledge, no definitive risk factors for esophageal fistula formation have been identified in esophageal cancer patients receiving dCRT, despite esophageal fistula being fatal, as previously reported [9, 10].
A supplemental analysis of JCOG0303 identified esophageal stenosis as a risk factor for esophageal fistula [7], although this was not found to be a risk factor under the definition used in the current study. However, there were some differences between the previous study and the present study. First, regarding the backgrounds of the subjects, better selection was performed in this study than in JCOG0303: JCOG0303 included patients with non-T4b ESCC, while those included in this study were limited to T4b ESCC. Therefore, we specifically investigated risk factors of esophageal fistula in T4b ESCC in this study, which is clinically relevant. A second difference between the studies was that, in JCOG0303, the definition of esophageal stenosis was not described, so it might have differed depending on the clinical investigator. In contrast, we defined esophageal stenosis as cases in which the endoscope could not pass through the lesion. This enabled us to perform a more precise evaluation of risk factors of esophageal fistula only in T4b ESCC patients.
CRP ≥1.00 mg/dL was also a risk factor for esophageal fistula in this study. This may reflect tissue damage induced by an elevated level of IL-6, which causes tissue inflammation [11]. Albumin concentration is usually decreased when IL-6 is overproduced; however, there were only a few patients with a low albumin concentration among the study population. A possible explanation for this is that T4b ESCC patients generally do not eat well and are often dehydrated. In this study, we did not measure the IL-6 level, so we could not verify this hypothesis.
Even patients with such risk factors are not a contraindication for dCRT because they have a chance of achieving a complete response, which could prolong the survival time [4]. In fact, five patients with esophageal fistula experienced fistula closure by continuing the treatment and had survived for more than 1 year at the data cut-off. However, overall survival of the EF+ group was significantly shorter than that of the EF− group in the current study. Therefore, the development of a treatment strategy for ESCC patients with a risk of fistula formation is warranted.
Recently, some reports have suggested that induction chemotherapy followed by dCRT reduces the incidence of esophageal fistula [12, 13]. The reported esophageal fistula rate was in the range of 3–6%, and one of these studies showed that this rate in the group with induction chemotherapy followed by CRT was significantly lower than in those with CRT alone (6% vs. 17%, p = 0.0379) [12]. Therefore, induction chemotherapy followed by CRT may be a feasible treatment strategy for T4b thoracic ESCC with such risk factors.
The present study has several limitations. First, this is a retrospective study with a small sample size from a single institution. Second, it was difficult to distinguish treatment-related esophageal fistula and disease progression precisely. Third, bronchoscopy was not performed routinely to diagnose esophageal fistula before dCRT. Finally, we selected all fistula cases in the study population regardless of the duration from the commencement of dCRT; therefore, some cases with esophageal fistula might have been due to progressive disease. Considering these limitations, we particularly focused on T4b disease and used a precise definition of esophageal stenosis, so that we could reveal reliable risk factors for esophageal fistula formation in T4b ESCC in the current study.