Clinical outcomes of radiation therapy for clinical T4b oesophageal cancer with airway invasion

In patients with oesophageal cancer, airway invasion with or without a fistula was considered a contraindication for radiation therapy (RT) and associated with a dismal prognosis. Left untreated, patients developed pulmonary infections and sepsis with median survivals of only 1 to 6 weeks [1, 2]. However, RT significantly improved the survival rate compared to that for only supportive care [2, 3]. Additionally, closures of fistulae and occasional long-term survivors were reported. Several studies reported a significant improvement in local control and overall survival with concurrent chemoradiotherapy (CCRT) compared with RT alone, even though it was associated with severe complications [4‐9]. In the current National Comprehensive Cancer Network (NCCN) guidelines, definitive CCRT is recommended for the treatment of patients with clinical T4b oesophageal cancer, and chemotherapy alone can be considered in cases of tracheal invasion. RT can alleviate symptoms and increase the chance of cure for oesophageal cancer patients with airway invasion with or without a fistula, but the treatment can have severe complications. In this study, we reviewed the clinical course of cT4b oesophageal cancer patients with airway invasion, who received RT.

In patients with oesophageal cancer, airway invasion with or without a fistula presents a challenge for therapy. In previous studies, the use of CCRT demonstrated long-term survival and closing of fistulae in a minority of patients. The first study from Japan [10] showed promising results of CCRT for patients with an oesophageal fistula. Closing of the fistula was observed in 71% of patients, with an MS time of 6.6 months from the fistula diagnosis. Later, the use of 60 Gy CCRT in 30 fractions with a protracted infusion of 5-FU and cisplatin for clinical T4 oesophageal cancer including both T4a and T4b was performed [11]. For patients with stage III disease, the MS time and 2-year OS rate were 12 months and 27%, respectively. Two of five clinical T4b tumours with fistulae showed disappearance of the fistula after RT. However, the aggravation or development of a fistula was noted in five of 25 patients (20%). Another study reported the results of CCRT in patients with a fistula that developed before or during treatment [12]. The MS time was 8.5 months and the 1- and 2-year OS rates were 33 and 22%, respectively. Disappearance of the fistula was noted during or after CCRT in seven of 16 patients (44%). However, treatment was terminated early for five patients (31%) because of worsening of the oesophageal fistula, including two treatment-related deaths (13%).

In the current study, the MS time for patients treated with a curative aim was 15 months and the 1- and 2-year OS rates were 51.8 and 34.3%, respectively. A significantly increased survival was achieved in patients treated with a curative aim compared to that in patients treated with a palliative aim (p = 0.001). In addition, the CCRT group showed a better survival than that in the RT-only group (p = 0.009). Like previous studies, closing of an oesophageal fistula was observed in about half of patients with fistula before treatment (3/7, 42.9%). Fistula aggravation and newly developed fistula were observed in one patient and 13 patients, respectively. Interestingly, only one patient (1/13, 7.7%) later experienced fistula closure. Nine of 13 patients died from aspiration pneumonia. Oesophageal fistulae developed after treatment might be associated with a lower chance for closing and a higher risk for aspiration pneumonia compared to those for a fistula present before treatment.

We tried to identify risk factors for fistula development. In a previous study [13, 14], oesophageal stenosis, circumferential involvement, and elevated C-reactive protein level were associated with the risk of fistula. In the current study, disease with gross invasion on bronchoscopy showed a higher incidence of fistula development than that for disease with mucosal change (37.5% vs. 25.0%, respectively), although the difference was not statistically significant (p = 0.770). The RT dose was also not associated with the risk of fistula.

As shown above, severe complications, including fistula development and treatment-related death, have been a major challenge in the treatment of patients with clinical T4b disease with airway invasion. Thus, a strategy to reduce these severe complications is needed. Several studies demonstrated several benefits of induction chemotherapy (ICT) as an initial treatment for patients with clinical T4 disease [15, 16]. This treatment might effectively downstage the tumour, improve the resectability, anticipate treatment response, and lower the rate of fistula formation. In 2007, the results of a phase II trial of docetaxel, cisplatin, and 5-FU (DCF) followed by CCRT in patients with unresectable, locally advanced oesophageal squamous-cell carcinoma were released. In a case report of oesophageal cancer with airway invasion treated with ICT followed by CCRT [17], the planned total dose was 50.4 Gy with concurrent cisplatin and irinotecan. There was no evidence of disease until the last follow-up date. Later, the efficacy of ICT using DCF for clinical T4 oesophageal squamous-cell carcinoma was evaluated [18]. Fifty patients who underwent ICT using DCF were propensity-score-matched with 50 patients who underwent CCRT with 5-FU and cisplatin. The DCF group had significantly higher overall resectability compared to that in the CCRT group (78.0% vs. 48.0%, p < 0.01). The oesophageal perforation rate during induction treatments was significantly lower in the DCF group than that in the CRT group (4.0% vs. 18.0%, p = 0.02). The prognosis was significantly better in the DCF group than that in the CRT group (5-year cancer-specific survival 42.1% vs. 22.2%, p = 0.01). Against this, we experienced fistulae aggravation in two of four patients after ICT with a regimen of 5-FU and cisplatin. These two patients were treated with palliative RT and all died from aspiration pneumonia during follow-up. One patient had a successful treatment with ICT followed by RT. The patient, who had a gross left main bronchus invasion of oesophageal cancer, was treated with four cycles of docetaxel and cisplatin followed by sequential RT with a total dose of 50 Gy in 20 fractions. During follow-up, there was no evidence of fistula development or disease progression until the last follow-up date. To determine the appropriate strategy for ICT, further studies on effective chemotherapeutic regimens are needed.

Our current study had several limitations. First, it was a retrospective study; therefore, some selection bias was possible. Second, there might have been chronological changes in radiotherapy techniques during the study period.

Even for clinical T4b disease with airway invasion, radiation therapy with a curative aim showed acceptable survival outcomes in patients with good performance status and no distant metastasis at initial diagnosis. However, the risk of fistula development associated with fatal events remains high. Further study on the association between ICT with an effective regimen and the risk of fistula development is warranted to decrease the risk of treatment and improve clinical outcomes.