| Cancer currently stands as the second leading cause of mortality worldwide,surpassed only by cardiovascular diseases.Lung cancer,in particular,maintains its position as the global malignancy with the second-highest incidence rate and the highest mortality rate.According to 2020 statistical reports,lung cancer accounted for 11.4% of all newly diagnosed cases of cancer,remaining the foremost cause of cancer-related fatalities.Non-small cell lung cancer(NSCLC)comprises approximately three-quarters of lung cancer cases;its insidious onset and inconspicuous early clinical manifestations often result in a diagnosis during advanced stages.Consequently,an integrative approach is commonly employed for lung cancer treatment.Immune checkpoint inhibitors(ICIs)are a novel class of immunotherapeutic agents that have significantly improved the prognosis of NSCLC patients.Radiotherapy,a traditional treatment modality for lung cancer,plays an indispensable role in alleviating symptoms,enhancing patients’ quality of life,and prolonging their survival.Not only can radiotherapy directly and effectively eradicate tumors,but it also activates the body’s intrinsic antitumor immune system,suppressing tumor growth and exerting a crucial influence.Phase II clinical trial PEMBRO-RT has demonstrated that the combination of radiotherapy and ICIs further enhances efficacy compared to ICIs monotherapy.In recent years,the combined treatment of radiotherapy and ICIs has garnered significant attention for the management of locally advanced and advanced NSCLC.Gradually validated through clinical trials,the synergistic effect of these combined therapeutic strategies is undeniable.However,the concomitant use of radiotherapy and ICIs may also increase the likelihood of cumulative pulmonary toxicity,potentially inducing pneumonitis.Therefore,predicting the possibility of pneumonitis occurrence prior to combined treatment and reducing the incidence of pulmonary toxicity reactions are essential for the successful implementation of optimal combined treatment plans and warrant further investigation.ObjectiveThis study aims to investigate the analysis of risk factors associated with severe pneumonitis in patients with stage Ⅲ and Ⅳ non-small cell lung cancer(NSCLC)undergoing radiotherapy combined with immunotherapy in real-world settings.By examining tumor tissue immunohistochemistry in individuals with grade 3 or higher severe pneumonitis following immunoradiotherapy,we seek to explore the proinflammatory cytokine levels within tumor tissues prior to combined treatment.Incorporating various factors,this study aims to provide clinically relevant references.MethodsData were collected from patients diagnosed with stage Ⅲ and Ⅳ NSCLC through radiological and pathological examinations at the Affiliated Hospital of Yangtze University between July 2018 and November 2022.These patients received immunotherapy for more than three cycles,received radical radiotherapy of 50 Gy or higher,and developed pneumonitis within six months following combined treatment.Clinical data,including gender,age,stage,smoking history,chronic obstructive pulmonary disease,histological type,treatment sequence,immune-related adverse events,and radiotherapy plan parameters derived from dose-volume histograms(DVH)such as bilateral lung V2.5,V5,V13,V20,MHD,MLD ipsilateral lung,MLD contralateral lung,and bilateral lung mean dose were collected.Pneumonitis severity was graded according to the Radiation Therapy Oncology Group(RTOG)acute radiation-induced lung injury and pneumonitis grading criteria.The primary endpoint was the occurrence of grade ≥2 pneumonitis within six months of combined treatment initiation,and the collected data were analyzed statistically in groups.Factors influencing the occurrence of pneumonitis of different grades(i.e.,≥3 and <3)were compared under combined treatment.The data were further divided into subgroups,analyzing factors affecting the occurrence of grade ≥3 severe pneumonitis in patients receiving immunoradiotherapy.Immunohistochemical experiments were performed on the pathological tissues of patients with severe pneumonitis,and the levels of IL-1,IL-6,and IL-8 within the tumor tissues before treatment were analyzed in the group receiving immunotherapy followed by radiotherapy.This assessment evaluated the levels of proinflammatory cytokines in the tumor tissues.Results1.Among the 179 cases,the incidence of pneumonitis less than grade 3 was72.63%(130/179),while the incidence of pneumonitis grade ≥3 was 27.37%(49/179),of which the incidence of grade 4 pneumonitis was 3.9%,and the mortality rate due to pneumonitis was 4.6%.2.Univariate analysis of clinical and pathological features in the 179 patients revealed significant associations between the occurrence of grade ≥3 pneumonitis and age(P <0.001),chronic lung disease(P=0.036),history of chronic pulmonary conditions(P <0.001),treatment sequence of immunotherapy and radiotherapy(P=0.044),and occurrence of immune-related adverse events(P <0.001)(P <0.05).There were no significant correlations between gender,tumor location,stage,smoking history,V2.5,V5,V13,V20,MHD,MLD ipsilateral lung,MLD contralateral lung,bilateral lung mean dose,and the occurrence of grade ≥3 pneumonitis.3.Multivariate analysis of statistically significant factors from the univariate analysis revealed that age ≥ 65 years,squamous cell carcinoma histology,and immune-related adverse events were independent risk factors for grade ≥ 3pneumonitis.4.The 102 patients who received immunotherapy followed by radiotherapy were divided into groups with pneumonitis grade <3 and ≥3.The incidence of pneumonitis grade <3 was 70.59%(72/102),while the incidence of grade ≥ 3 pneumonitis was29.41%(30/102),with a 3.92% incidence of grade 4 pneumonitis(4/102)and a mortality rate of 5.88%(6/102).5.Univariate analysis of the clinical and pathological characteristics and radiophysical parameters of the 102 patients receiving immunotherapy followed by radiotherapy revealed that age >65 years,combined treatment interval <45 days,and bilateral lung V5 Gy ≥ 45% were all factors related to the occurrence of grade ≥ 3pneumonitis.6.Logistic multivariate regression analysis of statistically significant factors from the univariate analysis showed that age >65 years,combined treatment interval <45days,and bilateral lung V5Gy≥45% were independent risk factors for the occurrence of grade ≥3 pneumonitis.7.Factors such as gender,age,tumor location,stage,histology,smoking history,chronic lung disease history,immune-related adverse events,V13,V20,MHD,MLD ipsilateral lung,MLD contralateral lung,and bilateral lung mean dose were not significantly correlated with the occurrence of grade ≥3 pneumonitis(P ≥0.05).8.Inflammatory markers: According to the pre-treatment expression levels of proinflammatory cytokines IL-1,IL-6,and IL-8 in the pathological tissue samples of 30 NSCLC patients with severe pneumonitis(i.e.,grade ≥ 3)who received immunotherapy followed by radiotherapy,the median composite scores for IL-1,IL-6,and IL-8 were 8 points each.Conclusions1.In the real-world setting,the incidence of pneumonitis in combined treatment is higher than reported in the literature,with a rate of 27.37% for grade ≥3 pneumonitis.Among the entire cohort of combined treatment,age ≥ 65 years,squamous cell carcinoma histology,and the occurrence of immune-related adverse events after combined treatment are independent risk factors for grade ≥3 pneumonitis.2.In the group receiving immunotherapy followed by radiotherapy,age >65 years,combined treatment interval <45 days,and bilateral lung V5Gy≥45% are independent risk factors for the occurrence of grade ≥3 pneumonitis.3.In the tumor tissue of NSCLC patients undergoing immunotherapy followed by radiotherapy,the baseline infiltration levels of IL-1,IL-6,and IL-8 are relatively high prior to combined treatment.For patients with composite scores exceeding 8 points for IL-1,IL-6,and IL-8,clinicians should pay close attention in advance. |
PDF Full Text Request