Stereotactic body-radiation therapy ( delivers large doses of radiation with millimeter accuracy.1 With SBRT, control rates for stage I non–small-cell lung cancer are 90% or greater, and this effectiveness has led to its worldwide adoption in treating patients with inoperable disease.1,2 Despite technological advances that permit the precision required for SBRT, normal tissues near the tumor receive higher biologic doses of radiation than with standard treatment. Consequently, patients with tumors adjacent to radiation-sensitive structures, such as the large airways, great vessels, heart, phrenic nerves, and spinal cord, may be at an increased risk for severe radiation injury.3 Documenting the extent of the toxic effects on these central structures represents a challenge given the competing risk of death in patients with lung cancer and the extended time required for toxicity to develop.

In a seminal study, patients with centralized tumors treated with a full-dose regimen of 60 to 66 Gy of radiation administered in three fractions, the risk of severe toxicity was 11 times as high as the risk of the development of peripheral tumors.3 Consequently, an SBRT “danger zone” was defined and subsequent multi-institutional trials have excluded patients with tumors in this area. A more protracted and presumably safer fractionation scheme (in which 50 Gy of radiation were administered in five fractions) has been widely adopted for the treatment of centrally located tumors and is the starting point for a dose-determination trial.4,5 Below we describe the clinicopathological features of central-airway necrosis in a patient who had received SBRT, with 50 Gy administered in five fractions, 8 months earlier.

A 61-year-old woman with a smoking history of 52 pack-years presented with two primary non–small-cell lung cancers: a central tumor measuring 1.4 cm in diameter (Figure 1AFigure 1

Initial Tumors and Post-SBRT Necrotic Tissue in a Patient with Non–Small-Cell Lung Cancer.) and a peripheral

tumor measuring 2.4 cm in diameter (Figure 1B). Biopsies of the tumors confirmed that both were adenocarcinomas. Staging studies revealed no metastatic disease. Poor pulmonary function precluded the performance of surgery.

The patient was treated with SBRT in accordance with a protocol for a registration study that allows for long-term surveillance of adverse events; the protocol was approved by an institutional review board. Dose, fractionation, technique, and constraints were established and applied in accordance with published standards.5 Acute toxicity was not observed, and the patient had an excellent radiographic response.

A surveillance scan obtained with the use of positron-emission tomography–computed tomography 8 months after treatment showed new mediastinal metastases, both of which were confirmed on the examination of biopsy specimens as recurrent adenocarcinomas. Incidental findings included an extensive area of necrosis in the proximal right airway (Figure 1C, 1D, and 1E) in the tissue within the radiated area. (A three-dimensional video reconstruction of the larynx, trachea, and proximal main bronchi that shows of the area of necrosis is available with the full text of this letter at NEJM.org.)

The patient received one cycle of treatment with pemetrexed and cisplatin before plans for salvage chemoradiotherapy were abandoned. Several weeks later hemoptysis developed, necessitating intubation. Bronchoscopy confirmed that the bleeding originated from the right proximal airway. With the consent of the family, care was transitioned to comfort-only measures, and the patient died 11 months after her original presentation.

This report of fatal central-airway necrosis in a patient treated with SBRT underscores the importance of long-term follow-up of patients with central tumors and the necessity of protocol-based treatment. Furthermore, it may be prudent to consider post-treatment bronchoscopic surveillance of patients with central tumors to determine the true frequency of tracheobronchial injury.

SBRT is an effective treatment for patients with peripheral stage I non–small-cell lung cancer that is inoperable. However, the long-term effects of this treatment, especially on central lesions, should be carefully documented and reported.

Source: NEJM