Severe Radiation-induced Lymphopenia Research Articles

Reduced Risk of Severe Radiation-Induced Lymphopenia in Carbon Ion Radiation Therapy for Locally Advanced Pancreatic Cancer: A Comparative Analysis of Carbon Versus Photon Therapy.

Radiation-induced lymphopenia (RIL) is associated with poor prognosis in patients with locally advanced pancreatic cancers. However, there are no reports comparing the effects of carbon ion radiation therapy (CIRT) and photon beam radiation therapy (RT) on the development of RIL. Differences in RIL after CIRT or photon beam RT and predictive factors for RIL in patients with locally advanced pancreatic cancer were investigated. This retrospective study cohort included 834 patients who received concurrent chemoradiotherapy (CCRT) in 2 separate institutions: 337 and 497 in the CIRT and photon beam RT groups, respectively. Severe RIL was defined as an absolute lymphocyte count (ALC) <0.5 × 109 cells/L. A 1:1 propensity score-matching analysis was performed between the CIRT and photon beam RT groups. Patients were categorized into 3 groups according to the development of recovery from severe RIL: no severe RIL (Group A), recovery from severe RIL (Group B), and no recovery from severe RIL (Group C). Logistic regression analysis was performed to identify the predictive value of severe RIL. The prognostic factors of overall survival (OS) were determined using Cox regression analysis. After propensity score matching, the baseline ALC and planning target volume of the CIRT and photon beam RT groups were comparable. During CCRT, the ALC of the entire cohort decreased and was significantly lower in the photon beam RT group than in the CIRT group (P < .001). Multivariate logistic regression analysis showed that CIRT reduced severe RIL more than photon beam RT. After adjusting for other factors, the RT modality and RIL were significantly associated with OS. Photon beam RT showed a significantly worse OS than CIRT, and Group C showed a significantly worse OS than Group A. CIRT seems to reduce the development of severe RIL. The RT modality and development/recovery from severe RIL were associated with OS in patients who received CCRT for locally advanced pancreatic cancer. The reduction of severe RIL through optimized RT may be essential for improving treatment outcomes.

Personalized Composite Dosimetric Score-Based Machine Learning Model of Severe Radiation-Induced Lymphopenia among Esophageal Cancer Patients

Radiation-induced lymphopenia (RIL) is common among patients undergoing radiotherapy (RT), and severe RIL has been linked with adverse outcomes. The severity and risk of RIL can be predicted from baseline clinical characteristics and dosimetric parameters. However, dose-volume (DV) indices are highly correlated with one another and are only weakly associated with RIL. Here we introduce the novel concept of "composite dosimetric score" (CDS) as the index that condenses the dose distribution in immune tissues of interest to study the dosimetric dependence of RIL. We derived an improved multivariate classification scheme for risk of grade 4 (G4) RIL, based on this novel RT dosimetric feature, for patients receiving chemoRT for esophageal cancer. DV indices were extracted for 734 patients who received chemoRT for biopsy-proven esophageal cancer. Non-negative matrix factorization was used to project the DV indices of lung, heart, and spleen into a single CDS; XGBoost was employed to explore significant interactions among predictors; and logistic regression was applied to combine the resultant CDS along with baseline clinical factors and interaction terms to facilitate individualized prediction of immunotoxicity. Five-fold cross-validation was applied to evaluate the model performance. The CDS for selected immune organs at risk (OARs, i.e., heart, lung, and spleen) (1.791, 95 CI [1.350,2.377]) was a statistically significant risk determinant for G4RIL. Pearson correlation coefficients for CDS vs. G4RIL risk for individual immune OARs were greater than any single DV indices. Personalized prediction of G4RIL based on CDS and 4 clinical risk factors yielded an area under the curve value of 0.78. Interaction between age and CDS revealed that G4RIL risk increased more sharply with increasing CDS for patients ≥65. Risk of immunotoxicity for patients undergoing chemoRT for esophageal cancer can be predicted by CDS. The CDS concept can be extended to immunotoxicity in other cancer types and in dose-response models currently based on DV indices. Personalized treatment planning should leverage CDS methods rather than using individual or subsets of DV indices.

