Lymphocyte Depletion and Change in Lymphocyte Functionality

Study Overview
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Brief Summary
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Lymphocytes are a type of white blood cell (WBC) found in the participant's blood. During radiation treatment, moving blood is exposed to radiation. 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 tx in lymphocytes in patients with Non-Small Cell Lung Cancer (NSCLC). The predicted decrease of lymphocytes will be compared to the actual decrease in lymphocytes found in 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.

Detailed Description
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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. Radiation therapy (RT) can induce lymphopenia in the absence of concomitant chemotherapy or steroids and even when neither bone marrow nor lymphatic tissue is included in the treatment field. It is highly possible that irradiation of blood rich organs such as the great vessels, would reduce the lymphocyte count significantly. Given this known radiation-induced toxicity, circulating blood should be considered an organ at risk during irradiation, and efforts should be made to understand the toxicity from radiation to circulating blood -normal tissue complication probabilities (NTCP) so that this may be included in the optimization strategy during radiation treatment. 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 protection of organs-at-risk (OAR), but will also reduce radiation to the regional great vessels, lungs, and heart 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.

Official Title
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A Pilot Randomized Study of Lymphocyte Depletion & Change in Lymphocyte Functionality During Lung Stereotactic Body Radiation (SBRT) Therapy Treatment by Selectively Reducing Irradiation of Circulating Blood Compared to Standard of Care Control Group

Conditions
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Lymphocyte Depletion

Intervention / Treatment
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* Radiation: SBRT with additional treatment planning dose optimization
* Radiation: SBRT with standard of care planning only
* Diagnostic Test: Blood Draws


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willingness and ability to provide written informed consent and to comply with the study protocol. 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. Patients must decline surgery or tumor(s) must be considered to be medically inoperable 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. Patients with recurrence of prior surgically treated lung cancers are eligible if no further surgery is planned and they otherwise meet the eligibility criteria. Measurable disease on chest CT, PET CT, CT simulation at diagnosis ( must be within 8 weeks of SBRT). Pre- radiation therapy total lymphocyte count > 0.5k/μL on blood count drawn within 2 weeks prior to registration. In the opinion of the treating clinician, patient is medically able to tolerate the study SBRT treatment of 50-60 Gy in 5 fractions. ECOG performance status of 0-2. Age ≥ 18 years. 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 Prior history of radiation therapy for any reason. Systemic anti-cancer therapy within the last year prior to registration or planned use during or within 6 months following SBRT. Major surgery within the last 30 days before registration and/or planned before the completion of the 6 months post SBRT follow up timeframe. Subject is a prisoner. Subject is a pregnant woman. Patient is not medically able to tolerate the study SBRT treatment of 50-60 Gy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SBRT Additional treatment planning dose optimization<br>Lung SBRT 50-60Gy in 5 fractions with standard of care planning and additional treatment planning dose optimization criteria to minimize decrease in lymphocyte count beyond dosimetric criteria from RTOG 0915/0813 SBRT trials. | Radiation: SBRT with additional treatment planning dose optimization<br>* Lung SBRT 50-60Gy in 5 fractions with standard of care planning and additional treatment planning dose optimization criteria to minimize decrease in lymphocyte count beyond dosimetric criteria from RTOG 0915/0813 SBRT trials.<br>Diagnostic Test: Blood Draws<br>* CBC w/ Diff and additional blood analysis for all participants in both groups. Blood draws will prior to treatment, end of treatment, 4 weeks after treatment, and 6 months after treatment.<br>|
| Active Comparator: SBRT with standard of care planning only<br>Lung SBRT 50-60Gy in 5 fractions with standard of care planning (no additional dose optimization beyond SOC) | Radiation: SBRT with standard of care planning only<br>* Lung SBRT 50-60Gy in 5 fractions with standard of care planning (no additional dose optimization beyond SOC)<br>Diagnostic Test: Blood Draws<br>* CBC w/ Diff and additional blood analysis for all participants in both groups. Blood draws will prior to treatment, end of treatment, 4 weeks after treatment, and 6 months after treatment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine the prediction accuracy of the algorithm for the lymphocyte depletion post RT for the treatment in 50 evaluable participants with NSCLC | Determine if the algorithm can independently predict the magnitude of lymphocyte reduction for all 50 evaluable patients | Baseline and 4 weeks post SBRT | 
| Impact of Lymphocyte-Sparing SBRT Planning Objectives on Post-SBRT Lymphocyte Count | Lymphocyte point of 4 weeks following SBRT treatment will be used to estimate both the actual and percentage decreases in lymphocyte counts seen in each arm | Changes from baseline and 4 weeks after SBRT completion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Event Profile | Describe the adverse event profile of participants treated with and without lymphocyte-sparing SBRT planning (Arms A and B). | Baseline through 6 months SBRT according to CTCAE version 5.0 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Lymphocyte Depletion and Change, SBRT, NSCLC, Lung Cancer, radiation therapy, non small cell, Stereotactic body radiation therapy, Treatment related lymphopenia