Dose-Limiting Late Toxicity Observed After Hypofractionated Dose-Escalated Radiotherapy in NSCLC
In a phase I study reported in Journal of Clinical Oncology, Donald M. Cannon, MD, of University of Wisconsin School of Medicine and Public Health and Mountain States Tumor Institute, and colleagues attempted to identify the maximum tolerated dose of dose-escalated hypofractionated radiation therapy in patients with locally advanced non–small cell lung cancer (NSCLC). They found that although no grade 3 or higher pneumonitis was observed and no maximum tolerated dose for acute toxicity could be identified, late grade 4 and 5 toxicities reflecting damage to central and perihilar structures occurred in several patients and were correlated with dose to the proximal bronchial tree.
Study Details
In this single-institution trial, 79 patients with NSCLC received dose-escalated hypofractionated radiation therapy without concurrent chemotherapy. Dose escalation per fraction was based on stratified risk for pneumonitis, with total radiation therapy doses ranging from 57 to 85.5 Gy in 25 daily fractions over 5 weeks using intensity-modulated radiation therapy. The primary endpoint was grade 3 pneumonitis. Maximum tolerated dose was defined as the maximum dose with ≤ 20% risk of severe toxicity.
No ≥ Grade 3 Pneumonitis or Acute Toxicity
Among 75 patients evaluable for toxicity analysis, none had grade 3 or higher acute or late esophageal toxicities, 48% had grade 2 acute esophageal toxicity, and 28% had grade 2 late esophageal toxicity. None of the patients developed grade 3 or greater radiation pneumonitis, with 16% developing grade 2 pneumonitis. Planning target volume, residual lung volume receiving at least 5 Gy (V5), V10, and mean residual lung dose, but not total dose, were significant predictors of grade 2 pneumonitis on univariate analysis.
Dose-Limiting Late Toxicity
Six patients developed late grade 4 or 5 toxicity considered to be possibly or likely related to radiation therapy, consisting of: herpes simplex virus/cytomegalovirus pneumonitis in a patient with history of pre–radiation therapy low-dose methotrexate who received 63.25 Gy; fatal hemoptysis in a patient receiving 85.5 Gy; fatal hemoptysis in a patient receiving 75 Gy; lung abscess in a patient receiving 75 Gy; fatal hemoptysis and lung abscess in a patient receiving 75 Gy; and lung abscess, bronchocavitary fistula, and tracheoesophageal fistula in a patient receiving 75 Gy.
Univariate analysis showed that higher delivered dose was significantly associated with development of grade 4 to 5 toxicity (hazard ratio = 1.13, P = .0036). The 2-year incidence of grade 4 or 5 toxicity was 31% in patients treated to 75 Gy or higher vs 1.8% in those receiving lower doses (P < .001). Maximum tolerated dose was identified as 63.25 Gy, largely determined by late toxicities in patients receiving ≥ 75 Gy. Since only three patients were treated to 69.25 Gy, the safety of this dose level could not be determined on the protocol definition of maximum tolerated dose.
An exploratory analysis of whether toxicity was associated with doses to normal tissue indicated no significant associations for lung, heart, or esophageal doses. Doses given to small volumes of the proximal bronchial tree were significant, including maximum dose (P = .020), D1cc (P = .012), D2cc (P = .007), and D3cc (P = .004).
The investigators concluded, “Although this dose-escalation model limited the rates of clinically significant pneumonitis, dose-limiting toxicity occurred and was dominated by late radiation toxicity involving central and perihilar structures. The identified dose-response for damage to the proximal bronchial tree warrants caution in future dose-intensification protocols, especially when using hypofractionation.”
The study was supported by a grant from the National Cancer Institute.
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