LymphoDose: a lymphocyte dose estimation framework—application to brain radiotherapy

Objective. Severe radiation-induced lymphopenia occurs in 40% of patients treated for primary brain tumors and is an independent risk factor of poor survival outcomes. We developed an in-silico framework that estimates the radiation doses received by lymphocytes during volumetric modulated arc therapy brain irradiation. Approach. We implemented a simulation consisting of two interconnected compartmental models describing the slow recirculation of lymphocytes between lymphoid organs ( M1 ) and the bloodstream ( M2 ). We used dosimetry data from 33 patients treated with chemo-radiation for glioblastoma to compare three cases of the model, corresponding to different physical and biological scenarios: (H1) lymphocytes circulation only in the bloodstream i.e. circulation in M2 only; (H2) lymphocytes recirculation between lymphoid organs i.e. circulation in M1 and M2 interconnected; (H3) lymphocytes recirculation between lymphoid organs and deep-learning computed out-of-field (OOF) dose to head and neck (H&N) lymphoid structures. A sensitivity analysis of the model’s parameters was also performed. Main results. For H1, H2 and H3 cases respectively, the irradiated fraction of lymphocytes was 99.8 ± 0.7%, 40.4 ± 10.2% et 97.6 ± 2.5%, and the average dose to irradiated pool was 309.9 ± 74.7 mGy, 52.6 ± 21.1 mGy and 265.6 ± 48.5 mGy. The recirculation process considered in the H2 case implied that irradiated lymphocytes were irradiated in the field only 1.58 ± 0.91 times on average after treatment. The OOF irradiation of H&N lymphoid structures considered in H3 was an important contribution to lymphocytes dose. In all cases, the estimated doses are low compared with lymphocytes radiosensitivity, and other mechanisms could explain high prevalence of RIL in patients with brain tumors. Significance. Our framework is the first to take into account OOF doses and recirculation in lymphocyte dose assessment during brain irradiation. Our results demonstrate the need to clarify the indirect effects of irradiation on lymphopenia, in order to potentiate the combination of radio-immunotherapy or the abscopal effect.

Abstract 1118: Mitigating radiation-induced lymphopenia using interleukin-15: Preclinical rationale for clinical translation

Abstract Background: Radiation therapy is a common treatment for cancer patients, with nearly 50% of them undergoing this procedure. While radiation is effective at targeting tumor cells, it also has the unintended consequence of killing lymphocytes, which are among the most sensitive cells to radiation within the erythroid, myeloid, and lymphoid lineages. This phenomenon is known as radiation-induced lymphopenia (RIL) and is considered a negative prognostic factor in various malignant solid tumors. It occurs severely in over 40% of solid tumor patients who receive radiotherapy. Some previous studies have shown promising results with IL15 therapy in increasing circulating lymphocytes in cancer patients. However, until now, no studies have investigated the impact of IL15 in the context of radiation-induced lymphopenia. Our study aims to investigate whether IL15 can boost lymphocyte numbers and decrease tumor burden following radiation treatment in a mouse model. Methods: To conduct our study, we subcutaneously injected TSA tumor cells into the flank region of mice. Once the tumors reached a palpable size, approximately 50mm3, we divided the mice into four groups: Control (Con), Irradiation (IR), Control with IL15 (Con+IL15), and Irradiation with IL15 (IR+IL15). The irradiated mouse groups received a radiation dose of 2 Gray in the thorax and 1 Gray in the spleen for five consecutive days, simulating the severe radiation-induced lymphopenia observed in cancer patients. After the radiation treatment, the IL15-treated groups received IL15 in combination with recombinant IL15 in a 1:6 ratio weekly. Throughout the experiment, we monitored the circulating lymphocytes and tumor growth. After two weeks following the last radiation dose, we euthanized the mice, collected blood, spleen, and tumor samples, and identified immune cells using flow cytometry. Results: The radiation treatment significantly increased tumor growth while decreasing the number of lymphocytes, including B cells, T cells, and NK cells, in the blood. IL15 administration led to an increase in the number of lymphocytes both in the blood and within the tumor compared to the irradiated group. We observed a trend toward reduced tumor growth in the group that received both IL15 and radiation (IR+IL15) compared to the group that received radiation alone (IR). Conclusion: IL15 effectively boosted the number of lymphocytes in both the bloodstream and tumors, resulting in slower tumor growth in the IL15-treated group compared to the irradiated group. This study is of significant importance as it demonstrates the potential of IL15 to counteract radiation-induced lymphopenia in mice with TSA tumors. Further testing of these findings is currently underway in MC38 tumor-bearing mice, a cell line known to be more radiation-sensitive. Citation Format: Priti Gupta, Min Wang, Steven Lin. Mitigating radiation-induced lymphopenia using interleukin-15: Preclinical rationale for clinical translation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1118.

