The incidence and risk factors for radiation pneumonia in anaplastic lymphoma kinase- positive non-small cell lung cancer patients treated with thoracic radiotherapy and simultaneous anaplastic lymphoma kinase tyrosine kinase inhibitor

The incidence and risk factors for radiation pneumonia in anaplastic lymphoma kinase- positive non-small cell lung cancer patients treated with thoracic radiotherapy and simultaneous anaplastic lymphoma kinase tyrosine kinase inhibitor | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The incidence and risk factors for radiation pneumonia in anaplastic lymphoma kinase- positive non-small cell lung cancer patients treated with thoracic radiotherapy and simultaneous anaplastic lymphoma kinase tyrosine kinase inhibitor Feihu Chen, Haoyu Liu, Xuquan Jing, Zhengqiang Yang, Hui Zhu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5340433/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Anaplastic lymphoma kinase tyrosine kinase inhibitor(ALK-TKI) is a first-line treatment regimen for patients with advanced non-small cell lung cancer harboring anaplastic lymphoma kinase-positive. For non-small cell lung cancer patients with slow progression, thoracic radiotherapy can provide significant local control and survival benefits as an effective local consolidation therapy. Radiation pneumonia, one of the typical adverse reactions to radiation therapy, has not yet been reported in studies on the incidence of radiation pneumonia when ALK is combined with thoracic radiotherapy. Therefore, in this study, we aimed to evaluate the incidence and risk factors for radiation pneumonia in such patients and provide a reference for clinical practice. Patients and methods: All medical records of patients with NSCLC who had ALK fusion between January 2016 and May 2023 at Shandong Cancer Hospital and Institute were reviewed using an institutional query system. All patients underwent intensity-modulated radiotherapy and 3-dimensional conformal radiation therapy with photon therapy. Radiation pneumonia was diagnosed via computed tomography and was classified according to the RTOG toxicity scoring system. The risk factors for radiation pneumonia were identified using univariate and multivariate analyses. The Kaplan–Meier method calculates progression-free survival (PFS) and overall survival (OS). Results : Ultimately, 39 patients were included; 14 (35.8%) had grade 2 or above radiation pneumonia, and 6 out of 39 patients (12.8%) had grade 3 or above radiation pneumonia. The median time interval between the onset of radiation pneumonia and thoracic radiotherapy was 1.7 months. In univariate analysis, V 20 ≥ 20.23%, V 5 ≥35.63%, and PTV-volume ≥ 223.05 cm 3 were associated with the occurrence of RP. In the multivariate analysis, V 20 ≥ 20.23% and PTV-volume ≥ 223.05 cm 3 was considered an independent predictor of radiation pneumonia occurrence. Crizotinib is also a risk factor for radiation pneumonia. The mPFS of all patients was 27.7 months. The mOS of all patients was 49.3 months. Conclusions: In summary, our study reports for the first time that the incidence of grade 2 or more severe radiation pneumonia is slightly higher in patients receiving combined treatment with thoracic radiotherapy and anaplastic lymphoma kinase tyrosine kinase inhibitors. Simultaneously, whole-lung V 20 and PTV volume are risk factors for radiation pneumonia. radiation pneumonitis anaplastic lymphoma kinase tyrosine kinase inhibitor thoracic radiotherapy non-small cell lung cancer Figures Figure 1 Figure 2 Figure 3 Background Currently, anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs), such as alectinib and crizotinib, have been approved as the first-line standard treatment for ALK-positive advanced non-small cell lung cancer patients. However, the pulmonary toxicity of ALK-TKIs has always been a concern for clinical doctors [ 1 – 3 ] . During targeted therapy, slow progression of the primary lesion is inevitable. Multiple studies have confirmed that adding local consolidation therapy can bring significant survival benefits to patients with oligometastatic NSCLC [ 4 – 6 ] . Thoracic radiotherapy (TRT) is a suitable control method for locally and slowly progressing lesions. Previous clinical studies have shown that combining TRT with different systemic therapies can reduce local progression rates to 30% and bring significant survival benefits to patients [ 7 ] . However, the toxic combination of TRT and targeted therapy is a particular concern for clinical doctors. Targeted treatment may increase the lung injury caused by radiotherapy, leading to a high incidence rate of radiation pneumonia (RP). In previous literature reports, it is not uncommon for epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to increase the risk of RP, but there has not been any literature reporting that ALK-TKIs are associated with an increased risk of RP [ 8 – 10 ] . In the combination therapy of ALK-TKI and TRT, though there has been research on radiation-induced lung injury in combination therapy, there are insufficient enrolled cases (8 cases and 9 cases) or where EGFR mutation patients were included at the time of enrollment. Given the benefits of local consolidation radiotherapy, the combination therapy of ALK-TKI and TRT should not be ignored. At the 2023 WCLC conference, the MD Anderson Cancer Center initiated a clinical trial to investigate local consolidation therapy (LCT) and brigatinib for metastatic NSCLC patients with primary ALK-TKI treatment of ALK fusion. One of the 27 patients who underwent brigatinib and TRT developed grade 3 RP. Survival is also superior to ALTA-1 L research. Therefore, it is necessary to carefully evaluate the pulmonary toxicity of TRT and the simultaneous use of ALK-TKIs. However, there are currently no literature reports on this issue. To address this, we included 39 cases with NSCLC receiving TRT and simultaneous ALK-TKI, which were retrospectively reviewed to explore the risk for RP. Patients and methods Study design and patients All medical records of patients with NSCLC who had ALK fusion between January 2016 and May 2023 at Shandong Cancer Hospital and Institute were reviewed using an institutional query system. Information such as gender, age, and radiation parameters were collected. According to the 2017 lung cancer diagnosis and treatment guidelines, the inclusion criteria were as follows: 1) gene sequencing results showing ALK fusion and 2) treatment with TRT and simultaneous ALK-TKI. Patients who received thoracic reirradiation, those with a history of ILD, or those previously treated with immune checkpoint inhibitors and surgical intervention were excluded. The tumor stage was assessed by systemic imaging (contrast-enhanced computed tomography [CT] of the chest and abdomen, bone scan, or positron emission tomography/computed tomography [PET-CT]) and brain imaging (either contrast-enhanced CT or magnetic resonance imaging [MRI]). Patients with an ILD history or poor essential lung function were excluded. Treatment protocol All patients underwent intensity-modulated radiotherapy and 3-dimensional conformal radiation therapy with photon therapy. V 5 and V 20 were recorded on each patient's DVH chart of the radiotherapy plan. Total lung V 5 and V 20 are the percentages of total lung volume receiving radiation exceeding 5 Gy and 20 Gy, respectively. Data were collected from the medical records. The study was approved by the Ethics Committee of Shandong Cancer Hospital and Institute, performed by the Declaration of Helsinki, and conducted under the supervision of Shandong Cancer Hospital and Institute. The need for informed consent was waived by the ethics committee/Institutional Review Board of The Shandong Cancer Hospital and Institute, because of the retrospective nature of the study. Diagnosis and classification of radiation pneumonitis RP was diagnosed via CT. At least two senior radiologists independently evaluated the follow-up CT examination, and differences were resolved by consulting with a third senior radiologist. According to the patient's clinical symptoms, laboratory test results, and treatment results, RP was scored from 1 to 5 points according to the RTOG toxicity scoring systems. Statistical analysis All statistical analyses were performed using GraphPad Prism software v.8.0 (GraphPad, Inc., CA, USA). The Kaplan‒Meier method was used to calculate PFS and OS. PFS was defined as the time from treatment commencement of ALK-TKI and TRT to confirmed disease progression or death from any cause. Overall survival (OS) was defined as the period from treatment commencement of ALK-TKI and TRT to the date of death. When statistically describing patient baseline characteristics and conducting factor analysis, the receiver operating characteristic (ROC) curve was first generated for noncategorical variables to determine the optimal cutoff value. After considering sensitivity and specificity, the cutoff value is determined based on the maximum Uden index. We used cutoff values as grouping criteria. Finally, it is converted into a categorical variable. We used logistic regression to perform univariate and multivariate analyses to analyze the risk factors for RP. Bilateral p values<0.05 were considered statistically significant. The elements included in the multivariate analysis were statistically significant variables in the univariate analysis. However, due to the strong collinearity of irradiation parameters (such as V 5 and V 20 ), we selected variables with smaller p values for multivariate analysis. Results Patient characteristics Based on screening criteria, we reviewed the case system and included 39 patients who received TRT during ALK-TKI treatment in stage IV. 34 people received intensity-modulated therapy (IMRT), 5 people received 3-dimensional conformal radiation therapy (3D-CRT). The clinical and radiation dosimetry characteristics of all patients are shown in Table 1 . The optimal thresholds for PTV-volume, V 20 , V 5 , and time of taking ALK-TKI before radiotherapy based on the maximum Youden index were 223.05 cm 3 , 20.23%, 35.63%, and 1.4 months, respectively. The median age was 54 years (range 36–80 years), and most patients were female (53.8%). The median follow-up time was 26.6 months. The median PTV-dose was 60 Gy (range 50–66 Gy), and most patients had PTV doses concentrated between 50 and 60 Gy (n = 33, 84.8%). Due to the proximity of the lesions in these patients to peripheral pulmonary lesions and the small residual lesions after ALK-TkIs treatment, three patients received stereotactic body radiationtherapy (SBRT) with a single amount of 7.5 and 8 Gy in order to better improve local control rate. The remaining patients the main radiation therapy protocol received is a single dose of 1.8-2 Gy, 25–30 doses. V 20 was well constrained (median 13%; range 3.5–28.7%). Among the 39 cases, ten patients experienced primary tumor progression during ALK-TKI maintenance therapy and subsequently received TRT as a local salvage treatment. The remaining 29 patients received TRT consolidation therapy during ALK-TKI maintenance therapy due to the better local control rate. In 29 patients receiving consolidation treatment, the average interval from initial medication to TRT was 2.4 months, while in 10 patients receiving salvage treatment, the gap was 15.6 months. In terms of drug selection, the majority of patients used alectinib (n = 26, 66.6%), while the rest of the patients used crizotinib, iruplinalkib, and other ALK-TKIs. Finally, most patients used ALK-TKIs as a first-line medication (n = 26,66.6%). (Table 1 ). Incidence of RP According to the results of CT follow-up, 14 out of 39 patients (35.8%) developed RP of grade 2 or above, and 6 out of 39 patients (12.8%) developed RP of grade 3 or above. No grade 4 or 5 RP occurred (Fig. 1 ). Among the 14 patients with RP, the middle interval between TRT and RP was 1.7 months, with RP occurring within one month after radiotherapy in both patients. Regarding the irradiation dose, the average V 20 is 16.1%, and the intermediate V 5 is 49.12%. In terms of target volume size, the average PTV-volume was 310 cm 3 . Among these fourteen patients who developed RP, seven took alectinib, and five took crizotinib. The incidence of RP in patients taking alectinib was 26.9%, while in patients taking crizotinib, it was 71.4%. Five of the six patients who developed grade 3 RP took crizotinib. The V 20 of these six patients was 12.1%, 28.7%, 16.8%, 24.45%, 21.37% and 28.07%. Regarding the time of taking ALK-TKI before TRT, there is a distribution from medication, and TRT starts simultaneously at 21.4 months. One typical image from 11 cases of Grade 3 RP is shown in Fig. 2 . Risk factors for RP In factor analysis, due to the different single doses of some patients, we standardized all patients to a single dose of 2Gy according to the (Equivalent Dose in 2-Gy fractions, EQD2) calculation formula, and recalculated the V 20 and V 5 of all patients based on the new EQD2. In univariate analysis, V 20 ≥ 20.23% (OR 8.22; 95% CI 2.41–55.94; p = 0.002), V 5 ≥ 35.63% (OR 14.2; 95% CI 3.3-67.88; p = 0.012), and PTV-volume ≥ 223.05 cm 3 (OR 28.76; 95% CI 4.51–183.3; p = 0.001) were associated with the occurrence of RP. Other factors, including age and sex, were not correlated with RP. Considering the strong collinearity of V 20 and V 5 and the smaller p value of V 20 , we selected V 20 and PTV-volume for