Lymphocytes are a type of white blood cell (WBC) responsible for adaptive immunity. Thoracic tumors are adjacent to many blood/immune rich organs including the great vessels, heart, thoracic-spine, and lymph-node-stations. During radiation treatment the impact to lymphocytes can be significant. This may cause a decrease in the amount of lymphocytes. A researcher at UVA has created a system to predict and reduce the immune cell reduction following lung SBRT treatments beyond standard of care. The predicted decrease in lymphocytes will be compared to the actual decrease in lymphocytes found in peripheral blood.

Researchers have found a way to give radiation that they think will result in a smaller decrease in lymphocytes after radiation. There will be two groups in this study, about half of the participants will have their radiation designed to decrease radiation to organs with a lot of blood and the other half will receive standard radiation therapy.

Participants are being asked to take part in this study because the participants have been diagnosed with NSCLC and will be receiving a type of radiation therapy called stereotactic body radiation therapy (SBRT) where high doses of radiation will be delivered to the tumor, while minimizing damage to healthy surrounding tissues.

Lymphocytes play a crucial role in the body's response to cancer by directly attacking tumors, inhibiting tumor growth and spread, and detecting and potentially eliminating emerging tumors. Tumor-infiltrating lymphocytes (TILs) are commonly found within tumors, and studies have shown that their presence is associated with more favorable outcomes. Radiation therapy (RT), particularly Stereotactic Body Radiation Therapy (SBRT), modulates the immune system by promoting the generation of Cytotoxic T Lymphocytes (CTLs) and enhancing T cell infiltration into tumors. These CTLs may eliminate distant metastases or residual disease (abscopal effect) not targeted by the primary treatment.

Lymphopenia, a known consequence of radiation therapy to virtually every part of the body, was first described in the early 20th century shortly after the discovery of X-rays. It is highly possible that irradiation of blood rich and lymphatic rich organs and bone marrow would reduce the lymphocyte counts significantly.

Additionally, recent data have suggested that lymphocyte subsets exhibit differential sensitivity to radiation, with helper CD4+ T cells being more sensitive than cytotoxic CD8+ T cells in glioblastoma (GBM) treated with RT and temozolomide, and naïve T cells more sensitive than memory T cells in prostate cancer.

Based on existing data on the effects of irradiation on total lymphocyte count and the effects on subsets of T cells, the investigators have created a lymphodepletion predictive algorithm. In this clinical trial, the investigators will test whether optimized SBRT plans lead to lower lymphocyte depletion and whether the algorithm can accurately predict lymphocyte decreases following SBRT. Optimized SBRT plans will meet all standard of care dose-volume objectives for SBRT and for the protection of organs-at-risk (OAR), but will also minimize radiation exposure to circulating blood and lymphatics, including the heart, great-vessels, lymph-node-stations, and thoracic-spine beyond what is currently optimized to reduce the integral dose to circulating blood/lymphocytes. This study will allow us to evaluate the performance of our predictive algorithm for post-SBRT decrease in lymphocyte count and to determine whether additional steps in SBRT planning will deliver lower risk of post-SBRT decreases in lymphocyte count.

Inclusion Criteria:

1. Willingness and ability to provide written informed consent and to comply with the study protocol.

2. Diagnosis of biopsy confirmed non-small cell lung cancer (NSCLC) with planned treatment with SBRT as definitive therapy OR imaging confirmed lung lesion for which SBRT is planned for primary lung cancer (when clinician determines biopsy is not indicated), Registration should occur within 5 business days (before or after) of planning CT.

3. Patients must decline surgery or tumor(s) must be considered to be medically inoperable

4. Location and size of tumor- Participants must have either:

   • peripherally located tumors (> 2 cm in all directions from the proximal bronchial tree; see Figure 2 above) as defined by RTOG 0915, OR
   • centrally located tumors (tumor size ≤ 5 cm, tumors within or touching the zone of the proximal bronchial tree or adjacent to mediastinal or pericardial pleura) as defined by RTOG 0813.

5. Patients with recurrence of prior surgically treated lung cancers are eligible if no further surgery is planned and they otherwise meet the eligibility criteria.

6. Measurable disease on chest CT, PET CT, CT simulation at diagnosis ( must be within 8 weeks of SBRT).

7. Pre- radiation therapy total lymphocyte count > 0.5k/μL on blood count drawn within 2 weeks prior to registration.

8. In the opinion of the treating clinician, patient is medically able to tolerate the study SBRT treatment of 50-60 Gy in 5 fractions.

9. ECOG performance status of 0-2.

10. Age ≥ 18 years.

11. If participant is a woman of childbearing potential (WOCBP), agreement to adhere to contraception requirements from the time of consent through completion of SBRT.

Exclusion Criteria

1. Prior history of radiation therapy within 2 years of registration, however radiation therapy for skin cancer is allowed
2. Systemic anti-cancer therapy within the last year prior to registration or planned use during or within 6 months following SBRT.
3. Major surgery within the last 30 days before registration and/or planned before the completion of the 6 months post SBRT follow up timeframe.
4. Subject is a prisoner.
5. Subject is a pregnant woman.
6. Patient is not medically able to tolerate the study SBRT treatment of 50-60 Gy in 5 fractions or cannot comply with other aspects of the study including serial bloodwork.
7. Subject has HIV, AIDS, any type of hepatitis and/or any blood borne infectious disease for which the research lab cannot receive blood samples.

Two participants were discontinued from the study before staring treatment but after randomization. One participant became ineligible after discovering new medical history information and the other participant withdrew consent.

From the time informed consent is obtained until 6 months after completion of SBRT (up to 11months)

Participants, clinical research staff, and treating clinicians will be aware of arm assignment. The labels on research blood will not include the treatment arm on which the participant is assigned and this information will not be provided to lab investigators and staff.