Normal Tissue Complication Probability Modeling of Severe Radiation-Induced Lymphopenia Using Blood Dose for Patients With Hepatocellular Carcinoma

PurposeThis study aims to develop a normal tissue complication probability (NTCP) model to estimate the risk of severe radiation-induced lymphopenia (SRIL, absolute lymphocyte count (ALC) < 500/μL) by using the blood dose of hepatocellular carcinoma (HCC) patients. Methods and MaterialsWe retrospectively collected data from 75 HCC patients who received radiotherapy (RT) between 2015 and 2018. The hematological dose framework calculated blood dose-volume histograms (DVHs) using a predefined blood flow model, organ DVHs, the number of treatment fractions, and beam delivery time. A Lyman-Kutcher-Burman (LKB) model with a generalized equivalent dose was used to establish the NTCP model, reflecting the whole blood DVHs. The optimization of the LKB parameters was conducted by minimizing a negative log-likelihood function. ResultsThere were 6, 4, 18, 33, and 14 patients in the groups with radiation-induced lymphopenia grades 0, 1, 2, 3, and 4, respectively. The median pre/post-RT ALC were 1410/μL (range, 520–3710/μL) and 470/μL (range, 60–1760/μL), respectively. There was a correlation between blood mean dose and ALC depletion (Pearson r = -0.664; p < 0.001). The average blood mean doses in each radiation-induced lymphopenia group were 2.90 Gy (95% CI, 1.96–3.85 Gy) for grade 0–1, 5.29 Gy (95% CI, 4.12–6.45 Gy) for grade 2, 8.81 Gy (95% CI, 7.55–10.07 Gy) for grade 3, and 11.69 Gy (95% CI, 9.82–17.57 Gy) for grade 4. When applying developed an NTCP model to predict SRIL, the area under the receiver operating characteristic curve and Brier score were 0.89 and 0.12, respectively. ConclusionWe developed the first NTCP model based on whole blood DVHs for estimating SRIL after abdominal RT in HCC patients. Our results showed a strong correlation between blood dose and ALC depletion, suggesting the potential to predict the risk of SRIL occurrence for using blood dose.

Severe radiation-induced lymphopenia during concurrent chemoradiotherapy for stage III non-small cell lung cancer: external validation of two prediction models.

Severe radiation-induced lymphopenia (RIL) in patients undergoing chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is associated with decreased immunotherapy efficacy and survival. At The Christie and MD Anderson Cancer Center (MDACC), prediction models for lymphopenia were developed in lung and esophageal cancer patients, respectively. The aim of this study was to externally validate both models in patients with stage III NSCLC. Patients who underwent concurrent CRT for stage III NSCLC in 2019-2021 were studied. Outcomes were grade ≥3 and grade 4 lymphopenia during CRT. The Christie model predictors for grade ≥3 lymphopenia included age, baseline lymphocyte count, radiotherapy duration, chemotherapy, mean heart and lung doses, and thoracic vertebrae V20Gy. MDACC predictors for grade 4 lymphopenia were age, baseline lymphocyte count, planning target volume (PTV), and BMI. The external performance of both models was assessed. Among 100 patients, 78 patients (78%) developed grade ≥3 lymphopenia, with grade 4 lymphopenia in 17 (17%). For predicting grade ≥3 lymphopenia, the Christie and MDACC models yielded c-statistics of 0.77 and 0.79, respectively. For predicting grade 4 lymphopenia, c-statistics were 0.69 and 0.80, respectively. Calibration for the Christie and MDACC models demonstrated moderate and good agreement, respectively. The PTV-based MDACC prediction model for severe RIL demonstrated superior external performance in NSCLC patients compared to the dosimetry-based Christie model. As such, the MDACC model can aid in identifying patients at high risk for severe lymphopenia. However, to optimize radiotherapy planning, further improvement and external validation of dosimetry-based models is desired.

A Risk Prediction Model for Severe Radiation Induced Lymphopenia in Patients with Pancreatic Cancer Treated with Concurrent Chemoradiotherapy

In pancreatic cancer, radiation induced lymphopenia (RIL) is associated with a poor prognosis. However, normal tissue complication probability (NTCP) models predicting RIL in pancreatic cancer treated with concurrent chemoradiotherapy (CCRT) have yet to be developed. This study aims to develop a least absolute shrinkage and selection operator (LASSO)-based multivariate NTCP model to predict severe RIL in patients with pancreatic cancer during CCRT and to validate the model internally. We retrospectively reviewed patients with localized pancreatic cancer who underwent CCRT using three-dimensional conformal radiation therapy from 2013 to 2021. The exclusion criteria were patients with distant metastasis; patients who did not complete RT due to tumor progression; patients who did not have absolute lymphocyte count (ALC) data available before or during RT. An ALC of < 0.5 K/μL during CCRT was defined as severe RIL. A NTCP model of severe RIL was developed by LASSO-based multivariate analysis. We used age, sex, Karnofsky performance status, maximum tumor size, carbohydrate antigen 19-9 level before RT, ALC before RT, volume of planning target volume (PTV), and dosimetric parameters for surrounding organs (including spleen, vertebrae, liver, bilateral kidneys, gastrointestinal tracts) as variables for LASSO. In addition, internal validation was performed by the bootstrap method. The predictive performance of the model was evaluated by the area under the curve (AUC) of the receiver operating characteristic curve and scaled Brier score. Of the 131 patients included in the study, the median age was 68 years (range, 42-84), and 55% were male. The median ALC before RT was 1.37 K/µL (0.52-3.50). The median PTV volume was 315.4 ml (86.3-1079.3). The median dose of radiotherapy was 50.4 Gy (16.2-50.4), with 1.8 Gy per fraction. Combination chemotherapy was S-1 in 99 cases (75.6%) and gemcitabine in 32 cases (24.4%). Induction chemotherapy before CCRT was performed in 39 patients (29.8%). Severe RIL was observed in 84 (63.6%) patients. The LASSO showed that low baseline ALC (p = 0.0002), large PTV volume (p < 0.0001), and a large kidney V5 defined as the percentage of bilateral kidneys receiving 5 Gy or more (p = 0.0338) were selected as parameters of the prediction model for severe RIL (AUC = 0.917) and scaled Brier score was 0.511. As a result of internal validation by the bootstrap method, the average AUC was 0.918 (95% confidence interval, 0.849-0.954). Severe RIL occurred frequently during CCRT for pancreatic cancer, and a NTCP model for severe RIL developed and validated internally in this study showed good predictive performance. External validation is needed before this NTCP model can be used as a benchmark for treatment planning to reduce the risk of severe RIL and for considering future treatment approaches.