multivariate analysis. PTV-volume ≥ 223.05 cm 3 (OR 20.46; 95% CI 2.74–86.78; p = 0.003) and V 20 ≥ 20.23% (OR 7.58; 95% CI 4.12–50.76; p = 0.017) was associated with the occurrence of RP (Table 2 ). In addition, in terms of the incidence of RP in different ALK-TKIs, crizotinib is also a risk factor, as the incidence of RP in crizotinib is significantly higher than that in alectinib (71.4% vs. 26.9%). Survival analysis The median follow-up time was 26.6 months. Twenty-two out of 39 patients had no progressive disease (PD) as of our last follow-up date. Seven patients experienced PD but did not die. Among them, five people continued receiving the original drug alectinib treatment, one underwent lymph node radiotherapy for lymph node progression, and the other developed brain metastasis and planned to receive stereotactic radiotherapy treatment. Finally, ten people eventually died due to PD. One patient showed slow lesion progression 24 months after the initial medication, but the overall efficacy evaluation was partial remission (PR). To prevent further disease progression, we performed local radiotherapy. This patient did not show any progress during multiple follow-up examinations within 56 months before our last follow-up date. The mPFS and mOS of patients taking alectinib were 25.4 months (95% CI, 22.8–32.6) and 49.3 months (95% CI, 32.05–66.61), respectively. The mPFS and mOS of patients taking crizotinib were 27.7 months (95% CI, 3.84–51.57) and 44.8 months (95% CI, not shown), respectively. (Fig. 3). Discussion The addition of TRT brings significant survival benefits to patients with oligoprogression when treated with ALK-TKI, which has been confirmed. Overall survival may benefit from the synergistic combination. Administering SBRT during crizotinib treatment in eight ALK-positive oligoprogressive NSCLCs resulted in 86% of one-year local control in the irradiated foci, allowing longer crizotinib exposure and providing OS benefit. Only one patient experienced advanced radiation-induced lung injury [ 11 ] . Similarly, a large clinical trial enrolled nine patients who used ALK-TKIs in combination with TRT. Although the experiment was closed midway due to technical issues and the survival outcome was unknown, these nine patients did not experience any adverse pulmonary events in terms of safety (RTOG3106). However, based on the treatment experience of the combination of targeted drugs and TRT, it is suggested that when targeted therapy and radiation therapy are used simultaneously, the occurrence of radiation-induced lung injury needs to be particularly vigilant. In 2014, Zhuang et al. and in 2020, Jia et al. reported a high incidence of RP during targeted therapy (erlotinib and osimertinib) combined with TRT, with rates of 37.5% and 63.6%, respectively, which undoubtedly concerns clinical doctors [ 9 , 12 ] . However, there are currently no independent reports on the safety of combining ALK-TKIs with TRT. We conducted this retrospective study to address this issue. Therefore, we conducted this study to evaluate the incidence of RP during the combined treatment of ALK-TKI and TRT, providing a reference for clinical medicine. The results showed that RP above level 2 was 35.8%, and RP above level 3 was 12.8%, higher than 13%-37% in patients receiving concurrent chemoradiotherapy [ 13 ] . Furthermore, through further analysis, the median interval between the onset of inflammation after TRT was 1.7 months, with two patients experiencing inflammation within one month after radiotherapy. This suggests that clinical doctors should pay close attention to acute inflammation in patients after radiotherapy and perform an excellent job of follow-up and observation. In addition, there is a fact worth being vigilant. Among the 39 enrolled patients, 5 out of 7 who took crizotinib developed RP, while only 7 out of 26 patients who took alectinib developed RP. This seems to suggest that the incidence of RP in crizotinib is higher than that in alectinib, but an uneven number of cases may also cause this significant difference in incidence. Finally, although half of the 14 patients who developed RP had grade 3, fortunately, there were no cases of grade 4 or death. Therefore, considering the local benefits of TRT, this treatment combination model is acceptable. Some therapeutic mechanisms may explain the relationship between ALK-TKIs and RP. NSCLC cells carrying EGFR/ALK fusion have a tendency toward radiosensitivity, mainly related to delayed DNA damage repair, deoxyribonucleic acid synthesis or mitosis stagnation, and a significant increase in cell apoptosis frequency [ 14 ] . In addition, the c-MET pathway inhibits radiation therapy, while crizotinib can bypass the radiosensitization effect of c-MET inhibition by activating the protein kinase B (AKT) route [ 15 ] . On the other hand, multiple preclinical study results have shown that G2 block can be detected after treatment with crizotinib [ 16 , 17 ] . This may also be based on the binding affinity between crizotinib and the c-MET pathway [ 18 ] . As is well known, the protein c-MET is involved in the cell cycle, and the G2 phase is more sensitive to radiation [ 19 ] . Numerous preclinical studies have shown that crizotinib has radiosensitization potential in ALK-positive NSCLC cell lines. Similarly, the differences in the incidence of pneumonia between crizotinib and alectinib can also be traced based on previous experiments. Compared to crizotinib, crizotinib can produce stronger reactions with tumor cells. Cells treated with alectinib did not show any impact on radiation outcomes. It is worth noting that in the A549 cell line, only crizotinib was observed to increase G2/M phase cell colonies with greater radiosensitivity, ultimately leading to a higher number of cell deaths. Compared to the cell cycle arrest associated with crizotinib causing cell death, aging seems to be the primary mode of action of alectinib [ 16 , 20 , 21 ] . Interestingly, in previous cell experimental results, the dominant factor in the superposition of ALK-TKI and radiation-induced toxicity may be ALK-TKI. Increasing the concentration of ALK-TKI can lead to increased toxicity, but increasing the radiation dose in the experimental protocol does not further enhance toxicity [ 16 ] . It is worth noting that according to the results of the multifactorial analysis in our study, the occurrence of RP is related to V 20 and PTV volume. We believe this is a deviation due to the small number of enrolled cases, but we cannot conclude that V 20 is not related to RP quality inspection but rather to the time of taking ALK-TKI before radiotherapy. Therefore, to reduce the incidence of RP, the timing of adding TRT can be delayed to a certain extent, and consolidation treatment can be performed after the lesion shrinks. On the other hand, it is still necessary to strictly limit the V 20 of such patients as low as possible to reduce the risk of RP. In the latest WCLC conference, the BRIGHTSTAR trial results showed the survival benefits and better safety of local consolidation therapy in populations with oligoprogression after receiving ALK-TKI treatment. However, due to its small sample size, this study cannot be promoted as a high-level clinical application. In the future, targeted therapy combined with local consolidation therapy may become the best treatment mode for this population. However, in locally advanced NSCLC, combining TRT with targeted drugs still raises issues regarding the optimal patient population selection, dosing time interval for minimal adverse events, and protective measures against radiation damage. These issues can be addressed only through large-scale, carefully designed multicenter clinical trials explicitly targeting molecular selection populations, careful long-term safety analysis, and specific categories of the best drugs. Our research also has some limitations. First, as a single institution study, all included patients were Chinese. Therefore, racial differences cannot be ruled out. Second, only 39 patients were enrolled in our study, which is too small for larger-scale statistical analysis. Finally, our focus in initiating this study is on the incidence of RP, which inevitably results in a short follow-up time and an uneven distribution of different ALK-TKI cohorts. Therefore, there is a bias in the evaluation of overall efficacy indicators (such as OS, PFS) and local control rate, which is also the reason why the 95% CI confidence interval of the crizotinib group is not shown. Conclusion In summary, our study reported a higher incidence of grade 2 or more severe RP in patients receiving treatment with TRT and simultaneous ALK-TKI for the first time. We hope it can help make clinical doctors more aware of RP. However, the optimal combination of systemic and local therapy should not be abandoned, which requires further exploration of how to reduce the incidence of adverse events, such as the optimal dosing interval or safer combination doses of drugs and radiation. Future research should also be based on preclinical studies on the mechanism of toxicity superposition at the cellular level, exploring effective protective measures. Abbreviations TRT: thoracic radiotherapy; NSCLC: non-small cell lung cancer; PFS: progression-free survival; OS: overall survival; RP: radiation pneumonia; PTV: planning target volume; ROC: receiver operating characteristic; CT: computed tomography; PET-CT: positron emission tomography/computed tomography; ALK: anaplastic lymphoma kinase ALK-TKI: anaplastic lymphoma kinase tyrosine kinase inhibitor; PD: progressive disease; PR: partial remission Declarations Acknowledgments Not applicable Authors' contributions Yang designed the study. Chen and Liu drafted the manuscript. All authors coordinated the study. Zhu checked and revised the content of the manuscript. Jing participated in imaging analysis. All authors read and approved the final manuscript. Funding This work was supported by the National Natural Science Foundation of China [grant number: 81972862], the CSCO Pilot Cancer Research Fund [Grant Number: Y-2019AZZD-0352], and the Key Research and Development Program of Shandong Province [Grant Number: 2018GSF118067]. Availability of data and materials All data generated or analyzed during this study are included in this publication article. Ethics approval and consent to participate The need for informed consent was waived by the ethics committee/Institutional Review Board of The Shandong Cancer Hospital and Institute, because of the retrospective nature of the study Consent for publication Agreed. Competing interests The authors declare that they have no competing interests. References Ikeda, S., et al., Interstitial lung disease induced by alectinib (CH5424802/RO5424802). Japanese Journal of Clinical Oncology, 2015. 45 (2): p. 221-224. Pellegrino, B., et al., Lung Toxicity in Non-Small-Cell Lung Cancer Patients Exposed to ALK Inhibitors: Report of a Peculiar Case and Systematic Review of the Literature. Clinical Lung Cancer, 2018. 19 (2): p. E151-E161. Watanabe, N., et al., Crizotinib-induced acute interstitial lung disease in a patient with EML4-ALK positive non-small cell lung cancer and chronic interstitial pneumonia. Acta Oncologica, 2014. 53 (1): p. 158-160. Al-Halabi, H., et al., Pattern of Failure Analysis in Metastatic EGFR-Mutant Lung Cancer Treated with Tyrosine Kinase Inhibitors to Identify Candidates for Consolidation Stereotactic Body Radiation Therapy. Journal of Thoracic Oncology, 2015. 10 (11): p. 1601-1607. Chen, Y., et al., Local consolidative therapy for synchronous oligometastatic non-small cell lung cancer treated with first-line pembrolizumab: A retrospective observational study. Thoracic Cancer, 2022. 13 (5): p. 732-741. Hu, F., et al., Additional local consolidative therapy has survival benefit over EGFR tyrosine kinase inhibitors alone in bone oligometastatic lung adenocarcinoma patients. Lung Cancer, 2019. 135 : p. 138-144. Arrieta, O., et al., Radical consolidative treatment provides a clinical benefit and long-term survival in patients with synchronous oligometastatic non-small cell lung cancer: A phase II study. Lung Cancer, 2019. 130 : p. 67-75. Zhu, H., et al., Severe Pulmonary Toxicity With Concurrent Anlotinib and Chemoradiotherapy in Stage III NSCLC: The ALTER-L042 Phase 1 Clinical Trial. JTO Clin Res Rep, 2022. 3 (6): p. 100339. Jia, W.X., et al., An especially high rate of radiation pneumonitis observed in patients treated with thoracic radiotherapy and simultaneous osimertinib. Radiotherapy and Oncology, 2020. 152 : p. 96-100. Zhuang, H.Q., et al., Preliminary analysis of the risk factors for radiation pneumonitis in patients with non-small-cell lung cancer treated with concurrent erlotinib and thoracic radiotherapy. Oncotargets and Therapy, 2014. 7 : p. 807-813. Gan, G.N., et al., Stereotactic Radiation Therapy can Safely and Durably Control Sites of Extra-Central Nervous System Oligoprogressive Disease in Anaplastic Lymphoma Kinase-Positive Lung Cancer Patients Receiving Crizotinib. International Journal of Radiation Oncology Biology Physics, 2014. 88 (4): p. 892-898. Zhuang, H.Q., et al., Radiation Pneumonitis in Patients with Non-Small-Cell Lung Cancer Treated with Erlotinib Concurrent with Thoracic Radiotherapy. Journal of Thoracic Oncology, 2014. 9 (6): p. 882-885. Rodriques, G., et al., Prediction of radiation pneumonitis by dose-volume histogram parameters in lung cancer - A systematic review. Radiotherapy and Oncology, 2004. 