CyberKnife for hilar lung tumors: report of clinical response and toxicity

Patients presenting with inoperable lung tumors are generally treated with conventionally fractionated radiotherapy. To improve local control and survival, researchers in the past decade have explored various means of delivering high doses of radiation in shorter intervals [1]. Lung tumors have been treated with relatively tight margins (10 mm) utilizing a body frame and abdominal compression to restrict lung motion [2]. This enhanced precision has facilitated the safe delivery of highly effective hypofractionated doses of radiation quickly to peripheral lung tumors [3‐16]. However, for central lung tumors, treatment related deaths have been attributed to radiation induced bronchial and esophageal injury [5, 13]. An ongoing Radiation Therapy Oncology Group (RTOG) protocol is exploring potentially safer 5 fraction treatment regimens for small (< 5 cm) centrally located non-small cell lung cancers (NSCLCs) [17].

The CyberKnife^® System (Accuray Incorporated, Sunnyvale, CA) has been successfully employed at Georgetown University Hospital since early 2002 to treat stationary extracranial tumors [18]. With the introduction of the Synchrony™ motion tracking module in 2004, small peripheral and perihilar lung tumors that move with respiration have been successfully treated using tighter margins than previously feasible [19, 20]. Here we report clinical results from 20 consecutive patients with hilar lung tumors abutting or invading the mainstem bronchus, treated in 5 fractions using the CyberKnife System with Synchrony™.

Continuous tracking of respiratory tumor motion and precise beam alignment throughout treatment permits greater dose conformality to the tumor contour and a sharp dose gradient [19, 24]. We observed prompt symptomatic relief in 16 patients, likely due to the high dose per fraction. Furthermore, within 6 months of treatment there was no evidence of local tumor progression and the local control rate at 1 year was 63%. Our results compare favorably to a large RTOG trial of conventionally fractionated radiation therapy for palliation of inoperable NSCLC, which demonstrated palliation of symptoms in 60% and local control in 41% [25]. We conclude that stereotactic radiosurgery with real-time tumor motion tracking and continuous beam correction provides a well-tolerated and effective treatment option for hilar lung tumors.

Prior to proceeding with our institutional study of CyberKnife radiosurgery for hilar lung tumors, maturing data of others suggested that critical central thoracic structures tolerate high-dose hypofractionated radiation poorly [5]. In a phase II trial using 60-66 Gy in 3 fractions for the treatment of NSCLC, severe toxicity was noted in 46% of patients with central lung tumors at 2 years [5]. Therefore, we limited doses to 30-40 Gy in 5 fractions prescribed to the gross tumor volume without additional margin. In the absence of validated esophagus and mainstem bronchus dose limits for stereotactic radiosurgery in 5 fractions, we limited the maximum point doses to 40 Gy and 50 Gy, respectively. Although these dose limits were not exceeded, one patient developed grade II esophagitis and a second patient developed Grade III pneumonitis. Finally, one patient with gross mainstem endobronchial disease developed a fatal airway complication after receiving a maximum point dose of 49 Gy to the mainstem bronchus. In a recently published trial, 6 patients with lung tumors directly involving major airways (i.e. main or lobar bronchi) received 40 to 48 Gy in 4 fractions [13]. As with our study, treatment related toxicity was observed, including 3 patients who developed severe pulmonary toxicity. A single patient with gross mainstem endobronchial disease, who had received 48 Gy in 4 fractions, died of complication related to radiosurgery without evidence of tumor recurrence.

Despite the short survival of treated patients and the aggressive radiation doses used, local control at 1 year was a disappointing 63%. However, in light of dose limiting major bronchus, lung, and esophageal toxicity, further dose escalation beyond 40 Gy is not a feasible approach to improve local control in hilar tumors with a significant endobronchial component. Additional clinical trials that exclude patients with gross mainstem endobronchial disease will be necessary to define the appropriate patient characteristics and doses. Alternatively, this study provides support for investigation of novel radiation sensitizers to enhance the therapeutic ratio of hilar lung tumor radiosurgery.

Hilar lung tumor patients may be treated with frameless stereotactic radiosurgery, resulting in encouraging early clinical responses, acceptable acute toxicity and reliable palliation. However, local control at 1 year remains poor despite aggressive radiation doses and life threatening late toxicity has been reported, especially for tumors with a significant endobronchial component. We propose additional clinical investigation optimizing patient selection and consideration of novel combination treatments with radiation sensitizing drugs.