Ku, Geoffrey Y. MD*; Goodman, Karyn A. MD†; Rusch, Valerie W. MD‡; Ilson, David H. MD, PhD*
*Gastrointestinal Oncology Service, Department of Medicine, †Department of Radiation Oncology, and ‡Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York City, New York.
Disclosure: The authors declare no conflict of interest.
Address for correspondence: David H. Ilson, MD, PhD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. E-mail: firstname.lastname@example.org
Esophageal cancer with airway invasion with or without fistula presents a challenging therapeutic dilemma with no standard therapy. Recent studies in Japan have focused on the use of definitive chemoradiotherapy. However, this approach is associated with significant treatment-related morbidity and mortality. We present a case report of a patient with thoracic esophageal squamous cell carcinoma with bronchial invasion who was treated to a clinical complete response with induction chemotherapy followed by consolidation with concurrent chemoradiotherapy. The patient also underwent restaging with a positron emission tomography scan after induction chemotherapy. Such a staged approach may reduce the morbidity of upfront radiation. The use of an interim positron emission tomography scan may also identify early treatment failure.
Esophageal cancer with airway invasion with or without fistula presents a challenging therapeutic dilemma with no standard therapy. Left untreated, patients with airway fistulas have median survivals of only 1 to 6 weeks.1
Recent studies from Japan have focused on the use of combined chemoradiotherapy to treat patients with T4 tumors with or without fistulas.2,3 While these studies have demonstrated long-term survival in a minority of patients, they have also been associated with the worsening or development of new fistulas as well as treatment-related deaths in a significant proportion of patients.
Here, we present a case report of a patient with a T4 esophageal squamous cell carcinoma (SCC) with invasion of the bronchus who experienced a clinical complete response to induction chemotherapy and consolidative chemoradiotherapy.
The patient is a 70-year-old man who presented in April 2007 with increasing dysphagia for solid foods and a 10 lb weight loss. Endoscopy established a tumor in the mid esophagus at 25 to 31 cm from the incisors, with biopsy positive for an invasive poorly differentiated SCC.
A position emission tomography/computed axial tomography (PET/CT) scan revealed intense uptake in the primary tumor (standard uptake value 13.6) without evidence of metastatic disease. A CT scan of the chest/abdomen demonstrated a paraesophageal fluid- and gas-containing structure that was concerning for a small fistula. There was also evidence of locoregional lymphadenopathy.
An endoscopic ultrasound initially staged the tumor as an uT3N1 lesion. However, slight mucosal irregularity of the left mainstem bronchus was seen on subsequent flexible bronchoscopy. Biopsy returned positive for a poorly differentiated carcinoma that was morphologically similar to the esophageal primary. As such, this was staged as a T4 esophageal cancer.
The patient received induction chemotherapy with weekly cisplatin 25 mg/m2 and irinotecan 50 mg/m2 on a 2-week on/1-week off schedule. After two cycles, the patient had experienced complete resolution of dysphagia. A repeat PET/CT scan indicated a significant decrease in standard uptake value to 5.7 of the primary tumor. CT scan of the chest/abdomen also demonstrated resolution of the prior paraesophageal fluid collection and improvement of esophageal thickening.
After an additional two cycles of chemotherapy, a repeat bronchoscopy revealed a complete response in the bronchus, with negative cytologic analysis of bronchial washings. Endoscopy showed significant downsizing of the primary tumor.
The patient then received consolidative radiation with 25 daily fractions of 1.8 Gy over 5½ weeks to a total dose of 50.4 Gy with concurrent cisplatin/irinotecan at the above doses and schedule. He tolerated all therapy without significant toxicity.
At the completion of therapy, he was followed expectantly. Endoscopy 3 months after completion of therapy confirmed a clinical complete response, with negative esophageal brushings. Repeat CT scans of the chest/abdomen obtained 2 and 5 months after completion of therapy also detected no evidence of recurrence. The patient is now without evidence of disease 12 months after his initial diagnosis and 6 months after completion of therapy. Representative CT images are presented in Figure 1.
In the United States, the incidence of esophageal cancer with airway invasion is fairly uncommon. In a series from the Washington, D.C. Veterans’ Affairs hospital from 1985 to 1998, 20% of patients with established esophageal cancer had airway involvement, with 9.4% having fistulous connections.4 Most (88%) of these patients had SCC, consistent with the location of these tumors in the cervical and proximal esophagus. As the incidence of the SCC histology has steadily decreased in the general population so that the adenocarcinoma histology now predominates, the incidence of airway invasion with or without fistulas also seems to have decreased.