73 : p. S26-S26. Hayashi, H., et al., Clinical Outcomes of Thoracic Radiotherapy for Locally Advanced NSCLC with Mutations or Rearrangement. Anticancer Research, 2012. 32 (10): p. 4533-4537. De Bacco, F., et al., Induction of MET by Ionizing Radiation and Its Role in Radioresistance and Invasive Growth of Cancer. Journal of the National Cancer Institute, 2011. 103 (8): p. 645-661. Jost, T., et al., Influence of alectinib and crizotinib on ionizing radiation - analysis of ALK/ROS1-wildtype lung tissue cells. Neoplasia, 2022. 27 . Shrestha, N., et al., Mechanisms of suppression of cell growth by dual inhibition of ALK and MEK in ALK-positive non-small cell lung cancer. Scientific Reports, 2019. 9 . Wood, G.E., et al., The role of MET in chemotherapy resistance. Oncogene, 2021. 40 (11): p. 1927-1941. Sinclair, W.K., Cyclic X-Ray Responses in Mammalian Cells. Radiation Research, 2012. 178 (2): p. Av112-Av124. Dai, Y., et al., Synergistic effects of crizotinib and radiotherapy in experimental fusion positive lung cancer. Radiotherapy and Oncology, 2015. 114 (2): p. 173-181. Sun, Y.G., et al., ALK Inhibitor PF02341066 (Crizotinib) Increases Sensitivity to Radiation in Non-Small Cell Lung Cancer Expressing EML4-ALK. Molecular Cancer Therapeutics, 2013. 12 (5): p. 696-704. Tables Table 1. Baseline characteristics of patients Characteristics Total (%) (n=39) Gender Male Female 18 (46.1) 21 (53.8) Age (y) (Median, range) <65 ≥65 54(36-80) 31 (79.5) 8 (20.5) Smoking history No Yes 29 (74.3) 10 (25.7) KPS score 60 60 (50-66) 11 (28.2) 22 (56.4) 6 (15.4) Fraction dose (Gy) (Median, range) ≤3 >3 2 (1.8-8) 36 (92.3) 3 (7.7) Time of taking ALK-TKI before radiotherapy (Median, range) 1.5 (0-35.8) ≤1.4 >1.4 18 (46.2) 21 (53.8) PTV-volume (cm³) (Median, range) ≤ 223.05 >223.05 V 20 total (%) (Median, range) ≤20.23 >20.23 159.7(13-980.1) 28 (62.2) 11 (37.8) 13(3.5-28.7) 28 (71.8) 11 (28.2) V 5 total (%) (Median, range) ≤35.63 >35.63 30.51 (14.3-83.95) 22 (56.4) 17 (43.6) Timing of radiotherapy addition consolidation salvage 29 (74.3) 10 (25.7) ALK-TKI alectinib crizotinib iruplinalkib brigatinib ceritinib The treatment line of ALK-TKI 1 2 3 26 (66.6) 7 (17.9) 3 (7.6) 1 (2.5) 2 (5.1) 26 (66.6) 8 (20.5) 5 (12.9) Abbreviations: KPS: Karnofsky performance status. PTV: plan tumor volume. Table 2. univariate and multivariate analysis of risk of developing RP Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5340433","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":372041387,"identity":"df53e6d7-8644-4449-a4b2-c309251de29c","order_by":0,"name":"Feihu Chen","email":"","orcid":"","institution":"Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Feihu","middleName":"","lastName":"Chen","suffix":""},{"id":372041389,"identity":"ab353b47-0b78-4c70-877e-abda9dc526f0","order_by":1,"name":"Haoyu Liu","email":"","orcid":"","institution":"Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Haoyu","middleName":"","lastName":"Liu","suffix":""},{"id":372041391,"identity":"1b52bf09-b718-4d1b-868a-5aec71b35947","order_by":2,"name":"Xuquan Jing","email":"","orcid":"","institution":"Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Xuquan","middleName":"","lastName":"Jing","suffix":""},{"id":372041392,"identity":"5a3558d4-bfc9-4a82-9af1-cb7a81eb48a8","order_by":3,"name":"Zhengqiang Yang","email":"","orcid":"","institution":"Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Zhengqiang","middleName":"","lastName":"Yang","suffix":""},{"id":372041393,"identity":"01a7cb3e-0430-46e9-b3c5-bdb4db88d6e5","order_by":4,"name":"Hui Zhu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAq0lEQVRIiWNgGAWjYDCCAwxsDIwNNjz87A2kaUmTkew5QJqWwzYGNxyI1MF3+/izx7w7zvMw3GBg/PAxhwgtkucS0o15z9zmYZzdwCw5cxsRWgzOMByT5m27zcMsc4CNmZc4LYxtQC3neNgkEojWwswG1HKAh4doLZJn2Ngk57Yl80jwHGwmzi98Z9ifSbxts7O3P9588MNHYrQgAcYG0tSPglEwCkbBKMANAN7CMwzb7kYwAAAAAElFTkSuQmCC","orcid":"","institution":"Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences","correspondingAuthor":true,"prefix":"","firstName":"Hui","middleName":"","lastName":"Zhu","suffix":""}],"badges":[],"createdAt":"2024-10-27 08:53:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5340433/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5340433/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":69437360,"identity":"42b1e7a3-dd6a-4b54-9ace-c88f4b46dbdc","added_by":"auto","created_at":"2024-11-20 10:46:58","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":24186,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe incidence of ≥ 2 grade RP in 39 patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThere are 14 (35.8%) patients who had developed ≥2 grade RP in total 39 patients, of which 8 (23.0%) had 2 grade RP and 6 (12.8%) had 3 grade radiation pneumonia. No one has developed grade 4 or 5 RP.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-5340433/v1/5435dc46ece530d9ef28e112.png"},{"id":69437361,"identity":"d2db049c-ef5a-4043-b38e-6b8fdda53b51","added_by":"auto","created_at":"2024-11-20 10:46:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":388167,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTypical images of one patient who experienced grade 3 RP after TRT.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ea.\u003c/strong\u003e \u003cstrong\u003ePrimary lesion b. The isodose curve of the treatment plan. c. two months after radiotherapy. d. dose distribution histogram of the total lung, right lung, PTV, GTV, and left lung\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5340433/v1/0b13b60d93c0e3487d1ec59d.png"},{"id":69438695,"identity":"66de289b-75bb-47bf-9de9-710c62a7ca7c","added_by":"auto","created_at":"2024-11-20 10:54:58","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":74691,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSurvival analysis of patients receiving different kinds of ALK-TKI and TRT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe mPFS and mOS of patients taking alectinib was 25.4 months (95% CI, 22.8-32.6) and 49.3 months (95% CI, 32.05-66.61). The mPFS and mOS of patients taking crizotinib was 27.7 months (95% CI, 3.84-51.57) and 44.8 months (95% CI, not shown)\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5340433/v1/028b2f7e432a7b031d7b28f3.png"},{"id":73884702,"identity":"1ff2af1d-0247-4ef6-8016-4e9c0c46cb69","added_by":"auto","created_at":"2025-01-15 14:24:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1517330,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5340433/v1/42689175-f556-4246-8418-a1ac4f68494b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The incidence and risk factors for radiation pneumonia in anaplastic lymphoma kinase- positive non-small