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* These authors contributed equally
Here, we present a protocol to evaluate the effects of radiation therapy on immune system lymphocytes in small cell lung cancer.
Small cell lung cancer (SCLC) has garnered significant attention due to its high malignancy, propensity for distant metastasis, and poor prognosis. Radiotherapy remains the cornerstone of treatment for limited-stage small cell lung cancer (LS-SCLC). However, outcomes with radiotherapy alone or in combination with chemotherapy remain suboptimal. Radiotherapy can induce lymphopenia by directly irradiating hematopoietic organs or destroying mature circulating lymphocytes, leading to immunosuppression and consequently diminishing therapeutic efficacy. The estimated dose of radiation to immune cells (EDRIC) model integrates factors such as hemodynamics, lymphocyte radiosensitivity, and proliferation capacity. This study employs the EDRIC model with enhancements to calculate the circulating immune cell radiation dose. By utilizing the EDRIC methodology, the study explores the correlation between EDRIC and tumor target size, average lung dose, average heart dose, clinical features, and peripheral blood lymphocytopenia during radiotherapy for LS-SCLC, aiming to inform personalized patient treatment strategies.
This study analyzed data from 64 LS-SCLC patients who met the inclusion criteria at the General Hospital of Ningxia Medical University from January 2023 to January 2024, all of whom received radical thoracic conventional fractionated radiotherapy. Lymphocyte counts were recorded at the following points: before radiotherapy, at the lowest observed value during radiotherapy, at the end of radiotherapy, and one-month post-radiotherapy. Dosimetric data, including average lung, heart, and body doses, were extracted from the treatment planning system, and the circulating EDRIC was calculated using this model. The relationship between EDRIC values and therapeutic outcomes was analyzed. In LS-SCLC, the EDRIC model effectively predicts lymphocyte count reduction, correlating with planning target volume (PTV; cm3), TNM stage, and the percentage of target lesion shrinkage. Post-radiotherapy, there was a significant decrease in peripheral blood lymphocyte counts, with greater EDRIC values indicating more pronounced lymphocyte reduction.
Lung cancer remains a leading cause of morbidity and mortality worldwide, with small cell lung cancer (SCLC) comprising 13%-17% of cases1,2. SCLC is characterized by a high degree of malignancy and a propensity for early distant metastasis, often leading to late-stage diagnosis and poor prognosis. Advances in medical technology and a deeper understanding of the biological characteristics of SCLC have highlighted the potential value of radiotherapy in its treatment. Nonetheless, outcomes with radiotherapy alone or in combination with chemotherapy remain suboptimal. Identifying key factors influencing the efficacy of radiotherapy in SCLC is essential to provide a theoretical basis for individualized treatment strategies and prognosis prediction.
The immune system exhibits intricate interactions with radiation or chemotherapy, enhancing tumor cell eradication during treatment3,4. Radiation therapy, for instance, can foster immune activation via cytokine or antigen release, thereby inducing tumor regression within the radiation field (known as the abscopal effect)5. However, radiotherapy may also induce immunosuppression when treating various solid tumors, potentially compromising therapeutic efficacy. This immunosuppression may stem from myelosuppression due to direct irradiation of hematopoietic organs or the destruction of mature circulating lymphocytes, resulting in reduced lymphocytes. Studies have pinpointed specific tumor size and radiation doses to critical organs such as the heart and lungs in small cell lung cancer as crucial predictors of immunosuppression, with potential implications for patient survival6.
Lymphocytes and their precursor cells rank among the most radiation-sensitive cell types7. Susannah Yovino's8 investigation into circulating cell radiation dose (DCC) in brain glioma patients post-radiotherapy revealed that alterations in the size of the planning target volume (PTV) influence the average DCC radiation dose. The radiation dose to circulating blood cells may significantly contribute to the mechanism of induced lymphocytopenia. While irradiation of bone marrow or lymph nodes can induce lymphocytopenia, irradiation of structures devoid of lymphoid tissue or bone marrow, such as the brain, can also trigger lymphocytopenia. Jin et al.9developed the estimated dose of radiation to immune cells (EDRIC) model and dosimetry to quantify radiotherapy-induced immune system damage. This study employs the EDRIC model with enhancements from Ladbury et al.6 to calculate the circulating immune cell radiation dose.
Consequently, the EDRIC method was utilized to compute the circulating lymphocyte radiation dose and investigate its relationship with treatment efficacy and prognosis during radiotherapy for small cell lung cancer10. The correlation between EDRIC values and factors such as age, gender, Karnofsky Performance Status (KPS) score, smoking history, tumor size, and tumor stage was analyzed through stratification. Furthermore, the correlation between peripheral blood lymphocytopenia and circulating lymphocyte radiation dose was compared to lay the groundwork for personalized treatment strategies and prognosis prediction.
Following stringent adherence to this study's inclusion and exclusion criteria, informed consent for radiotherapy was obtained from each patient and their guardian. Clinical staging was conducted in accordance with the American Joint Committee on Cancer (AJCC) TNM staging system (8th edition). The Ethics Committee of Ningxia Medical University General Hospital (KYLL-2022-0984) granted approval for this study.
NOTE: The inclusion criteria were as follows: (i) pathologically confirmed limited-stage small cell lung cancer (TNM stage II and III); (ii) initial radiotherapy treatment utilizing conformal intensity-modulated radiotherapy (IMRT) or volumetric arc intensity-modulated radiotherapy (VMAT), with a total radiation dose ranging from 50-60 Gy and a single dose of 2 Gy; (iii) pre-radiotherapy blood parameters within the normal range (WBC ≥ 4 x 109 cells/L, Hb ≥ 100 g/L, PLT ≥ 100 x 109/L), and normal function of vital organs such as the heart, liver, and kidneys; (iv) availability of complete clinical data and radiotherapy records; (v) expected survival of more than 3 months; (vi) non-pregnant or lactating women. The exclusion criteria included: (i) patients with blood or immune system disorders or significant organ damage; (ii) history of prolonged oral steroid therapy; (iii) patients who did not complete planned radiotherapy; (iv) recent history of confirmed infection.
1. General clinical information
2. Pretreatment preparation
3. Radiotherapy
4. Evaluation method and index
5. Statistical methods
Clinical outcome
The operative time changes in chest CT lesions and mediastinal lymph nodes were observed in all patients before and 1 month after radiotherapy, with therapeutic efficacy evaluated using RECIST criteria. Among the 64 patients with limited-stage small cell lung cancer, 4 cases exhibited complete response, while 57 cases showed partial response, and three patients had stable disease.
The correlation analysis between EDRIC and various clinical features revea...
The immune system plays a pivotal role in tumor control during radiotherapy, yet radiation-induced immunotoxicity, such as lymphocytopenia, is linked to unfavorable survival outcomes13,14. SCLC is characterized by its high malignancy, often diagnosed in advanced stages with a dismal prognosis. Radiotherapy stands as the cornerstone treatment for LS-SCLC. However, its impact on the immune system is complex. The efficacy of radiotherapy alone or in combination with...
The authors have nothing to disclose.
This work was supported by the University-level Research Project of Ningxia Medical University (XM2022017).
Name | Company | Catalog Number | Comments |
CT machine | Siemens Healthcare | SOMATOM Force | |
MRI machine | Siemens Healthcare | MAGNETOM Terra | |
Varian Clinac_IX Medical electron linear Accelerator | Siemens Healthcare | IX |
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