Initial Report of a Randomized Trial Comparing Conventional vs. Novel Treatment Planning Technique to Ameliorate Immunosuppression from Lung SBRT

Abstract

SBRT is highly effective against early-stage non-small cell lung cancer. Radiation Therapy (RT) is known to modulate the immune system and contribute to the generation of anti-tumor T cells and stimulate T cell infiltration into tumors. However, this anti-tumor activity is offset by radiation-induced immunosuppression (RIIS) which results in lower tumor control and survival. Lymphocytes are highly radiosensitive and RIIS means destroying existing as well as newly created cytotoxic and helper T lymphocytes. We hypothesized that optimizing RT treatment planning by considering circulating blood and lymphatics as a critical Organ at Risk (OAR) may mitigate RIIS. We conducted an IRB approved NCI funded clinical trial for 50 early-stage lung cancer patients treated with SBRT alone, from 2020 to 2023, to investigate the ability to reduce RIIS by reducing dose to circulating blood and lymphatics with the aid of a predictive algorithm. All SBRT plans adhered to treatment parameters from RTOG 0813 (central) or RTOG 0915 (peripheral). Patients were randomized to two arms: experimental optimization for RIIS (to reduce dose to blood and lymphatic rich organs) versus standard SBRT planning (without optimization for RIIS). Peripheral blood samples were collected at baseline, end of Tx, 4 weeks and 6 months post Tx. Patients with baseline absolute lymphocyte counts (ALC) less than 0.5x109 cells/L were ineligible for the trial. Data acquired for all blood cell types as well as lymphocyte sub populations CD3+, CD4+, CD8+, CD19+, CD56+. Two sample t-test was used to determine the statistical significance between the cohorts at the time points. The standard arm had an ALC reduction of 28% at one week post Tx and a nadir at 4 weeks with a 34% reduction. Absolute percentage reductions in ALC from baseline in the optimized arm compared to the standard arm are: end of treatment point (13%, p = 0.03), 4 weeks (12%, p = 0.08), 6 months (15%, p = 0.1), and all three time points together 13% (p = 0.001). ALC recovery appears to be faster in the optimized arm. Radiation induced suppression of all blood cell types are also reduced in the optimized arm with respect to standard arm (relative percentages): ALC (34%), WBC (47%), RBC (46%), platelets (40%), monocytes (100%), and neutrophils (62%) at 4-week mark. Average percentage reductions on integral doses, and V5 (volume receiving a 5 Gy dose) of optimized compared to standard plans are: aorta: 26%, 41% heart: 8%, 33%, vena cava: 32%, 52%, T spine: 51%, 81%, lymph nodes: 35%, 57%, total lung- ITV: 1.6%, 1%, body: 10%, 14%. For the first time, we have shown that it is possible to reduce RIIS in a statistically significant manner, compared to standard of care, via optimized RT planning using a predictive model. This has implications in increasing the efficacy of immunotherapy by preserving the existing tumor reactive T cells in the immune system to enhance anti-tumor activity, and in reducing hospitalizations and improving survival.