The treatment of esophageal cancer with airway invasion with or without fistula continues to present difficult management decisions. Primary surgical resection is generally considered inadvisable because of the substantial treatment-related mortality and morbidity. In a series of 28 patients with known airway invasion without fistulas who underwent surgical exploration with or without esophagectomy, the operative mortality was 17%.5
Other approaches have included palliative treatments, such as the placement of endoesophageal stents to relieve malignant dysphagia or to occlude a fistula or single-modality radiation therapy.1
The seminal Radiation Therapy Oncology Group 85-01 trial established the superiority of chemoradiotherapy over radiotherapy alone for the nonsurgical management of locally advanced esophageal cancer.6 As such, there has also been significant interest in the use of chemoradiotherapy either as preoperative or definitive therapy for T4 esophageal tumors—despite potential concerns for creating or worsening fistulas.1,4
In a phase I/II evaluation, Nishimura et al.3 treated 28 patients with esophageal squamous cell cancers with airway invasion with or without fistulas. Patients received protracted infusion 5-fluorouracil and cisplatin, along with split-dose radiation to a total dose of 60 Gy over 30 fractions. This study reported an encouraging 2-year survival rate of 27% for the patients with stage III (T4N+M0) disease. However, this was at the expense of significant toxicity, including the development or worsening of fistulas in 18% of patients and treatment-related deaths in 7% of patients.
In our case report, the patient received induction therapy with weekly cisplatin/irinotecan followed by chemoradiotherapy with the same regimen and achieved a clinical complete response. Induction chemotherapy in the setting of T4 tumors has several theoretical benefits. As the use of radiation therapy has been associated with concerns about worsening fistulas, chemotherapy alone may effectively downstage the primary tumor but may be associated with a lower rate of fistula formation. Chemotherapy is also highly effective in relieving malignant dysphagia in up to 70 to 80% of patients7 and may obviate the need for placement of an esophageal stent or enteral feeding tube.
In addition, the use of an interim PET scan after induction chemotherapy offers several potential advantages. A patient who develops metastatic disease despite effective systemic chemotherapy may be spared the toxicity of radiation therapy. At the same time, there are anecdotal data to suggest that patients who experience local progression after induction chemotherapy may be successfully salvaged with alternative chemotherapy during concurrent radiation.8
Finally, the benefit of surgery after chemoradiotherapy is unclear, particularly in the setting of a baseline T4 tumor. Two recent randomized trials (which included patients with T4 tumors) have not demonstrated a survival benefit for surgery after chemoradiotherapy in patients with esophageal SCC,9,10 justifying the approach of expectant observation in this patient with a clinical complete response.
To our knowledge, there has been no prior description of the use of induction chemotherapy followed by concurrent chemoradiotherapy to treat patients with T4 esophageal tumors. Such an approach represents a staged and potentially effective treatment paradigm. Initial chemotherapy may be associated with a lower risk of fistula formation than chemoradiotherapy and may also downstage the tumor and improve dysphagia. The use of an interim PET scan after induction chemotherapy may identify early treatment failure in the form of overt metastatic disease or local progression that can permit a modulation in therapy. Patients who achieve a clinical complete response can be followed expectantly while salvage surgery remains an option for those with locally persistent disease.
1. Burt M, Diehl W, Martini N, et al. Malignant esophagorespiratory fistula: management options and survival. Ann Thorac Surg
1991;52:1222–1228; discussion 1228–1229.
2. Koike R, Nishimura Y, Nakamatsu K, Kanamori S, Shibata T. Concurrent chemoradiotherapy for esophageal cancer with malignant fistula. Int J Radiat Oncol Biol Phys
3. Nishimura Y, Suzuki M, Nakamatsu K, et al. Prospective trial of concurrent chemoradiotherapy with protracted infusion of 5-fluorouracil and cisplatin for T4 esophageal cancer with or without fistula. Int J Radiat Oncol Biol Phys
4. Alexander EP, Trachiotis GD, Lipman TO, et al. Evolving management and outcome of esophageal cancer with airway involvement. Ann Thorac Surg
5. Altorki NK, Migliore M, Skinner DB. Esophageal carcinoma with airway invasion. Evolution and choices of therapy. Chest
6. Herskovic A, Martz K, al-Sarraf M, et al. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med
7. Ilson DH, Bains M, Kelsen DP, et al. Phase I trial of escalating-dose irinotecan given weekly with cisplatin and concurrent radiotherapy in locally advanced esophageal cancer. J Clin Oncol
8. Ku G, Bains M, Rizk N, et al. Phase II trial of pre-operative cisplatin/irinotecan and radiotherapy for locally advanced esophageal cancer: PET scan after induction therapy may identify early treatment failure. Proc Gastrointest Amer Soc Clin Oncol
9. Bedenne L, Michel P, Bouche O, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol
10. Stahl M, Stuschke M, Lehmann N, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol