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Immune system modulation, with the use of immune checkpoint inhibitors, has drastically changed the field of oncology. Strong preclinical data indicate that radiation therapy (RT) may enhance the response rate to such drugs via in situ vaccination, although these data do not consider immune radiotoxicity. This meta-analysis investigates whether radio-induced lymphopenia (RIL) is associated with overall survival (OS).
Methods and Materials
A systematic literature search and quantitative analysis were planned, conducted, and reported per the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Quality of Reporting of Meta-analyses checklists. The literature from January 1990 to March 2021 was searched to identify clinical studies with OS data in patients treated with RT and presenting with lymphopenia. A random-effect model was employed for the meta-analysis. Heterogeneity was assessed using the I2 statistic. Publication bias was estimated using a P-curve analysis.
Results
A total of 56 studies with 13 223 patients and 11 types of cancers were selected. The mean follow-up time was 35.9 months. Over a third of patients had RIL (37.25%). After removing outlying studies (n = 14), the between-study heterogeneity variance was estimated at t2 = 0.018 (P = .01) with an I2 value of 36.0% (95% confidence interval, 6%-56%). The results showed that RIL was significantly associated with worse OS (hazard ratio: 1.70; 95% confidence interval, 1.55-1.86; P < .01; 95% prediction interval, 1.27-2.26). A subgroup analysis was performed based on the type of primary tumor, and a difference between the subgroups was found (P < .01). Based on the P-curve analysis, a significant evidential value was found, and no significant publication bias was identified among the studies.
Conclusions
RIL is a significant prognostic factor for mortality in virtually all solid cancers. Pooled-effect estimates indicate a significantly reduced risk of death in patients without RIL. Tailoring RT regimens to spare the immune system and updating dosimetric constraints for new organs at risk, such as major blood vessels, organs with rich blood supplies, bones, and all lymph node areas, may improve prognoses.
Introduction
Since the 1950s, oncologists have described the abscopal effect, which refers to the systemic effects of radiation on out-of-field tumor deposits.
Historically, our comprehension of radio-induced cell death was DNA-centered; however, new molecular biology techniques challenge the ubiquity of this model.
These cellular effects have molecular consequences that mobilize the immune system. This phenomenon is known as immunogenic cell death or in situ vaccination.
Exploration of the immune antitumor response has revealed concrete clinical repercussions with the use of drugs, such as the checkpoint inhibitors (CPIs).
CPIs target, for example, programmed cell death protein 1 (PD-1), which belongs to the superfamily of B7 immunoglobulins. These molecules are expressed on the T-cell membrane, and either amplify or diminish the immune response.
Programmed death-ligand 1 (PD-L1) can be upregulated in certain tumor cells; thus, transmitting an antiapoptotic signal and protecting tumor cells from T-cell attack.
Antibodies against PD-1 or PD-L1 have shown major therapeutic success in melanoma, kidney cancer, and lung cancer, because they permit a T-cell-mediated immune response.
although these data do not consider radio-induced lymphopenia (RIL).
Indeed, immune cells (specifically lymphocytes) are described as one of the most radiosensitive cells in the body, which can be counterintuitive considering that lymphocytes are well-differentiated and nondividing cells. In the 1950s, Trowell
showed that the dose required to produce 50% pyknotic nuclei in circulating lymphocytes within 5 hours ranged from 1.6 Gy to 0.4 Gy. More recent studies
Sensitivity of CD3/CD28-stimulated versus non-stimulated lymphocytes to ionizing radiation and genotoxic anticancer drugs: Key role of ATM in the differential radiation response.
corroborated the very high radiosensitivity of lymphocytes demonstrated by Trowell using modern techniques. Overall, the authors concurred that immune cells die at doses >2 Gy per fraction.
If the balance between immunotoxicity and immune stimulation seems uncertain, RIL may have a clear clinical effect. RIL was described first when x-rays were discovered. Indeed, after exposing virtually any body part through x-rays, a decline in circulating lymphocytes was observed,
and then most noticeably studied in cerebral irradiation in the early 1980s. The skull contains hardly any bone marrow and has no lymph nodes; however, several children undergoing prophylactic cranial radiation for lymphoblastic acute leukemia developed lymphopenia. Lymphocyte drops were correlated with the number of fractions administered.
