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

Dai, Dongjun; Tian, Qiaoying; Yu, Genhua; Shui, Yongjie; Jiang, Hao; Wei, Qichun

doi:10.3390/cancers14123024

Cited by 18 publications

(12 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, a study that included 110 ESCC receiving IMRT showed that radiation‐induced lymphopenia (RIL) was associated with cardiac and pulmonary dose parameters, and the results also demonstrated that RIL could predict survival and radiation pneumonia 29 . A meta‐analysis also revealed that RIL was associated with dosimetric factors such as PTV, cardiac dose, and effective dose to immune cells (EDIC), and it was correlated with lower pCR rates, as well as poorer OS and progression‐free survival (PFS) 30 . However, none of them analyzed the pericardial dose.…”

Section: Discussionmentioning

confidence: 99%

Pericardial irradiation dose may be strongly associated with grade 4 lymphopenia and affect prognosis in patients with locally advanced esophageal cancer receiving definitive concurrent chemoradiotherapy

Chen

Tian²,

Zhang

et al. 2023

Thoracic Cancer

View full text Add to dashboard Cite

BackgroundThe immune system may influence prognosis, and lymphopenia is a frequent side effect of concurrent chemoradiotherapy (CCRT). Radical irradiation for locally advanced esophageal cancer (LA‐EC) exposes significant vascular and heart volumes. In this study, we hypothesized that lymphopenia is linked to cardiac and pericardial doses and affects patient prognosis.Methods and MaterialsWe identified 190 LA‐EC patients who received radical CCRT. Multivariate analysis (MVA) was performed to correlate clinical factors and dosimetric parameters with overall survival (OS). We collected lymphocyte‐related variables and ratios before and during CCRT. MVA was performed to correlate hematologic toxicity with OS. The relationship between dosimetric parameters and G4 lymphopenia was determined using logistic stepwise regression. Finally, a nomogram of G4 lymphopenia was developed and validated externally.ResultsMedian follow‐up time for all patients was 27.5 months. On MVA for OS, higher pericardial V30 (PV30) was linked to worse survival (HR: 1.013, 95% CI: 1.001–1.026, p = 0.039). The median OS stratified by PV30 > 55.3% and PV30 ≤ 55.3% was 24.0 months and 54.0 months, respectively (p = 0.004). G4 lymphopenia was shown to be linked with worse OS in the MVA of hematological toxicity with OS (HR: 2.042, 95% CI: 1.335–3.126, p = 0.001). Thirty of the 100 patients in the training set had G4 lymphopenia. Logistic stepwise regression was used to identify variables associated with G4 lymphopenia, and the final model consisted of stage‐IVA (p = 0.017), platelet‐to‐lymphocyte ratio during CCRT (p = 0.008), Heart V50 (p = 0.046), and PV30 (p = 0.048). Finally, a nomogram predicting G4 lymphocytopenia were constructed and externally validated. The ROC curve showed an AUC for internal validation of 0.775 and external validation of 0.843.ConclusionHigher doses of pericardial radiation might affect LA‐EC patients' prognosis by inducing G4 lymphopenia during CCRT. Further prospective studies are warranted to confirm these findings, especially in the era of immune‐checkpoint inhibitor treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Pericardial irradiation dose may be strongly associated with grade 4 lymphopenia and affect prognosis in patients with locally advanced esophageal cancer receiving definitive concurrent chemoradiotherapy

Chen

Tian²,

Zhang

et al. 2023

Thoracic Cancer

View full text Add to dashboard Cite

show abstract

“…The development of severe lymphopenia after radiation without concurrent chemotherapy or steroids use has been reported in patients with brain, head and neck, breast, pancreatic, esophageal, cervical, uterine, and lung cancer ( 52 , 78 ). Notably, according to systematic reviews and meta-analyses, post-radiation lymphopenia is associated with shorter survival in pancreatic and lung cancer ( 79 – 81 ), head and neck and esophageal cancer ( 79 , 82 – 84 ), urological cancer ( 85 ), nasopharyngeal and cervical cancer ( 47 ) and many other solid tumors ( 69 , 78 , 79 , 86 – 88 ). In agreement, a meta-analysis including 16 cancer types supports that radiation-induced lymphopenia is a significant prognostic factor for mortality in virtually all solid cancers ( 79 ).…”

Section: Standard Therapy-related Immunosuppression In Glioblastomamentioning

confidence: 99%

The need for paradigm shift: prognostic significance and implications of standard therapy-related systemic immunosuppression in glioblastoma for immunotherapy and oncolytic virotherapy

Stepanenko,

Sosnovtseva,

Valikhov

et al. 2024

Front. Immunol.