The Incidence of Severe Radiation-Induced Lymphopenia during Chemoradiotherapy for Stage Ⅲ Non-Small Cell Lung Cancer: A Comparative Study of Proton Versus Photon-Based Radiotherapy

To investigate the incidence of severe radiation-induced lymphopenia (SRL) and the survival in patients with stage Ⅲ non-small cell lung cancer treated with concurrent chemoradiotherapy with passive scattering proton beam (PSPT) or photon-based radiotherapy (XRT) including 3D-CRT and IMRT. We conducted a retrospective cohort study including 355 patients who received definitive concurrent chemoradiotherapy with PSPT (n = 38) or XRT (n = 317) at our institution between January 2010 and December 2020. SRL during concurrent chemoradiotherapy was defined as absolute lymphocyte counts (ALCs) of <500 cells/mm3. Propensity score matching (PSM) analysis was performed to adjust for the patient characteristics between the PSPT and XRT groups. Propensity scores were calculated using age, sex, PS (0-1 vs. 2), primary tumor location (upper/middle vs. lower lobe), pathology (Adeno vs. Others), PTV volume, ALCs at pretreatment, year of treatment (before vs. after July 2018, when durvalumab approved in Japan), and platinum-based chemotherapy regimen (CDDP based vs. CBDCA based). After PSM, the incidence of SRL and the overall survival (OS) were analyzed. The GTV and PTV volumes were significantly lower in the PSPT group than in the XRT group (median, 57 vs. 103 mm3; p < 0.05, 322 vs. 399 mm3; p < 0.05, respectively). ALCs at pretreatment were significantly lower in the PSPT group than in the XRT group (median, 1531 vs. 1718 cells/mm3; p < 0.05). SRL was observed in 275 patients (87%) in the XRT group and 27 patients (71%) in the PSPT group (p < 0.05). After PSM, PSPT significantly reduced the incidence of SRL compared to XRT (68.6 % vs. 88.6 %, p < 0.05), and the patients without SRL may have better 3-year OS than those with SRL (71.1 % vs. 55.3 %; p = 0.062). Compared with XRT, PSPT significantly reduced the incidence of SRL, and the patients without SRL had a good prognosis.

Higher radiation dose on immune cells is associated with radiation-induced lymphopenia and worse prognosis in patients with locally advanced esophageal squamous cell carcinoma.

To explore the effective dose to immune cells (EDIC) for better prognosis while avoiding radiation-induced lymphopenia (RIL) in patients with locally advanced esophageal squamous cell carcinoma (ESCC). Overall, 381 patients with locally advanced ESCC receiving definitive radiotherapy with or without chemotherapy (dRT ± CT) between 2014 and 2020 were included in this study. The EDIC model was calculated by radiation fraction number and mean doses to the heart, lung, and integral body. The correlation between EDIC and clinical outcomes was analyzed using Cox proportional hazards regression, and risk factors for RIL were determined by logistic regression analysis. The median EDIC was 4.38 Gy. Multivariate analysis revealed that low-EDIC significantly improved the OS of patients when compared with high-EDIC (HR = 1.614, P = 0.003) and PFS (HR = 1.401, P = 0.022). Moreover, high-EDIC was associated with a higher incidence of grade 4 RIL (OR = 2.053, P = 0.007) than low-EDIC. In addition, we identified body mass index (BMI), tumor thickness, and nodal stage as independent prognostic factors of OS and PFS, while BMI (OR = 0.576, P = 0.046) and weight loss (OR = 2.214, P = 0.005) as independent risk factors of grade 4 RIL. In subgroup analyses, the good group had better clinical outcomes than the remaining two groups (P< 0.001). This study demonstrated that EDIC significantly correlates with poor clinical outcomes and severe RIL. Optimizing treatment plans to decrease the radiation doses to immune cells is critical for improving the outcomes.