Analysis of treatment in childhood leukemia. IV. The critical association between dose fractionation and immunosuppression induced by cranial irradiation.
Later, other studies showed a trend toward inferior clinical outcomes (overall survival [OS] and progression-free survival) in patients treated for solid cancers and presenting with RIL. Moreover, several published studies found that RIL's association with OS was independent of pretreatment prognostic factors, tumor histology, chemotherapy regimen, or corticosteroid use.
The aim of this study was to formally determine whether RIL is correlated with OS in solid cancers. All available clinical data were systematically reviewed and processed in this meta-analysis.
Methods and Materials
A systematic literature search and quantitative analysis were planned, conducted, and reported per the Preferred Reporting Items for Systematic Reviews and Meta-analyses and Quality of Reporting of Meta-analyses checklists (Appendix Tables 1 and 2). The search was performed on February 2021, and articles published from 1990 to this date were retrieved. We reviewed all papers published since 1990, because nearly 90% of articles related to our subject were issued after 1989, but we decided to process only articles dated after 2010 to have more up-to-date RT techniques and chemotherapy regimens. The PubMed (National Institutes of Health), Cochrane Central (Cochrane collaboration), Embase (Elsevier), and Web of Science databases were queried with the search terms “radiotherapy”, “radiation therapy”, “lymphopenia”, and “cancer.”
Table 1Description of patients, intervention, comparison, and outcome strategy
CRITERION
DESCRIPTION
PATIENTS
Patients treated with RT for malignant disease, with at least 6 mo follow up who had lymphocyte count monitoring during or after RT
INTERVENTION
Quantitative analysis of absolute lymphocyte count or lymphocyte count relative to neutrophil count during or after RT
COMPARISON
Predictive value of lymphocyte count during or after RT
Association between severe treatment-related lymphopenia and progression-free survival in patients with newly diagnosed squamous cell head and neck cancer.
Association of Posttreatment Lymphopenia and Elevated Neutrophil-to-Lymphocyte Ratio With Poor Clinical Outcomes in Patients With Human Papillomavirus-Negative Oropharyngeal Cancers.
The prognostic value of the ratio of neutrophils to lymphocytes before and after intensity modulated radiotherapy for patients with nasopharyngeal carcinoma.
Changes in neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios during chemoradiation predict for survival and pathologic complete response in trimodality esophageal cancer patients.
The relationship of lymphocyte recovery and prognosis of esophageal cancer patients with severe radiation-induced lymphopenia after chemoradiation therapy.
Systemic inflammation biomarkers predict survival in patients of early stage non-small cell lung cancer treated with stereotactic ablative radiotherapy–A single center experience.
Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio associations with heart and body dose and their effects on patient outcomes in locally advanced non-small cell lung cancer treated with definitive radiotherapy.
Pretreatment Immune Parameters Predict for Overall Survival and Toxicity in Early-Stage Non-Small-Cell Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy.
Association Between Circulating Lymphocyte Populations and Outcome After Stereotactic Body Radiation Therapy in Patients With Hepatocellular Carcinoma.
Postradiotherapy persistent lymphopenia as a poor prognostic factor in patients with cervical cancer receiving radiotherapy: a single-center, retrospective study.
Clinical predictors of radiation-induced lymphopenia in patients receiving chemoradiation for glioblastoma: Clinical usefulness of intensity-modulated radiotherapy in the immuno-oncology era.
Systemic inflammatory dynamics during chemoradiotherapy predict response, relapse, metastasis, and survival in esophageal carcinoma [e-pub ahead of print].
Lymphopenia Is Associated with Gross Target Volumes and Fractions in Hepatocellular Carcinoma Patients Treated with External Beam Radiation Therapy and Also Indicates Worse Overall Survival.
Radiation-induced lymphopenia predicts poorer prognosis in patients with breast cancer: A post hoc analysis of a randomized controlled trial of postmastectomy hypofractionated radiation therapy.