View full text Add to dashboard Cite

Despite significant advances in our knowledge regarding the genetics and molecular biology of gliomas over the past two decades and hundreds of clinical trials, no effective therapeutic approach has been identified for adult patients with newly diagnosed glioblastoma, and overall survival remains dismal. Great hopes are now placed on combination immunotherapy. In clinical trials, immunotherapeutics are generally tested after standard therapy (radiation, temozolomide, and steroid dexamethasone) or concurrently with temozolomide and/or steroids. Only a minor subset of patients with progressive/recurrent glioblastoma have benefited from immunotherapies. In this review, we comprehensively discuss standard therapy-related systemic immunosuppression and lymphopenia, their prognostic significance, and the implications for immunotherapy/oncolytic virotherapy. The effectiveness of immunotherapy and oncolytic virotherapy (viro-immunotherapy) critically depends on the activity of the host immune cells. The absolute counts, ratios, and functional states of different circulating and tumor-infiltrating immune cell subsets determine the net immune fitness of patients with cancer and may have various effects on tumor progression, therapeutic response, and survival outcomes. Although different immunosuppressive mechanisms operate in patients with glioblastoma/gliomas at presentation, the immunological competence of patients may be significantly compromised by standard therapy, exacerbating tumor-related systemic immunosuppression. Standard therapy affects diverse immune cell subsets, including dendritic, CD4+, CD8+, natural killer (NK), NKT, macrophage, neutrophil, and myeloid-derived suppressor cell (MDSC). Systemic immunosuppression and lymphopenia limit the immune system’s ability to target glioblastoma. Changes in the standard therapy are required to increase the success of immunotherapies. Steroid use, high neutrophil-to-lymphocyte ratio (NLR), and low post-treatment total lymphocyte count (TLC) are significant prognostic factors for shorter survival in patients with glioblastoma in retrospective studies; however, these clinically relevant variables are rarely reported and correlated with response and survival in immunotherapy studies (e.g., immune checkpoint inhibitors, vaccines, and oncolytic viruses). Our analysis should help in the development of a more rational clinical trial design and decision-making regarding the treatment to potentially improve the efficacy of immunotherapy or oncolytic virotherapy.

show abstract

“…The implications of identifying some predictors of radiationinduced lymphopenia (RIL) are highlighted by the studies that analyze the correlations between the parameters of the multimodal treatment including radiation dosimetry and the decrease in absolute lymphocyte count. (Table 2) [71][72][73][74][75][76]. Esophagus Larger planning target volume (PTV), higher heart and body dose, higher EDIC Lymphocyte nadir after 4-6 weeks of radiotherapy [73] Brain (glioma), lung, pancreas Field size, dose per fraction, and fraction number SBRT, Proton therapy Increased risk of RIL [74] Reduction of RIL risk [74] Spleen Volumes receiving at least 5 Gy (V15) and maximum dose (Dmax) an increase of 1 Gy in mean splenic dose Nadir lymphocyte count [75] 1% decrease in absolute lymphocyte count at nadir [75] Esophagus EDIC < 2, 2 to 4, and >4 Gy, respectively 2-year OS rates were 66.7%, 42.7%, and 16.7% [76]…”

Section: Radiotherapy and Immunotherapy-from Research To Clinical Pra...mentioning

confidence: 99%

Radiotherapy and Immunotherapy—A Future Partnership towards a New Standard

Mireștean

Iancu

2023

Applied Sciences

View full text Add to dashboard Cite

The impressive results in terms of survival brought by immune checkpoint inhibitors (ICI) in metastatic malignant melanoma and the transformation of this disease with a poor prognosis into a chronic disease even with long-term survival cases have opened horizons for a new era in cancer treatments. Later, therapy with CTLA-4 and PD-1/PD-L1 inhibitors became standard in other solid tumors, especially in relapsed and metastatic settings. The PACIFIC clinical trial revolutionized the concept of consolidation immunotherapy after the favorable response to curative chemoradiotherapy in non-small cell lung carcinoma (NSCLC). Two new effects will govern the future of the immunotherapy–radiotherapy association: the local “in situ” vaccination effect and the systemic remote “abscopal” response. Even if stereotactic body irradiation (SBRT) or stereotactic radiosurgery (SRT) seems to be more effective in generating the synergistic effect, the PACIFIC trial demonstrates the role of conventional irradiation in combination with chemotherapy in modulating the host’s immune response. Thus, the radiotherapy–chemotherapy–immunotherapy triad may become the future standard in locally advanced disease. The different mechanisms of producing immune-mediated cell death and the indirect role of augmenting the immune effect induced by radiotherapy make the old theories related to the therapeutic sequence, fractionation, doses, and target volumes as well as the protection of healthy tissues to be re-evaluated. The new concept of immuno-radiotherapy in synergistic association has as its physiopathological substrate the dual immunosuppressive and enhancement of antitumor response to irradiation, including the activation of the immune effectors in the tumor microenvironment (TME). The choice of sequential treatment, a hypofractionated irradiation regime, and the possible omission of lymph node irradiation with the limitation of lymphopenia could tilt the balance in favor of the activation and potentiation of the antitumor immune response. The selection of therapeutic targets chosen for the combination of immunotherapy and associated radiotherapy can be conducted based on the classification of tumors in the three immune phenotypes that characterize “cold” and “hot” tumors from the point of view of the response to therapy.

show abstract

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

Cited by 18 publications

References 51 publications

Pericardial irradiation dose may be strongly associated with grade 4 lymphopenia and affect prognosis in patients with locally advanced esophageal cancer receiving definitive concurrent chemoradiotherapy

Pericardial irradiation dose may be strongly associated with grade 4 lymphopenia and affect prognosis in patients with locally advanced esophageal cancer receiving definitive concurrent chemoradiotherapy

The need for paradigm shift: prognostic significance and implications of standard therapy-related systemic immunosuppression in glioblastoma for immunotherapy and oncolytic virotherapy

Radiotherapy and Immunotherapy—A Future Partnership towards a New Standard

Contact Info

Product

Resources

About