We propose to deliver personalized radiation therapy to patients with locally advanced NSCLC that improves the therapeutic ratio by: (1) increasing local control through FDG PET/CT-guided tumor dose escalation in select patients at high risk of local failure, and (2) limiting pulmonary toxicity through radiation dose avoidance of functiona lung defined on perfusion SPECT/CT. RT is a major treatment option for patients with locally advanced non-small cell lung cancer (NSCLC), but current treatments result in suboptimal tumor control with local failures up to 50%, while carrying substantial risk of toxicity, with grad 3+ pulmonary toxicity seen in 20% of patients. In this proposal, we will explore the fundamental questions of whether radiation dose to functional lung better predicts clinical toxicity than radiation dose to anatomic lung, and whether selective dose escalation to patients at high risk of local failure improves tumor control, while limiting toxicity.
The specific aims are: (1) to evaluae toxicity of Functional Lung Avoidance & Response-adaptive Escalation (FLARE) RT in a cohort of locally advanced NSCLC patients; (2) to correlate baseline perfusion imaging parameters with post-treatment radiation pneumonitis; and (3) to predict changes in pulmonary function tests from regional RT dose-induced changes in perfusion imaging parameters. In support of the above aims, patients with locally advanced NSCLC receiving RT will undergo pulmonary function tests (PFTs) and perfusion/ventilation SPECT/CT and PET/CT at baseline, during week 3 of RT and 3 months post-RT. High precision radiation therapy will be administered by combining differential avoidance planning to reduce mean dose to SPECT/CT-defined perfused lung, and differential tumor dose escalation defined on 3 week mid-treatment FDG PET/CT in select patients classified as early FDG PET non-responders. SPECT/CT perfusion image histogram and textural features of lung function heterogeneity will be compared against CT-based dose-volume parameters for correlation to pulmonary toxicity. Spatially mapped changes in SPECT/CT perfusion image uptake will be modeled as a dichotomous dose-response with complete loss of function above dose thresholds, a binned dose-response with partial loss of function in each dose bin, and continuous dose-response at the voxel scale. This project will precisely combine functional lung avoidance and selective dose escalation in an innovative approach that can benefit each segment of a heterogeneous patient population with locally advanced lung cancer. Successful completion will pave the way for efficacy evaluation of FLARE RT in a phase II / III multi-center trial with the potential to significantly improve outcome of patients with locally advanced NSCLC.

Public Health Relevance

Radiation is a major treatment option for patients with locally advanced non-small cell lung cancer, but current treatment regimens result in suboptimal tumor control while carrying substantial risk of toxicity. We propose to improve patient outcomes by limiting pulmonary toxicity risk through radiation dose avoidance of functional lung, and increasing cancer control through PET/CT guided tumor dose escalation in select patients at high risk of local failure. We will explore the fundamental questions of whether radiation dose burden to functional lung better predicts clinical lung toxicity than radiation dose burden to anatomic lung, and whether the combination of selective tumor dose escalation and functional lung avoidance synergistically impacts patient outcomes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA204301-03
Application #
9487977
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Vikram, Bhadrasain
Project Start
2016-06-01
Project End
2021-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Washington
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
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Thomas, Hannah Mary; Kinahan, Paul E; Samuel, James Jebaseelan E et al. (2018) Impact of tumour motion compensation and delineation methods on FDG PET-based dose painting plan quality for NSCLC radiation therapy. J Med Imaging Radiat Oncol 62:81-90
Lee Jr, Howard J; Zeng, Jing; Vesselle, Hubert J et al. (2018) Correlation of Functional Lung Heterogeneity and Dosimetry to Radiation Pneumonitis using Perfusion SPECT/CT and FDG PET/CT Imaging. Int J Radiat Oncol Biol Phys 102:1255-1264
Dhami, Gurleen; Zeng, Jing; Vesselle, Hubert J et al. (2017) Framework for radiation pneumonitis risk stratification based on anatomic and perfused lung dosimetry. Strahlenther Onkol 193:410-418
Lee, Eunsin; Zeng, Jing; Miyaoka, Robert S et al. (2017) Functional lung avoidance and response-adaptive escalation (FLARE) RT: Multimodality plan dosimetry of a precision radiation oncology strategy. Med Phys 44:3418-3429