Reduced radiation exposure to circulating blood cells in proton therapy compared with X-ray therapy in locally advanced lung cancer: Computational simulation based on circulating blood cells.

We estimated the dose of circulating blood cells (CBCs) in patients with locally advanced non-small cell lung cancer for predicting severe radiation-induced lymphopenia (SRIL) and compared pencil-beam scanning proton therapy (PBSPT) and intensity-modulated (photon) radiotherapy (IMRT). After reviewing 325 patients who received definitive chemoradiotherapy with PBSPT (n = 37) or IMRT (n = 164). SRIL was diagnosed when two or more events of an absolute lymphocyte count < 200 µL occurred during the treatment course. Dose information for the heart and lungs was utilized for the time-dependent computational dose calculation of CBCs. The dose distribution of CBCs was significantly lesser in the PBSPT group than that in the IMRT group. Overall, 75 (37.3%) patients experienced SRIL during the treatment course; 72 and 3 patients were treated with IMRT and PBSPT, respectively. SRIL was associated with poor progression-free and overall survival outcomes. Upon incorporating the dose information of CBCs for predicting SRIL, CBC D90% > 2.6 GyE was associated with the development of SRIL with the baseline lymphocyte count and target volume. Furthermore, PBSPT significantly reduced the dose of CBC D90% (odds ratio = 0.11; p = 0.004) compared with IMRT. The results of this study demonstrate the significance of the dose distribution of CBCs in predicting SRIL. Furthermore, reducing the dose of CBCs after PBSPT minimized the risk of SRIL. Lymphocyte-sparing radiotherapy in PBSPT could improve outcomes, particularly in the setting of maintenance immunotherapy.

Severe Radiation-Induced Lymphopenia during Concurrent Chemoradiotherapy for Lung Cancer: External Validation of Two Prediction Models

<h3>Purpose/Objective(s)</h3> Severe radiation-induced lymphopenia in patients undergoing chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is associated with detrimental survival outcomes and decreased efficacy of subsequent immunotherapy. This impact provides a strong incentive to identify patients at high risk who could benefit from lymphopenia-mitigating strategies. At The Christie, a prediction model for grade ≥3 lymphopenia was developed in lung cancer patients. At MDACC, a model for grade 4 lymphopenia was developed in esophageal cancer patients. The aim of this study was to validate both models for predicting grade ≥3 and grade 4 lymphopenia during concurrent CRT in patients with stage III NSCLC. <h3>Materials/Methods</h3> Consecutive patients who underwent concurrent CRT for stage III NSCLC at our comprehensive cancer center between 2019 and 2020 were included. Mildly hypofractionated radiotherapy was administered (24 × 2.75 Gy to primary tumor and 24 × 2.42 Gy to involved lymph nodes). Chemotherapy consisted of daily low-dose cisplatin. The primary outcomes of grade ≥3 and grade 4 lymphopenia were defined as absolute lymphocyte count (ALC) nadirs during CRT of <0.5 and <0.2 K/mL, respectively. Predictors of the Christie model included age, baseline ALC, mean heart and lung doses, and thoracic vertebrae V20Gy. Predictors of the MDACC model were age, baseline ALC, and PTV in interaction with BMI. The prediction models' performance was assessed in terms of discrimination and calibration. <h3>Results</h3> A group of 68 patients was studied in which 51 patients (75%) developed grade ≥3 lymphopenia during CRT, with grade 4 lymphopenia in 9 patients (13%). For prediction of grade ≥3 lymphopenia, application of the Christie and MDACC models yielded c-statistics of 0.82 (95%CI: 0.71-0.94) and 0.85 (95%CI: 0.73-0.97), respectively. For prediction of grade 4 lymphopenia, the Christie and MDACC models yielded c-statistics of 0.68 (95%CI: 0.51-0.86) and 0.78 (95%CI: 0.62-0.94), respectively. Calibration (adjusted for the a-priori risk) demonstrated moderate agreement between the observed and predicted risk for grade ≥3 and grade 4 lymphopenia using the Christie model (Table 1). Good calibration was found using the MDACC model for both grade ≥3 and grade 4 risk predictions. <h3>Conclusion</h3> The MDACC prediction model for severe radiation-induced lymphopenia demonstrated superior external performance in the setting of concurrent CRT in patients with stage III NSCLC as compared with the Christie prediction model. As such, the prediction model may aid in identifying thoracic cancer patients at high risk for severe lymphopenia.