The impact of the effective dose to immune cells on lymphopenia and survival of esophageal cancer after chemoradiotherapy.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology [Internet].mai 2020; ([cité 9 mai 2021];146. Disponible sur)
Furthermore, conference proceedings from the American Society of Radiation Oncology, European Society of Therapeutic Radiation Oncology, European Society of Therapeutic Radiation Oncology, and American Society of Clinical Oncology were probed for any additional articles. The articles retrieved from the initial search were imported into reference manager software (EndNote X9, version 3.3). Duplicates were excluded, and the titles of articles were assessed. Papers found to be relevant to the topic were shortlisted, and the selected full-length papers were reviewed according to the eligibility criteria. The references of the included studies were manually searched for additional studies. References from review articles were assessed for cross-references. Abstracts and other unfinished works were excluded. All selected articles were reviewed by YEH and JC.
Eligibility criteria
The patients, intervention, comparison, and outcome criteria for the review are shown in Table 1. Any prospective clinical trial, retrospective study, or cohort study on solid malignancies in humans was eligible. RT had to be part of the treatment, and the intent was curative in either a neoadjuvant, definitive, or adjuvant setting. The study was required to have data on OS and lymphocyte count measurements, whether absolute or relative to the polynuclear neutrophil or platelet count. Studies without clinical information, preclinical models, and studies on lymphopenia in patients undergoing immunotherapy, chemotherapy, or surgery alone were excluded. Studies reporting outcomes in patients infected with the human immunodeficiency virus or those with immunodeficient states were also rejected. No limit was set for the minimum follow-up time. Articles focusing on advanced disease stages or palliative therapy were excluded. Studies reporting only pre-RT lymphocyte counts were excluded.
The selected studies were assessed for risk of bias on the basis of the following 5 variables: Retrospective versus prospective study design, sufficient descriptions of lymphocyte count data collection and treatment modality, uniform inclusion criteria, incomplete outcome data, and number of patients included (studies with <40 patients were automatically excluded). The risk of bias was classified as high if no was the response for ≥3 criteria. The level of evidence was scored according to the Oxford Center for Evidence-Based Medicine (OCEBM) 2011 level of evidence guide
, as follows: Systematic review of inception cohort studies, inception cohort studies, cohort study or control arm of a randomized trial, and case series or case-control studies or poor-quality prognostic cohort studies.
Statistical analysis
Categorical variables are presented as percentages, and continuous variables are presented as medians. When not available, confidence intervals (CIs) of hazard ratios (HRs) were calculated with the P value and the population number for each group. HRs and mean differences were plotted with the generic inverse variance method, and depicted in forest plots comparing patients with and without RIL. When neither the population number nor the HR was published, the study was excluded from the final analysis. P < .05 was considered statistically significant.
We anticipated considerable between-study heterogeneity; thus, a random-effect model was used to pool effect sizes. The restricted maximum likelihood estimator was used to calculate the heterogeneity variance t2 for analysis. We used Knapp–Hartung adjustments to calculate the CI around the pooled effect. Study heterogeneity was assessed using the inconsistency index (I2), and prediction intervals were used to calculate the estimated between-study heterogeneity variance t2. The presence of outlying cases within the selected studies was assessed using a generic outlier removal process that excluded every study with a CI that did not overlap with the CI of the pooled effect.
Publication bias was appraised with funnel plots, tested for asymmetry through Egger's test, and adjusted with the trim-and-fill method. Due to the limitation of the trim-and-fill method when the between-study heterogeneity is large,
publication bias was also assessed using the P-curve method to test for right-skewness and flatness. All statistical analyses were performed using R, version 4.0.5 (Shake and Throw) using the Meta Package.
Results
We reviewed 195 papers reporting studies published between 2005 and 2021. Of these 195 papers, we selected 56 studies, 8 of which were prospective. The review process is depicted in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses chart in Fig. 1. The 56 studies reported outcomes for 13,223 patients. Eight articles addressed stereotactic RT. Most papers studied lung cancer (n = 15), esophageal cancer (n = 10), head and neck cancer (n = 10), and pancreatic cancer (n = 4). The mean follow-up time was 32.9 months (range, 10.1-82 months) for the 50 studies reporting these data. The number of patients with RIL was 4926 (37.25% of entire population).