cell lung cancer patients treated with thoracic radiotherapy and simultaneous anaplastic lymphoma kinase tyrosine kinase inhibitor","fulltext":[{"header":"Background","content":"\u003cp\u003e Currently, anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs), such as alectinib and crizotinib, have been approved as the first-line standard treatment for ALK-positive advanced non-small cell lung cancer patients. However, the pulmonary toxicity of ALK-TKIs has always been a concern for clinical doctors \u003csup\u003e[\u003cspan additionalcitationids=\"CR2\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e–\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDuring targeted therapy, slow progression of the primary lesion is inevitable. Multiple studies have confirmed that adding local consolidation therapy can bring significant survival benefits to patients with oligometastatic NSCLC\u003csup\u003e[\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e–\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]\u003c/sup\u003e. Thoracic radiotherapy (TRT) is a suitable control method for locally and slowly progressing lesions. Previous clinical studies have shown that combining TRT with different systemic therapies can reduce local progression rates to 30% and bring significant survival benefits to patients\u003csup\u003e[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e. However, the toxic combination of TRT and targeted therapy is a particular concern for clinical doctors.\u003c/p\u003e \u003cp\u003eTargeted treatment may increase the lung injury caused by radiotherapy, leading to a high incidence rate of radiation pneumonia (RP). In previous literature reports, it is not uncommon for epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to increase the risk of RP, but there has not been any literature reporting that ALK-TKIs are associated with an increased risk of RP\u003csup\u003e[\u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e–\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. In the combination therapy of ALK-TKI and TRT, though there has been research on radiation-induced lung injury in combination therapy, there are insufficient enrolled cases (8 cases and 9 cases) or where EGFR mutation patients were included at the time of enrollment. Given the benefits of local consolidation radiotherapy, the combination therapy of ALK-TKI and TRT should not be ignored. At the 2023 WCLC conference, the MD Anderson Cancer Center initiated a clinical trial to investigate local consolidation therapy (LCT) and brigatinib for metastatic NSCLC patients with primary ALK-TKI treatment of ALK fusion. One of the 27 patients who underwent brigatinib and TRT developed grade 3 RP. Survival is also superior to ALTA-1 L research.\u003c/p\u003e \u003cp\u003eTherefore, it is necessary to carefully evaluate the pulmonary toxicity of TRT and the simultaneous use of ALK-TKIs. However, there are currently no literature reports on this issue. To address this, we included 39 cases with NSCLC receiving TRT and simultaneous ALK-TKI, which were retrospectively reviewed to explore the risk for RP.\u003c/p\u003e\n\n \n\n "},{"header":"Patients and methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design and patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll medical records of patients with NSCLC who had ALK fusion between January 2016 and May 2023 at Shandong Cancer Hospital and Institute were reviewed using an institutional query system. Information such as\u0026nbsp;gender, age, and radiation parameters\u0026nbsp;were\u0026nbsp;collected.\u003c/p\u003e\n\u003cp\u003eAccording to the 2017 lung cancer diagnosis and treatment guidelines, the inclusion criteria were\u0026nbsp;as follows: 1) gene sequencing results\u0026nbsp;showing\u0026nbsp;ALK fusion\u0026nbsp;and\u0026nbsp;2)\u0026nbsp;treatment\u0026nbsp;with TRT and simultaneous ALK-TKI. Patients who received thoracic reirradiation, those with a history of ILD, or those previously treated with immune checkpoint inhibitors and surgical intervention were excluded. The tumor stage was assessed by systemic imaging (contrast-enhanced computed tomography [CT] of the chest and abdomen, bone scan, or positron emission tomography/computed tomography [PET-CT]) and brain imaging (either contrast-enhanced CT or magnetic resonance imaging [MRI]).\u0026nbsp;Patients with an ILD history\u0026nbsp;or poor essential lung function\u0026nbsp;were excluded.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment protocol\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients underwent intensity-modulated radiotherapy and 3-dimensional conformal radiation therapy with photon therapy. V\u003csub\u003e5\u003c/sub\u003e and V\u003csub\u003e20\u003c/sub\u003e were recorded on each patient's DVH chart of the radiotherapy plan. Total lung V\u003csub\u003e5\u003c/sub\u003e and V\u003csub\u003e20\u003c/sub\u003e are the percentages of total lung volume receiving radiation exceeding 5 Gy and\u0026nbsp;20 Gy, respectively.\u003c/p\u003e\n\u003cp\u003eData were collected from the medical records. The study was approved by the Ethics Committee of Shandong Cancer Hospital and Institute,\u0026nbsp;performed by the Declaration of Helsinki, and conducted under the supervision of Shandong Cancer Hospital and Institute. The need for informed consent was waived by the ethics committee/Institutional Review Board of The Shandong Cancer Hospital\u0026nbsp;and Institute, because of the retrospective nature of the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDiagnosis and classification of radiation pneumonitis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRP was diagnosed via CT. At least two senior radiologists independently evaluated the follow-up CT examination, and differences were resolved by consulting with a third senior radiologist. According to the patient's clinical symptoms, laboratory test results, and treatment results, RP\u0026nbsp;was\u0026nbsp;scored from 1 to 5 points according to the RTOG toxicity scoring systems.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were performed using GraphPad Prism software v.8.0 (GraphPad, Inc., CA, USA). The Kaplan‒Meier method was used to calculate PFS and OS.\u0026nbsp;PFS was defined as the time from treatment commencement of ALK-TKI and TRT to confirmed disease progression or death\u0026nbsp;from\u0026nbsp;any cause. Overall survival (OS) was defined as the period from treatment commencement of ALK-TKI and TRT to the date of death.