Dose and Fractionation Effects on Lymphocyte-Sparing after Stereotactic Body Radiation Therapy in Patients with Pancreatic Cancer

<h3>Purpose/Objective(s)</h3> Radiation-induced lymphopenia (RIL) is caused by exposing the blood pool to radiation therapy and is associated with inferior survival in patients with pancreatic cancer (PC). Dose escalation with stereotactic body radiation therapy (SBRT) is associated with decreased severity of RIL and improved survival compared to conventional chemoradiation, however, there is also increasing appreciation for the need for larger field sizes to treat occult microscopic disease. We retrospectively analyzed patients undergoing SBRT for PC to explore if the number of fractions, BED10 dose, and PTV volume correlated with lymphopenia. <h3>Materials/Methods</h3> Total lymphocyte counts (TLCs) were compared before and up to 2 months after SBRT for 139 patients treated with SBRT for PC at two institutions. Univariate and multivariate analyses (MVA) were used to identify associations between TLC and G2+ lymphopenia (<800/mm^3), number of fractions, total BED10, and PTV. Baseline TLC were compared using Kruskal-Wallis test. PTV threshold for G2+ RIL was determined with receiver operating characteristic analysis. <h3>Results</h3> Median BED10 was 54.8Gy (48-100) (Table 1). Median baseline and post-SBRT ALC were 1.6/uL (0.59-6.09) and 0.85/uL (0.18-1.99), respectively. All groups had similar median baseline TLCs (p=0.567). G2+ lymphopenia was seen in 49/139 (35%) patients after SBRT. Median planning target volume (PTV) and tumor diameter was 85.5 (11.5-381.6) cm³ and 2.5 (0.3-7.8) cm³. On MVA, only PTV volume was associated with decrease in ALC (95% CI 0.24 - 0.95; P=0.001) and with G2+ lymphopenia (95% CI 1.2-12.9; p=0.019). G2+ lymphopenia was more common with PTV ≥ 178 cm^3 (P<0.01). There was no association between ALC or G2+ lymphopenia and age, gender, tumor diameter, tumor location, BED10, treatment with 5 vs 3 fractions, or treatment with 50 Gy in 5 fractions versus 36-39 Gy in 3 fractions. <h3>Conclusion</h3> While previous studies have shown that SBRT has improved RIL compared to conventional CRT, this effect appears to be independent of SBRT fractionation and total BED, but dependent on PTV size, a surrogate for the volume of lymphocytes exposed to RT. Given the association of severe RIL with survival in LAPC, our study suggests that PTV volume may drive development of lymphopenia and survival. Therefore, we demonstrate the need to balance the lymphopenia effect by limiting PTV size with SBRT with expansion of PTVs to include elective nodes at risk of harboring microscopic disease.

Severe radiation-induced lymphopenia during postoperative radiotherapy or chemoradiotherapy has poor prognosis in patients with stage IIB-III after radical esophagectomy: A post hoc analysis of a randomized controlled trial.

ObjectiveTo investigate whether radiation-induced lymphopenia (RIL) affects survival and identify the predictors of RIL in postoperative esophageal cancer.Materials and methods Post hoc analysis was conducted on data from 116 patients with esophageal cancer from a randomized controlled trial comparing adjuvant therapy with surgery alone. Doses of 54 Gy in 27 fractions was delivered in the postoperative radiotherapy (PORT) group and 50.4 Gy in 28 fractions combined with chemotherapy was delivered in postoperative concurrent chemoradiotherapy (POCRT) group. Blood counts were obtained before, during, and at first follow-up after treatment. Lymphopenia was graded per version 4.03 of the Common Terminology Criteria for Adverse Events. Disease-free survival (DFS) and overall survival (OS) were analyzed using the Kaplan-Meier method, and compared between groups using the log-rank test. Receiver operating characteristic curves identified thresholds for preventing grade 4 (G4) lymphopenia.ResultsMedian follow-up duration was 56.0 months. During treatment, 16 patients (13.8%) had G4 lymphopenia. All cases of G4 lymphopenia occurred in group PORT (30.2% vs 0.0%, p<0.001). Baseline absolute lymphocyte count was comparable between G1-3 and G4 patients (2.0 ± 0.8 *109/L vs 1.7 ± 0.5 *109/L; p=0.101). The 3-year DFS was significantly lower in group G4 lymphopenia than that in group G1-3 (31.3% vs 57.6%, p=0.036). The 3-year OS was comparable between both groups (50.0% vs 66.5%, p=0.095). Logistic regression analysis revealed that exposed more thoracic marrow (TM V20 ≥75%; TVB V20 ≥71%), heart (V15 ≥40%) and PTV (volume ≥507 ml) were associated with G4 lymphopenia (p<0.05).ConclusionsG4 RIL had poor disease-free survival, which may be related to more dose exposure of thoracic marrow and heart due to larger PTV. Reasonably reducing the radiation field combined with concurrent chemotherapy, or radiation dose constraints for these normal tissues may be sufficient to decrease the incidence of G4 lymphopenia, but further prospective trials are needed to verify the results.Clinical Trial Registration clinicaltrials.gov, identifier NCT02279134