Figure 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses flowchart of retrieved studies OS, overall survival.
The mean radiation dose, biomarkers used to analyze RIL, and thresholds to define lymphopenia are shown in Table 2. Most articles used the lymphocyte count at 2 to 3 months after treatment to characterize the relationship between RIL and survival. The results for all studies showed that RIL was significantly associated with worse OS with an HR of 1.74 (95% CI, 1.54-1.97; P < .01) and a nonsignificant predicted interval (95% CI, 0.85-3.6). The between-study heterogeneity variance was estimated at t2 = 0.12 (P < .01), with an I2 value of 88% (95% CI, 85%-90%; Appendix Fig. 1).
Using a generic outlier removal process, we identified 14 outlying studies because their CI did not overlap with the CI of the pooled effect.
Systemic inflammation biomarkers predict survival in patients of early stage non-small cell lung cancer treated with stereotactic ablative radiotherapy–A single center experience.
Systemic inflammatory dynamics during chemoradiotherapy predict response, relapse, metastasis, and survival in esophageal carcinoma [e-pub ahead of print].
Radiation-induced lymphopenia predicts poorer prognosis in patients with breast cancer: A post hoc analysis of a randomized controlled trial of postmastectomy hypofractionated radiation therapy.
Clinical predictors of radiation-induced lymphopenia in patients receiving chemoradiation for glioblastoma: Clinical usefulness of intensity-modulated radiotherapy in the immuno-oncology era.
Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio associations with heart and body dose and their effects on patient outcomes in locally advanced non-small cell lung cancer treated with definitive radiotherapy.
Without outliers, the between-study heterogeneity was significantly less important, with a variance of t2 = 0.018 (95% CI, 0.002-1.13) and a I2 value of 36% (95% CI, 6%-56%). The HR for OS was 1.70 (95% CI, 1.55-1.86; P < .01), with a predicted interval of 2.13 (95% CI, 1.27-2.26), showing that RIL is a prognostic factor for poor OS (Fig. 2). The results for all studies with and without outliers are compared in Table 3. Due to the high between-study heterogeneity, a funnel plot was computed without outlying studies (Appendix Fig. 2). Funnel plot asymmetry was tested with Egger's test (Suppl. Table 1). The Egger's test indicated the presence of funnel plot asymmetry. The trim-and-fill method added 14 studies, and the HR was still significant (HR: 1.56; 95% CI, 1.40-1.74; P < .0001; Appendix Fig. 3).
Figure 2Forest plot of subgroup analysis for overall survival in patients presenting with radio-induced lymphopenia compared with patients without lymphopenia, stratified by cancer groups, without outlying studies.
Systemic inflammation biomarkers predict survival in patients of early stage non-small cell lung cancer treated with stereotactic ablative radiotherapy–A single center experience.
Systemic inflammatory dynamics during chemoradiotherapy predict response, relapse, metastasis, and survival in esophageal carcinoma [e-pub ahead of print].
Radiation-induced lymphopenia predicts poorer prognosis in patients with breast cancer: A post hoc analysis of a randomized controlled trial of postmastectomy hypofractionated radiation therapy.
Clinical predictors of radiation-induced lymphopenia in patients receiving chemoradiation for glioblastoma: Clinical usefulness of intensity-modulated radiotherapy in the immuno-oncology era.
Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio associations with heart and body dose and their effects on patient outcomes in locally advanced non-small cell lung cancer treated with definitive radiotherapy.
The P-curve analysis showed the presence of evidential value for the main analysis (Suppl. Fig. 1A) and the analysis without outliers (Suppl. Fig. 1B). From the group of studies without outliers, a subgroup analysis was performed based on the type of primary tumor. The studies were divided into 6 groups: Lung cancer,
Pretreatment Immune Parameters Predict for Overall Survival and Toxicity in Early-Stage Non-Small-Cell Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy.
Association between severe treatment-related lymphopenia and progression-free survival in patients with newly diagnosed squamous cell head and neck cancer.
Association of Posttreatment Lymphopenia and Elevated Neutrophil-to-Lymphocyte Ratio With Poor Clinical Outcomes in Patients With Human Papillomavirus-Negative Oropharyngeal Cancers.
