Abstract
This case series analyzes the association between antiangiogenic agents plus stereotactic body radiation for ultracentral lung tumors and toxic effects.
Lung stereotactic body radiation therapy (SBRT) is an effective and generally safe treatment for lung cancer, but a higher rate of toxic effects has been reported for SBRT within the central lung zone.1 Patients receiving SBRT for tumors abutting the proximal bronchial tree (PBT) or esophagus, known as “ultracentral” tumors, may have a particularly high risk of toxic effects.2 Antiangiogenic agents (AAAs) have been suspected to potentiate SBRT toxic effects in other body sites.3 Herein, we report on the toxic effects associated with SBRT for ultracentral lung tumors, with a focus on exposure to AAAs.
Methods
The institutional review board at Memorial Sloan Kettering Cancer Center approved this study. Because this is a retrospective study, the requirement for patient written informed consent was waived. We identified patients with lung tumors abutting the PBT or a planning target volume (PTV) overlapping the esophagus who were undergoing SBRT. Patients received 5, 8, or 15 fractions of image-guided radiotherapy with a biologically effective dose of 84 Gy or higher (alpha/beta = 10). The primary end point was radiation-related toxic effects (using the Common Terminology Criteria for Adverse Events version 4.0). The Kaplan-Meier method was used to assess survival in patients with grade 3 or higher toxic effects. We used cumulative incidence analysis to assess the association of AAA with fatal hemorrhagic events. A 2-sided P < .05 was considered significant.
Results
We included 88 patients in the study (39 men, 49 women; median age, 74 years [range, 25-91 years]), 53 (60%) of whom had primary or locally recurrent lung cancer, and 35 had lung metastases. Most patients (n = 76) had tumors abutting the PBT, and 23 had a PTV overlapping the esophagus (patients could meet both criteria). Nine patients (10%) received an AAA (bevacizumab, pazopanib, or ramucirumab) within 90 days of SBRT, with a median interval of 30 days (range, 1-87 days) between the AAA dose and the start of SBRT. All 9 patients then resumed AAA therapy a median of 29 days after the end of SBRT (range, 1-230 days). Median follow-up for living patients was 19.6 months.
Nineteen patients (22%) experienced grade 3 or higher toxic effects. Ten patients (11%) experienced fatal events possibly related to SBRT, including 6 with fatal pulmonary hemorrhage (Table). Four of these 6 patients had received an AAA, all within 30 days of SBRT. Patients receiving an AAA had a significantly higher probability of fatal pulmonary hemorrhage compared with those who did not receive an AAA (hazard ratio, 16.9; 95% CI, 3.2%-88.8%; P < .001) (Figure). Six additional patients received an AAA more than 90 days before or after SBRT; none had fatal hemorrhage. Four other SBRT-related deaths were attributed to radiation pneumonitis. Two patients developed tracheoesophageal fistula; both patients had PTV overlapping the esophagus, and one received bevacizumab before and after SBRT. The 1-year survival rate of patients with grade 3 or higher toxic effects was 78.1%.
Table. Clinical Characteristics of Patients With SBRT-related Fatal Pulmonary Hemorrhage.
| Clinical Scenario | Antiangiogenic Agent (Interval Before/After SBRT, d)a | SBRT Dose, Gy/Fractions, No. | PTV, mL | Maximum Point Dose to PBT, Gy | Other Grade ≥3 Toxic Effects |
|---|---|---|---|---|---|
| Oligometastatic NSCLC | Bevacizumab (14/14) | 45/5 | 100 | 49.4 | None |
| Oligometastatic colorectal cancer | Bevacizumab (6/5) | 50/5 | 95 | 51.4 | None |
| Oligoprogressive NSCLC | Bevacizumab (30/230) | 60/15 | 100 | 65.2 | Grade 4 tracheal necrosis |
| Grade 3 tracheoesophageal fistula | |||||
| Oligometastatic renal cell carcinoma | Pazopanib (30/140) | 60/15 | 335 | 65.9 | Grade 3 pneumomediastinum |
| T2aN0 NSCLC | No | 60/8 | 133 | 63.8 | None |
| Metastatic NSCLC | No | 50/5 | 63 | 55 | None |
Abbreviations: NSCLC, non-small cell lung cancer; PBT, proximal bronchial tree; PTV, planning tumor volume; RT, radiation therapy; SBRT, stereotactic body radiation therapy.
Antiangiogenic agents were never given concurrently with SBRT. The interval refers to the elapsed days between the last dose of antiangiogenic agent and the start of SBRT, and the elapsed days between the end of SBRT and the resumption of antiangiogenic agent.
Figure. Cumulative Incidence of Fatal Pulmonary Hemorrhage .
Cumulative incidence was stratified by antiangiogenic agent (AAA) use, and nonhemorrhagic death was treated as a competing risk.
Discussion
Local control of ultracentral lung tumors is important because progression may cause airway obstruction or bleeding. However, this location is challenging to address with surgery or radiofrequency ablation owing to its proximity to central airways and mediastinal structures. The feasibility and safety of noninvasive local therapy such as SBRT is therefore of particular interest. To our knowledge, this is the largest reported series of SBRT for ultracentral lung tumors.
The observed incidence of grade 3 or higher toxic effects (n = 19 of 88 patients, 22%) and fatal toxic events (n = 10 of 88 patients, 11%) is considerable, indicating that patients with ultracentral lung tumors treated with SBRT and an AAA are at high risk of grade 3 or higher toxic effects. However, some studies of SBRT have reported no excess risk associated with SBRT for ultracentral tumors compared with other central tumors.4 This discrepancy may be partly owing to broader definitions of ultracentral tumors or to the use of regimens with a lower biologically effective dose.
The most important finding is the association of AAA with fatal hemorrhage. One study recently reported a high rate of fatal hemorrhage in patients with ultracentral non–small cell lung cancer, but identified no risk factors.5 In our series, all but 2 fatal hemorrhagic events occurred in patients receiving AAA in close proximity to SBRT (within 30 days), and this association proved statistically significant. Antiangiogenic therapy is not indicated for early-stage lung cancer but is often used for oligometastatic disease, an indication for which the use of lung SBRT is likely to increase.6 Although this report is limited by its retrospective nature, these findings strongly suggest that AAAs potentiate severe SBRT-related toxic effects. We therefore recommend that this combination be avoided in patients with ultracentral lung tumors.
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