EP05.01-010 External Validation of Two Prediction Models for Severe Radiation-induced Lymphopenia during Concurrent Chemoradiotherapy for Lung Cancer

Severe radiation-induced lymphopenia in patients undergoing chemoradiotherapy (CRT) for non-small cell lung cancer (NSCLC) is associated with detrimental survival outcomes and decreased efficacy of subsequent immunotherapy. This impact provides a strong incentive to identify patients at high risk who could benefit from lymphopenia-mitigating strategies. At The Christie, a prediction model for grade ≥3 lymphopenia was developed in lung cancer patients. At MDACC, a model for grade 4 lymphopenia was developed in esophageal cancer patients.

Severe Radiation-Induced Lymphopenia Attenuates the Benefit of Durvalumab After Concurrent Chemoradiotherapy for NSCLC

IntroductionDurvalumab after concurrent chemoradiation (CCRT) for NSCLC improves survival, but only in a subset of patients. We investigated the effect of severe radiation-induced lymphopenia (sRIL) on survival in these patients. MethodsOutcomes after CCRT (2010–2019) or CCRT followed by durvalumab (2018–2019) were reviewed. RIL was defined by absolute lymphocyte count (ALC) nadir in samples collected at end of CCRT; sRIL was defined as nadir ALC less than 0.23 × 109/L (the lowest tertile). Progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method. Cox proportional hazard modeling evaluated associations between clinical variables and survival. ResultsOf 309 patients, 192 (62%) received CCRT only and 117 (38%) CCRT plus durvalumab. Multivariable logistic regression analysis indicated that sRIL was associated with planning target volume (OR = 1.002, p = 0.001), stage IIIB disease (OR = 2.77, p = 0.04), and baseline ALC (OR = 0.36, p < 0.01). Durvalumab extended median PFS (23.3 versus 14.1 mo, p = 0.003) and OS (not reached versus 30.8 mo, p < 0.01). sRIL predicted poorer PFS and OS in both treatment groups. Among patients with sRIL, durvalumab did not improve survival (median = 24.6 mo versus 18.1 mo CCRT only, p = 0.079). On multivariable analyses, sRIL (OR = 1.81, p < 0.01) independently predicted poor survival. ConclusionsSevere RIL compromises survival benefits from durvalumab after CCRT for NSCLC. Measures to mitigate RIL after CCRT may be warranted to enhance the benefit of consolidation durvalumab.

Severe Radiation-Induced Lymphopenia Affects the Outcomes of Esophageal Cancer: A Comprehensive Systematic Review and Meta-Analysis.

Simple SummaryRadiotherapy is as an important part of esophageal cancer (EC) treatment. However, it often causes severe radiation-induced lymphopenia (RIL). The aim of the current study was to evaluate the influence of severe RIL on the outcomes of EC. A systematic review and meta-analysis including 17 studies was performed. Our meta-analysis found that severe RIL was associated with a lower pathologic complete response rate and inferior overall survival and progression-free survival of EC patients. The lymphocyte nadir was found during 4–6 weeks after the start of radiotherapy. A series of dosimetric factors and clinical factors associated with RIL were summarized. Our results provide important evidence for the clinical application of radiotherapy. Minimizing the dosimetric risk factors, especially in patients with clinical risk factors, might benefit their outcomes. Our results might also offer clues for the strategy of combining radiotherapy and immunotherapy in EC patients.The aim of the current study was to evaluate the influence of severe radiation-induced lymphopenia (RIL) on the outcomes of esophageal cancer (EC). A systematic review and meta-analysis was performed through the PRISMA guideline. Seventeen studies were included in the current systematic review, with eight included in the meta-analyses. Meta-analyses found that severe RIL was associated with lower pathologic complete response (pCR) rate (odds ratio (OR) = 0.44, 95% confidence interval (CI) = 0.30–0.66, I2 = 0%), inferior overall survival (OS) (hazard ratio (HR) = 1.50, 95% CI = 1.29–1.75, I2 = 6%), and worse progression-free survival (PFS) (HR = 1.70, 95% CI = 1.39–2.07, I2 = 0%) of EC patients. The lymphocyte nadir was found during 4–6 weeks after the start of radiotherapy. The leading dosimetric factors associated with severe RIL included larger PTV, higher dose to heart and body, and higher effective dose to the immune cells (EDIC). Clinical risk factors for RIL mainly comprised lower baseline ALC, higher tumor length and clinical stage, and distal EC. In conclusion, severe RIL might be associated with a lower pCR rate and worse OS and PFS of EC patients. Minimizing the dosimetric risk factors, especially in patients with clinical risk factors, might benefit their outcomes.