The prognostic value of the ratio of neutrophils to lymphocytes before and after intensity modulated radiotherapy for patients with nasopharyngeal carcinoma.
Postradiotherapy persistent lymphopenia as a poor prognostic factor in patients with cervical cancer receiving radiotherapy: a single-center, retrospective study.
Systemic inflammatory dynamics during chemoradiotherapy predict response, relapse, metastasis, and survival in esophageal carcinoma [e-pub ahead of print].
Changes in neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios during chemoradiation predict for survival and pathologic complete response in trimodality esophageal cancer patients.
The relationship of lymphocyte recovery and prognosis of esophageal cancer patients with severe radiation-induced lymphopenia after chemoradiation therapy.
The impact of the effective dose to immune cells on lymphopenia and survival of esophageal cancer after chemoradiotherapy.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology [Internet].mai 2020; ([cité 9 mai 2021];146. Disponible sur)
Postradiotherapy persistent lymphopenia as a poor prognostic factor in patients with cervical cancer receiving radiotherapy: a single-center, retrospective study.
Association Between Circulating Lymphocyte Populations and Outcome After Stereotactic Body Radiation Therapy in Patients With Hepatocellular Carcinoma.
Lymphopenia Is Associated with Gross Target Volumes and Fractions in Hepatocellular Carcinoma Patients Treated with External Beam Radiation Therapy and Also Indicates Worse Overall Survival.
because each entity was represented <3 articles. A forest plot of studies without outliers, stratified by the 6 subgroups, is depicted in Fig. 2. A forest plot of all studies (with outliers) divided into the 6 subgroups is depicted in Appendix Fig. 4.
When dividing the studies into cancer subtypes, the analysis showed a significant HR of 1.57 (95% CI, 1.36-1.82; 95% prediction interval [PI], 1.36-1.82) for lung cancer and a low between-study heterogeneity of 20% (Fig. 2). The analysis processed 1026 patients who showed RIL and 1036 patients without RIL. Of note, of the 15 studies on lung cancer, 3 exclusively analyzed small cell lung cancer (SCLC),
Systemic inflammation biomarkers predict survival in patients of early stage non-small cell lung cancer treated with stereotactic ablative radiotherapy–A single center experience.
Pretreatment Immune Parameters Predict for Overall Survival and Toxicity in Early-Stage Non-Small-Cell Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy.
For esophageal cancer, the analysis showed significantly poorer OS for the 801 patients showing RIL, with an HR of 1.44 (95% CI, 1.25-1.66; 95% PI, 1.25-1.67) and low between-study heterogeneity (I2 = 25%; Fig. 2). Among the 9 remaining studies without outliers, only 1 did not determine precisely whether patients received chemotherapy.
Changes in neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios during chemoradiation predict for survival and pathologic complete response in trimodality esophageal cancer patients.
For head and neck cancer, 10 studies reported outcomes for 1167 patients presenting with RIL. The analysis showed that RIL was associated with worse OS, with an HR of 2.15 (95% IC, 1.46-3.18; 95% PI, 0.93-4.95) and moderate between-study heterogeneity of 36% (Fig. 2). Only 1 study did not report whether the selected patients received chemoradiotherapy or not;
The 4 pancreatic cancer studies included 202 patients with RIL among a population of 601 patients. RIL was significantly associated with worse OS, with an HR of 2.04 (95% CI, 1.02-4.08; 95% PI, 0.15-27.87) and very low between-study heterogeneity (I2 = 9%; Fig. 2). All patients presenting with RIL also received systemic treatment.
Six studies investigated glioblastoma, with a population of 429 patients presenting with RIL among 887 patients. RIL was significantly associated with death, with an HR of 1.86 (95% CI, 1.64-2.10; 95% PI, 1.57-2.20; Fig. 2). The I2 and t2 in the glioblastoma group were too low to be generated. The 429 patients presenting with RIL were also treated with concomitant systemic therapy. Two glioblastoma papers were prospective in nature.
Clinical predictors of radiation-induced lymphopenia in patients receiving chemoradiation for glioblastoma: Clinical usefulness of intensity-modulated radiotherapy in the immuno-oncology era.
Association Between Circulating Lymphocyte Populations and Outcome After Stereotactic Body Radiation Therapy in Patients With Hepatocellular Carcinoma.
Lymphopenia Is Associated with Gross Target Volumes and Fractions in Hepatocellular Carcinoma Patients Treated with External Beam Radiation Therapy and Also Indicates Worse Overall Survival.
Postradiotherapy persistent lymphopenia as a poor prognostic factor in patients with cervical cancer receiving radiotherapy: a single-center, retrospective study.
Radiation-induced lymphopenia predicts poorer prognosis in patients with breast cancer: A post hoc analysis of a randomized controlled trial of postmastectomy hypofractionated radiation therapy.
Association Between Circulating Lymphocyte Populations and Outcome After Stereotactic Body Radiation Therapy in Patients With Hepatocellular Carcinoma.
Lymphopenia Is Associated with Gross Target Volumes and Fractions in Hepatocellular Carcinoma Patients Treated with External Beam Radiation Therapy and Also Indicates Worse Overall Survival.
The analysis shows that RIL is associated with poor OS in this group (HR: 2.21; 95% CI, 1.51-3.25; 95% PI, 0.89-5.49) and, as expected, moderate between-study heterogeneity of 52% (Fig. 2). A difference between the subgroups was found (P < .01; Fig. 2).
Discussion
According to our study, RIL seem to have an effect on survival outcomes, regardless of the localization of the radiation. All 6 subgroups of cancer showed that lymphopenia was a significant prognostic factor for poor OS. Three of the subgroups (head and neck, pancreas, and mixed pathologies group), although showing an association between RIL and death, had a statistically nonsignificant prediction interval, probably due to a lack of power in the analysis. After removing outlying studies, the low between-study heterogeneity and absence of publication bias support the robustness of these results.
Preclinical data have shown that the abscopal effect is, in fact, mediated by immune mechanisms.
However, RT can be a double-edged sword. Even if numerous molecular and cellular effects of RT lead to immune stimulation, radiation has been described also to be immunosuppressive. For example, radiation can upregulate PD-L1 expression in tumor and T cells, preventing an adequate antitumor response.
Lymphopenia, has been shown to be a prognostic factor for poor survival for patients receiving immunotherapy. A few papers showed that patients with lymphopenia before and during treatment with immunotherapy demonstrated significantly poorer outcomes.
Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival.
Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-1 checkpoint inhibitors.
However, whether a decline in the number and function of lymphocytes decreases the efficacy of immunotherapeutic agents or if lymphopenia is mainly a good biologic surrogate for performance status as shown in previous papers remains uncertain.
Systemic inflammatory dynamics during chemoradiotherapy predict response, relapse, metastasis, and survival in esophageal carcinoma [e-pub ahead of print].
The mechanisms of interaction between the immune stimulatory and suppressive effects of RT remain to be fully understood. We hypothesize that RIL could tilt the balance toward immune suppression and significantly diminish any hope of potentializing immunotherapy with RT; however, the results of this meta-analysis need to be interpreted with caution. Indeed, these results do not imply that a better OS was obtained by abscopal effect in the group of patients not showing RIL, but only indicate that patients showing RIL during treatment seem to have poorer OS than those not having lymphopenia. Nevertheless, the preclinical data mentioned previously and the results of this analysis hint that a better understanding of the mechanisms of RIL and protecting the antitumor immune response during radiation could help us understand the process by which RT may potentiate immunotherapy or create an out-of-field response.
The Etiology of Treatment-related Lymphopenia in Patients with Malignant Gliomas: Modeling Radiation Dose to Circulating Lymphocytes Explains Clinical Observations and Suggests Methods of Modifying the Impact of Radiation on Immune Cells.
Second, RIL could be explained also by the radiation dose received by hematopoietic and lymphopoietic organs. For example, the heart, lungs, liver, prominent blood vessels, and body, represent structures with abundant blood circulation, and the spleen, bone marrow, thymus, and lymph nodes are the proper lymphoid and hematopoietic organs.