\u0026nbsp;When statistically describing patient baseline characteristics and conducting factor analysis, the receiver operating characteristic (ROC) curve was first generated for\u0026nbsp;noncategorical\u0026nbsp;variables to determine the optimal cutoff value. After considering sensitivity and specificity, the cutoff value is determined based on the maximum Uden index. We\u0026nbsp;used\u0026nbsp;cutoff values as grouping criteria. Finally,\u0026nbsp;it is converted\u0026nbsp;into a categorical variable. We used logistic regression to perform univariate and multivariate analyses to analyze the risk factors\u0026nbsp;for\u0026nbsp;RP.\u0026nbsp;Bilateral p values\u0026lt;0.05 were considered statistically significant. The elements included in the multivariate analysis were statistically significant variables in the univariate analysis. However, due to the strong collinearity of irradiation parameters (such as V\u003csub\u003e5\u003c/sub\u003e and V\u003csub\u003e20\u003c/sub\u003e), we selected variables with smaller p values for multivariate analysis.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n \u003ch2\u003ePatient characteristics\u003c/h2\u003e\n \u003cp\u003eBased on screening criteria, we reviewed the case system and included 39 patients who received TRT during ALK-TKI treatment in stage IV. 34 people received intensity-modulated therapy (IMRT), 5 people received 3-dimensional conformal radiation therapy (3D-CRT). The clinical and radiation dosimetry characteristics of all patients are shown in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The optimal thresholds for PTV-volume, V\u003csub\u003e20\u003c/sub\u003e, V\u003csub\u003e5\u003c/sub\u003e, and time of taking ALK-TKI before radiotherapy based on the maximum Youden index were 223.05 cm\u003csup\u003e3\u003c/sup\u003e, 20.23%, 35.63%, and 1.4 months, respectively. The median age was 54 years (range 36\u0026ndash;80 years), and most patients were female (53.8%). The median follow-up time was 26.6 months. The median PTV-dose was 60 Gy (range 50\u0026ndash;66 Gy), and most patients had PTV doses concentrated between 50 and 60 Gy (n\u0026thinsp;=\u0026thinsp;33, 84.8%). Due to the proximity of the lesions in these patients to peripheral pulmonary lesions and the small residual lesions after ALK-TkIs treatment, three patients received stereotactic body radiationtherapy (SBRT) with a single amount of 7.5 and 8 Gy in order to better improve local control rate. The remaining patients the main radiation therapy protocol received is a single dose of 1.8-2 Gy, 25\u0026ndash;30 doses. V\u003csub\u003e20\u003c/sub\u003e was well constrained (median 13%; range 3.5\u0026ndash;28.7%). Among the 39 cases, ten patients experienced primary tumor progression during ALK-TKI maintenance therapy and subsequently received TRT as a local salvage treatment. The remaining 29 patients received TRT consolidation therapy during ALK-TKI maintenance therapy due to the better local control rate. In 29 patients receiving consolidation treatment, the average interval from initial medication to TRT was 2.4 months, while in 10 patients receiving salvage treatment, the gap was 15.6 months. In terms of drug selection, the majority of patients used alectinib (n\u0026thinsp;=\u0026thinsp;26, 66.6%), while the rest of the patients used crizotinib, iruplinalkib, and other ALK-TKIs. Finally, most patients used ALK-TKIs as a first-line medication (n\u0026thinsp;=\u0026thinsp;26,66.6%). (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n \u003ch2\u003eIncidence of RP\u003c/h2\u003e\n \u003cp\u003eAccording to the results of CT follow-up, 14 out of 39 patients (35.8%) developed RP of grade 2 or above, and 6 out of 39 patients (12.8%) developed RP of grade 3 or above. No grade 4 or 5 RP occurred (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Among the 14 patients with RP, the middle interval between TRT and RP was 1.7 months, with RP occurring within one month after radiotherapy in both patients. Regarding the irradiation dose, the average V\u003csub\u003e20\u003c/sub\u003e is 16.1%, and the intermediate V\u003csub\u003e5\u003c/sub\u003e is 49.12%. In terms of target volume size, the average PTV-volume was 310 cm\u003csup\u003e3\u003c/sup\u003e. Among these fourteen patients who developed RP, seven took alectinib, and five took crizotinib. The incidence of RP in patients taking alectinib was 26.9%, while in patients taking crizotinib, it was 71.4%. Five of the six patients who developed grade 3 RP took crizotinib. The V\u003csub\u003e20\u003c/sub\u003e of these six patients was 12.1%, 28.7%, 16.8%, 24.45%, 21.37% and 28.07%. Regarding the time of taking ALK-TKI before TRT, there is a distribution from medication, and TRT starts simultaneously at 21.4 months. One typical image from 11 cases of Grade 3 RP is shown in Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eRisk factors for RP\u003c/h3\u003e\n\u003cp\u003eIn factor analysis, due to the different single doses of some patients, we standardized all patients to a single dose of 2Gy according to the (Equivalent Dose in 2-Gy fractions, EQD2) calculation formula, and recalculated the V\u003csub\u003e20\u003c/sub\u003e and V\u003csub\u003e5\u003c/sub\u003e of all patients based on the new EQD2. In univariate analysis, V\u003csub\u003e20\u003c/sub\u003e\u0026thinsp;\u0026ge;\u0026thinsp;20.23% (OR 8.22; 95% CI 2.41\u0026ndash;55.94; p\u0026thinsp;=\u0026thinsp;0.002), V\u003csub\u003e5\u003c/sub\u003e\u0026thinsp;\u0026ge;\u0026thinsp;35.63% (OR 14.2; 95% CI 3.3-67.88; p\u0026thinsp;=\u0026thinsp;0.012), and PTV-volume\u0026thinsp;\u0026ge;\u0026thinsp;223.05 cm\u003csup\u003e3\u003c/sup\u003e (OR 28.76; 95% CI 4.51\u0026ndash;183.3; p\u0026thinsp;=\u0026thinsp;0.001) were associated with the occurrence of RP. Other factors, including age and sex, were not correlated with RP. Considering the strong collinearity of V\u003csub\u003e20\u003c/sub\u003e and V\u003csub\u003e5\u003c/sub\u003e and the smaller p value of V\u003csub\u003e20\u003c/sub\u003e, we selected V\u003csub\u003e20\u003c/sub\u003e and PTV-volume for multivariate analysis. PTV-volume\u0026thinsp;\u0026ge;\u0026thinsp;223.05 cm\u003csup\u003e3\u003c/sup\u003e (OR 20.46; 95% CI 2.74\u0026ndash;86.78; p\u0026thinsp;=\u0026thinsp;0.003) and V\u003csub\u003e20\u003c/sub\u003e\u0026thinsp;\u0026ge;\u0026thinsp;20.23% (OR 7.58; 95% CI 4.12\u0026ndash;50.76; p\u0026thinsp;=\u0026thinsp;0.017) was associated with the occurrence of RP (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). In addition, in terms of the incidence of RP in different ALK-TKIs, crizotinib is also a risk factor, as the incidence of RP in crizotinib is significantly higher than that in alectinib (71.4% vs. 26.9%).