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Figure.  Cumulative Incidence of Fatal Pulmonary Hemorrhage
Cumulative Incidence of Fatal Pulmonary Hemorrhage

Cumulative incidence was stratified by antiangiogenic agent (AAA) use, and nonhemorrhagic death was treated as a competing risk.

Table.  Clinical Characteristics of Patients With SBRT-related Fatal Pulmonary Hemorrhage
Clinical Characteristics of Patients With SBRT-related Fatal Pulmonary Hemorrhage
1.
Timmerman  R, McGarry  R, Yiannoutsos  C,  et al.  Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer.  J Clin Oncol. 2006;24(30):4833-4839. doi:10.1200/JCO.2006.07.5937PubMedGoogle ScholarCrossref
2.
Haseltine  JM, Rimner  A, Gelblum  DY,  et al.  Fatal complications after stereotactic body radiation therapy for central lung tumors abutting the proximal bronchial tree.  Pract Radiat Oncol. 2016;6(2):e27-e33. doi:10.1016/j.prro.2015.09.012PubMedGoogle ScholarCrossref
3.
Barney  BM, Markovic  SN, Laack  NN,  et al.  Increased bowel toxicity in patients treated with a vascular endothelial growth factor inhibitor (VEGFI) after stereotactic body radiation therapy (SBRT).  Int J Radiat Oncol Biol Phys. 2013;87(1):73-80. doi:10.1016/j.ijrobp.2013.05.012PubMedGoogle ScholarCrossref
4.
Chang  JH, Poon  I, Erler  D, Zhang  L, Cheung  P.  The safety and effectiveness of stereotactic body radiotherapy for central versus ultracentral lung tumors.  Radiother Oncol. 2018;129(2):277-283. doi:10.1016/j.radonc.2018.07.001PubMedGoogle ScholarCrossref
5.
Tekatli  H, Haasbeek  N, Dahele  M,  et al.  Outcomes of hypofractionated high-dose radiotherapy in poor-risk patients with “ultracentral” non-small cell lung cancer.  J Thorac Oncol. 2016;11(7):1081-1089. doi:10.1016/j.jtho.2016.03.008PubMedGoogle ScholarCrossref
6.
Gomez  DR, Blumenschein  GR  Jr, Lee  JJ,  et al.  Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study.  Lancet Oncol. 2016;17(12):1672-1682. doi:10.1016/S1470-2045(16)30532-0PubMedGoogle ScholarCrossref
Research Letter
April 4, 2019

Analysis of Toxic Effects With Antiangiogenic Agents Plus Stereotactic Body Radiation in Ultracentral Lung Tumors

Author Affiliations
  • 1Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York
  • 2Department of Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
  • 3Department of Medical Physics Memorial Sloan Kettering Cancer Center, New York, New York
JAMA Oncol. 2019;5(5):737-739. doi:10.1001/jamaoncol.2019.0205

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%.

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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Article Information

Accepted for Publication: January 16, 2019.

Corresponding Author: Abraham J. Wu, MD, Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, 1275 York Ave, New York, NY 10065 (wua@mskcc.org).

Published Online: April 4, 2019. doi:10.1001/jamaoncol.2019.0205

Author Contributions: Dr Wu had full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.

Study concept and design: Rimner, Wu.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Wang, Rimner, Jackson, Wu.

Critical revision of the manuscript for important intellectual content: Rimner, Gelblum, Flynn, Yorke, Wu.

Statistical analysis: Flynn, Jackson.

Administrative, technical, or material support: Wang, Rimner, Wu.

Study supervision: Rimner, Wu.

Conflict of Interest Disclosures: Dr Rimner reports grants and personal fees from Varian Medical Systems and AstraZeneca, grants from Boehringer Ingelheim and Pfizer, personal fees from Merck, and nonfinancial support from Elekta. Dr Wu has served as consultant for AstraZeneca and has received research funding from CivaTech Oncology and a travel grant from Alpha Tau Medical. No other disclosures were reported.

Funding/Support: Dr Wang’s research was partly supported by the China Scholarship Council. This research was supported in part by National Institutes of Health grant P30 CA008748 and the Dalle Pezze foundation.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Meeting Presentations: Part of this research was presented at the 19th World Conference of Lung Cancer; September 23-26, 2018; Toronto, Ontario, Canada; and at the 60th Annual Meeting of the American Society for Radiation Oncology; October 21-24, 2018; San Antonio, Texas.

Additional Contributions: Zhigang Zhang, PhD, Department of Biostatistics, Memorial Sloan Kettering Cancer Center, assisted with data analysis for this study and received no compensation for his contribution.

References
1.
Timmerman  R, McGarry  R, Yiannoutsos  C,  et al.  Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer.  J Clin Oncol. 2006;24(30):4833-4839. doi:10.1200/JCO.2006.07.5937PubMedGoogle ScholarCrossref
2.
Haseltine  JM, Rimner  A, Gelblum  DY,  et al.  Fatal complications after stereotactic body radiation therapy for central lung tumors abutting the proximal bronchial tree.  Pract Radiat Oncol. 2016;6(2):e27-e33. doi:10.1016/j.prro.2015.09.012PubMedGoogle ScholarCrossref
3.
Barney  BM, Markovic  SN, Laack  NN,  et al.  Increased bowel toxicity in patients treated with a vascular endothelial growth factor inhibitor (VEGFI) after stereotactic body radiation therapy (SBRT).  Int J Radiat Oncol Biol Phys. 2013;87(1):73-80. doi:10.1016/j.ijrobp.2013.05.012PubMedGoogle ScholarCrossref
4.
Chang  JH, Poon  I, Erler  D, Zhang  L, Cheung  P.  The safety and effectiveness of stereotactic body radiotherapy for central versus ultracentral lung tumors.  Radiother Oncol. 2018;129(2):277-283. doi:10.1016/j.radonc.2018.07.001PubMedGoogle ScholarCrossref
5.
Tekatli  H, Haasbeek  N, Dahele  M,  et al.  Outcomes of hypofractionated high-dose radiotherapy in poor-risk patients with “ultracentral” non-small cell lung cancer.  J Thorac Oncol. 2016;11(7):1081-1089. doi:10.1016/j.jtho.2016.03.008PubMedGoogle ScholarCrossref
6.
Gomez  DR, Blumenschein  GR  Jr, Lee  JJ,  et al.  Local consolidative therapy versus maintenance therapy or observation for patients with oligometastatic non-small-cell lung cancer without progression after first-line systemic therapy: a multicentre, randomised, controlled, phase 2 study.  Lancet Oncol. 2016;17(12):1672-1682. doi:10.1016/S1470-2045(16)30532-0PubMedGoogle ScholarCrossref
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