For the first set of organs, the literature already alludes to a significant association between radiation to the heart,
Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio associations with heart and body dose and their effects on patient outcomes in locally advanced non-small cell lung cancer treated with definitive radiotherapy.
Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio associations with heart and body dose and their effects on patient outcomes in locally advanced non-small cell lung cancer treated with definitive radiotherapy.
Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio associations with heart and body dose and their effects on patient outcomes in locally advanced non-small cell lung cancer treated with definitive radiotherapy.
The effect of radiation on proper lymphoid structures was evaluated in a study comparing leukocyte counts before, during, and 3 months after the beginning of treatment for 23 patients receiving pelvic radiation (70-78 Gy to the prostate and seminal vesicles, with or without 50.4 Gy to pelvic lymph node areas) with a control group not receiving RT.
The study showed a significantly lower lymphocyte count associated with lymph node irradiation. The same question was asked for Berg lymph node radiation, with the same results.
Furthermore, radiation to the spleen was also assessed and showed that in some cohorts, the median cumulative spleen dose of patients with grade ≥3 lymphopenia was only 9.8 Gy,
Mean cardiopulmonary dose and vertebral marrow dose differentially predict lineage-specific leukopenia kinetics during radiotherapy for esophageal cancer.
A few authors have tried to combine the different plausible components of RIL into 1 mathematical model to estimate the effective dose to circulating immune cells (EDIC) to help risk-stratify patients and predict disease outcomes. In esophageal cancer, a study of 488 patients treated with concurrent chemoradiotherapy concurred that the EDIC was strongly associated with severe lymphopenia, especially when >4 Gy.
The impact of the effective dose to immune cells on lymphopenia and survival of esophageal cancer after chemoradiotherapy.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology [Internet].mai 2020; ([cité 9 mai 2021];146. Disponible sur)
Higher Radiation Dose to Immune System is Correlated With Poorer Survival in Patients With Stage III Non–small Cell Lung Cancer: A Secondary Study of a Phase 3 Cooperative Group Trial (NRG Oncology RTOG 0617).
International Journal of Radiation Oncology, Biology, Physics.2017; 99: S151‑2
Considering EDIC instead of dose constraints to organs at risk of the immune system might be a more rounded approach to RIL, even if EDIC does not consider all alleged contributors of RIL, such as field size and overall treatment time.
This analysis has several limitations. First, because we colligated >11 types of cancers and >13,000 patients, the population we analyzed had mixed histologic data and mixed stages of disease. However, after removing outlying studies, the between-study heterogeneity was acceptable at 35%, and a significant effect of RIL on OS was found in all cancer subtypes. The included studies were published between 1991 and 2020, resulting in the inclusion of outdated RT techniques and old chemotherapy regimens, which is why we did not analyze the role of RT doses and techniques or chemotherapy on RIL. Treatment modality and dose–volume histogram constraints might differ between studies, which can influence the occurrence of lymphopenia, but because this is not an individual patient data meta-analysis, their input is impossible to assess.
Additionally, considering that the effect of RIL on survival was our main focus, the means by which lymphopenia may occur is beyond the scope of this paper. We focused only on OS without considering other important clinical endpoints (eg, local control or disease-free survival), because OS might be the least subject to bias, especially considering the primarily retrospective data. Furthermore, the studies did not all use the same definition of lymphopenia. Some used lymphocyte count relative to the neutrophil count, others used a selected cutoff value for the absolute lymphocyte count or neutrophil to lymphocyte ratio that was optimal for survival prediction based on receiver operating characteristic curves and the most used the Common Terminology Criteria for Adverse Events, version 4.0 or 5.0, thresholds. When determining the most discriminating biomarker for survival prediction, most studies used lymphocyte count (relative or absolute) 2 to 3 months after the end of RT, but no consensus regarding when blood sampling would be the most relevant was established.
Finally, this meta-analysis did not employ an individual patient data approach; therefore, we were not able to pool the raw data from each participant from each included study, which might be considered the ideal approach in meta-analysis statistical models.
