Retrospective analyses have suggested that there could be a radiotherapeutic dose-response effect for local control of non-small-cell lung cancer (NSCLC), with doses greater than 60 Gy improving overall survival and local disease control, although no randomized trials have been performed using these dose levels. There are concerns about injury to normal tissue, especially lung tissue, and radiation pneumonitis is an important dose-limiting toxicity.OBJECTIVES
To determine the maximum safe dose of radiation that could be administered in patients with NSCLC as a function of normal-lung volume irradiated, and to identify potential predictors for clinically relevant radiation pneumonitis and fibrosis.DESIGN AND INTERVENTION
This radiation-dose escalation trial enrolled patients with newly diagnosed or recurrent in operable Stage I-III NSCLC who had good performance status and had not previously received thoracic radiation. Radiation alone was given between 1992 and 1997, whereas neo adjuvant therapy (cisplatin and vinorelbine) was permitted from 1997 to 2000 in selected patients. The gross tumor volume for 3D conformal radiation was designed to include the primary tumor, any enlarged mediastinal or hilar lymph nodes, and any lesions detected by bronchoscopy or mediastinoscopy. Clinical target volume was formed by expanding the gross tumor volume by 0.5 cm, and additional volume was allowed for setup error and respiratory motion. Patients whose primary tumor or involved nodes were no longer visible on CT scan following chemotherapy still received radiotherapy to the former sites of disease. Radiation dose was escalated in 5 lung-effective volume (Veff) bins independently, starting at 63-84 Gy. Daily treatment was administered in 2.1-Gy fractions.OUTCOME MEASURES
The primary outcome measure was radiation-induced lung toxicity, defined as pneumonitis and fibrosis. Secondary endpoints were non-lung toxicities.RESULTS
Estimated median follow-up duration was 110 months (9.2 years) in 109 patients. A dose of 103 Gy was reached before the trial was halted. Approximately one-third of patients had Grade 2 to 3 acute toxicity. Pneumonitis, pulmonary fibrosis and esophagitis occurred most frequently, but nausea (with or without emesis), fatigue, skin reactions, rib fractures, bronchial stenosis and pericardial effusion were also reported. Eighty-three patients received a radiation dose of 69.3 Gy or more, of whom 17 (14.6%) had Grade 2-3 pneumonitis and 15 (13.8%) had Grade 2-3 clinical fibrosis. No Grade 4-5 lung toxicity occurred. Grade 2-3 pneumonitis, fibrosis or both occurred in 22 patients (20%). Toxicity was not associated with the dose prescribed for delivery to the tumor, but was significantly associated with the mean lung dose, percent of lung receiving doses of at least 13 and 20 Gy (V13 and V20 respectively), and lung normal-tissue complication probability (P<0.001).CONCLUSION
Higher doses of radiation than previously used can be safely delivered to a majority of patients with NSCLC using individualized 3D conformal techniques and by omitting nodal irradiation.