PD-0076 Predictive factors of severe radiation-induced lymphopenia in proton-treated patients

PD-0076 Predictive factors of severe radiation-induced lymphopenia in proton-treated patients

Lymphocyte Depletion Rate as a Biomarker of Radiation Dose to Circulating Lymphocytes During Fractionated Partial-Body Radiation Therapy

PurposeRadiation causes exponential depletion of circulating lymphocyte populations; in turn, radiation-induced lymphopenia is associated with worse survival for many solid tumors, possibly owing to attenuated antitumor immune responses. Identifying reliable and reproducible methods of calculating the radiation dose to circulating immune cells may facilitate development of techniques to reduce the risk and severity of radiation-induced toxic effects to circulating lymphocytes. Methods and MaterialsPatient-specific lymphocyte loss rates were derived from a clinical data set including 684 adult patients with solid tumors. Multivariable linear regression was used to model the relationship between the lymphocyte loss rate and physical parameters of the radiation plan that determine circulating blood dose. ResultsDuring partial-body radiation, lymphocyte loss rates are determined by physical parameters of the radiation plan that reflect radiation exposure to circulating cells, including target volume size, dose per fraction squared, and anatomic site treated. Differences in observed versus predicted lymphocyte loss rates may be partly explained by variations in concurrent chemotherapy regimens. ConclusionsWe describe a novel method of using patient-specific lymphocyte loss kinetics to approximate the effective radiation dose to circulating lymphocytes during focal fractionated photon radiation therapy. Clinical applications of these findings include the early identification of patients at particularly high risk of severe radiation-induced lymphopenia based on physical parameters of the radiation therapy plan.

The impact of radiation induced lymphopenia in the prognosis of head and neck cancer: A systematic review and meta-analysis

ObjectivesRadiotherapy is a key part of head and neck cancer (HNC) treatment. Radiation induced lymphopenia (RIL) is a severe complication of radiotherapy. The aim of this study was to evaluate the prognostic role of RIL in HNC patients. MethodWe conducted a PRISMA guideline based systematic review and meta-analysis. The studies were identified on the PubMed, Embase and Cochrane Library from 2007 to October 2021. The quality of each study was assessed by Newcastle-Ottawa Quality Assessment Form for Cohort Studies (NOS). ResultsThere were 8 studies with 2,733 samples finally included in current study. The meta-analysis showed that the odds ratio of developing grade 3–4 RIL was 13.49 (95%CI = 7.03–25.89, I2 = 94%). The incidence rate of grade 3–4 RIL ranged from 73%-88%. Multivariate meta-analysis found that the RIL significantly decreased the overall survival (HR = 2.94, 95%CI = 1.83–4.74, I2 = 0%) and distant metastasis free survival of HNC (HR = 3.79, 95%CI = 2.06–6.97, I2 = 0%). After sensitivity analysis and excluding a potential study that caused heterogeneity, the new pooled multivariate meta-analysis showed RIL was a risk factor to the progression free survival of HNC patients (HR = 3.16, 95%CI = 1.77–5.63, I2 = 0%). ConclusionThis is the first meta-analysis which showed severe RIL decreased the overall survival and promoted the progression of HNC patients. Future large-scale prospective studies are required to evaluate the association between severe RIL and the prognosis of HNC.

Prognosis of severe lymphopenia after postoperative radiotherapy in non-small cell lung cancer: Results of a long-term follow up study

PurposeTo investigate the incidence and prognosis of severe radiation-induced lymphopenia (sRIL) after postoperative radiotherapy (PORT) for resected NSCLC. Patients and methodsBetween 1998 and 2017, 170 patients treated with PORT for NSCLC were retrospectively reviewed. Lymphopenia was divided into tertiles with severe lymphopenia defined as absolute lymphocyte counts (ALC) < 0.37 × 103/ul. ResultssRIL was observed in 32.3% of patients. Multivariable logistic regression analysis indicated sRIL was associated with planning target volume radiation fraction numbers (OR 1.09, p = 0.005) and total lung mean dose (OR 1.12, p = 0.006). With a median follow-up time of 12.2 years, the median progression-free survival and overall survival were 14.8 months and 28.4 months respectively in patients with sRIL, vs. 21.7 months (p = 0.008) and 48.3 months (p = 0.01) respectively in patients without sRIL. Multivariable analyses indicated sRIL significantly decreased OS (HR 1.95, p < 0.01). Since PORT for stage I-II NSCLC was done largely for positive margins, which may confound the contribution of severe RIL, we analyzed stage III separately and found that sRIL also significantly decreased OS (HR 1.88, p = 0.004) in multivariable analysis. ConclusionFor this long-term outcome study, severe RIL correlated with total lung mean dose and radiation fractionation numbers, and was a strong prognostic factor for poor survival in PORT patients, particularly in patients with stage III NSCLC, highlighting the importance of an intact immune system for post-radiation immunologic disease surveillance.