Conclusions
This meta-analysis confirms that RIL is a significant prognostic factor for survival in virtually all solid cancers. Pooled-effect estimates indicate a significantly reduced risk of death in patients without RIL. Tailoring RT regimens to spare the immune system and updating dosimetric constraints for new organs at risk, such as major blood vessels, organs with rich blood supplies, bones, and all lymph node areas, may be important to improve prognoses.
Sensitivity of CD3/CD28-stimulated versus non-stimulated lymphocytes to ionizing radiation and genotoxic anticancer drugs: Key role of ATM in the differential radiation response.
Analysis of treatment in childhood leukemia. IV. The critical association between dose fractionation and immunosuppression induced by cranial irradiation.
Systemic inflammation biomarkers predict survival in patients of early stage non-small cell lung cancer treated with stereotactic ablative radiotherapy–A single center experience.
Systemic inflammatory dynamics during chemoradiotherapy predict response, relapse, metastasis, and survival in esophageal carcinoma [e-pub ahead of print].
Radiation-induced lymphopenia predicts poorer prognosis in patients with breast cancer: A post hoc analysis of a randomized controlled trial of postmastectomy hypofractionated radiation therapy.
Clinical predictors of radiation-induced lymphopenia in patients receiving chemoradiation for glioblastoma: Clinical usefulness of intensity-modulated radiotherapy in the immuno-oncology era.
Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio associations with heart and body dose and their effects on patient outcomes in locally advanced non-small cell lung cancer treated with definitive radiotherapy.
Pretreatment Immune Parameters Predict for Overall Survival and Toxicity in Early-Stage Non-Small-Cell Lung Cancer Patients Treated With Stereotactic Body Radiation Therapy.
Association between severe treatment-related lymphopenia and progression-free survival in patients with newly diagnosed squamous cell head and neck cancer.
Association of Posttreatment Lymphopenia and Elevated Neutrophil-to-Lymphocyte Ratio With Poor Clinical Outcomes in Patients With Human Papillomavirus-Negative Oropharyngeal Cancers.
The prognostic value of the ratio of neutrophils to lymphocytes before and after intensity modulated radiotherapy for patients with nasopharyngeal carcinoma.
Changes in neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios during chemoradiation predict for survival and pathologic complete response in trimodality esophageal cancer patients.
The relationship of lymphocyte recovery and prognosis of esophageal cancer patients with severe radiation-induced lymphopenia after chemoradiation therapy.
The impact of the effective dose to immune cells on lymphopenia and survival of esophageal cancer after chemoradiotherapy.
Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology [Internet].mai 2020; ([cité 9 mai 2021];146. Disponible sur)
Postradiotherapy persistent lymphopenia as a poor prognostic factor in patients with cervical cancer receiving radiotherapy: a single-center, retrospective study.
Association Between Circulating Lymphocyte Populations and Outcome After Stereotactic Body Radiation Therapy in Patients With Hepatocellular Carcinoma.
Lymphopenia Is Associated with Gross Target Volumes and Fractions in Hepatocellular Carcinoma Patients Treated with External Beam Radiation Therapy and Also Indicates Worse Overall Survival.
Single-institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting: lymphocyte count after 2 doses correlates with survival.
Relationships between lymphocyte counts and treatment-related toxicities and clinical responses in patients with solid tumors treated with PD-1 checkpoint inhibitors.
The Etiology of Treatment-related Lymphopenia in Patients with Malignant Gliomas: Modeling Radiation Dose to Circulating Lymphocytes Explains Clinical Observations and Suggests Methods of Modifying the Impact of Radiation on Immune Cells.
Mean cardiopulmonary dose and vertebral marrow dose differentially predict lineage-specific leukopenia kinetics during radiotherapy for esophageal cancer.
Higher Radiation Dose to Immune System is Correlated With Poorer Survival in Patients With Stage III Non–small Cell Lung Cancer: A Secondary Study of a Phase 3 Cooperative Group Trial (NRG Oncology RTOG 0617).
International Journal of Radiation Oncology, Biology, Physics.2017; 99: S151‑2
Sources of support: This work had no specific funding.
Disclosures: The authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Data sharing statement: Research data are stored in an institutional repository and will be shared upon request to the corresponding author.
Prospective study.
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