\u003c/p\u003e\n\u003ch3\u003eSurvival analysis\u003c/h3\u003e\n\u003cp\u003eThe median follow-up time was 26.6 months. Twenty-two out of 39 patients had no progressive disease (PD) as of our last follow-up date. Seven patients experienced PD but did not die. Among them, five people continued receiving the original drug alectinib treatment, one underwent lymph node radiotherapy for lymph node progression, and the other developed brain metastasis and planned to receive stereotactic radiotherapy treatment. Finally, ten people eventually died due to PD. One patient showed slow lesion progression 24 months after the initial medication, but the overall efficacy evaluation was partial remission (PR). To prevent further disease progression, we performed local radiotherapy. This patient did not show any progress during multiple follow-up examinations within 56 months before our last follow-up date. The mPFS and mOS of patients taking alectinib were 25.4 months (95% CI, 22.8\u0026ndash;32.6) and 49.3 months (95% CI, 32.05\u0026ndash;66.61), respectively. The mPFS and mOS of patients taking crizotinib were 27.7 months (95% CI, 3.84\u0026ndash;51.57) and 44.8 months (95% CI, not shown), respectively.\u003c/p\u003e\n\u003cp\u003e(Fig.\u0026nbsp;3).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe addition of TRT brings significant survival benefits to patients with oligoprogression when treated with ALK-TKI, which has been confirmed. Overall survival may benefit from the synergistic combination. Administering SBRT during crizotinib treatment in eight ALK-positive oligoprogressive NSCLCs resulted in 86% of one-year local control in the irradiated foci, allowing longer crizotinib exposure and providing OS benefit. Only one patient experienced advanced radiation-induced lung injury\u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]\u003c/sup\u003e. Similarly, a large clinical trial enrolled nine patients who used ALK-TKIs in combination with TRT. Although the experiment was closed midway due to technical issues and the survival outcome was unknown, these nine patients did not experience any adverse pulmonary events in terms of safety (RTOG3106). However, based on the treatment experience of the combination of targeted drugs and TRT, it is suggested that when targeted therapy and radiation therapy are used simultaneously, the occurrence of radiation-induced lung injury needs to be particularly vigilant. In 2014, Zhuang et al. and in 2020, Jia et al. reported a high incidence of RP during targeted therapy (erlotinib and osimertinib) combined with TRT, with rates of 37.5% and 63.6%, respectively, which undoubtedly concerns clinical doctors\u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, there are currently no independent reports on the safety of combining ALK-TKIs with TRT. We conducted this retrospective study to address this issue. Therefore, we conducted this study to evaluate the incidence of RP during the combined treatment of ALK-TKI and TRT, providing a reference for clinical medicine. The results showed that RP above level 2 was 35.8%, and RP above level 3 was 12.8%, higher than 13%-37% in patients receiving concurrent chemoradiotherapy\u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e. Furthermore, through further analysis, the median interval between the onset of inflammation after TRT was 1.7 months, with two patients experiencing inflammation within one month after radiotherapy. This suggests that clinical doctors should pay close attention to acute inflammation in patients after radiotherapy and perform an excellent job of follow-up and observation. In addition, there is a fact worth being vigilant. Among the 39 enrolled patients, 5 out of 7 who took crizotinib developed RP, while only 7 out of 26 patients who took alectinib developed RP. This seems to suggest that the incidence of RP in crizotinib is higher than that in alectinib, but an uneven number of cases may also cause this significant difference in incidence. Finally, although half of the 14 patients who developed RP had grade 3, fortunately, there were no cases of grade 4 or death. Therefore, considering the local benefits of TRT, this treatment combination model is acceptable.\u003c/p\u003e \u003cp\u003eSome therapeutic mechanisms may explain the relationship between ALK-TKIs and RP. NSCLC cells carrying EGFR/ALK fusion have a tendency toward radiosensitivity, mainly related to delayed DNA damage repair, deoxyribonucleic acid synthesis or mitosis stagnation, and a significant increase in cell apoptosis frequency\u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. In addition, the c-MET pathway inhibits radiation therapy, while crizotinib can bypass the radiosensitization effect of c-MET inhibition by activating the protein kinase B (AKT) route\u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]\u003c/sup\u003e. On the other hand, multiple preclinical study results have shown that G2 block can be detected after treatment with crizotinib\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e. This may also be based on the binding affinity between crizotinib and the c-MET pathway\u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. As is well known, the protein c-MET is involved in the cell cycle, and the G2 phase is more sensitive to radiation\u003csup\u003e[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]\u003c/sup\u003e. Numerous preclinical studies have shown that crizotinib has radiosensitization potential in ALK-positive NSCLC cell lines.\u003c/p\u003e \u003cp\u003eSimilarly, the differences in the incidence of pneumonia between crizotinib and alectinib can also be traced based on previous experiments. Compared to crizotinib, crizotinib can produce stronger reactions with tumor cells. Cells treated with alectinib did not show any impact on radiation outcomes. It is worth noting that in the A549 cell line, only crizotinib was observed to increase G2/M phase cell colonies with greater radiosensitivity, ultimately leading to a higher number of cell deaths. Compared to the cell cycle arrest associated with crizotinib causing cell death, aging seems to be the primary mode of action of alectinib\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Interestingly, in previous cell experimental results, the dominant factor in the superposition of ALK-TKI and radiation-induced toxicity may be ALK-TKI. Increasing the concentration of ALK-TKI can lead to increased toxicity, but increasing the radiation dose in the experimental protocol does not further enhance toxicity\u003csup\u003e[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIt is worth noting that according to the results of the multifactorial analysis in our study, the occurrence of RP is related to V\u003csub\u003e20\u003c/sub\u003e and PTV volume. We believe this is a deviation due to the small number of enrolled cases, but we cannot conclude that V\u003csub\u003e20\u003c/sub\u003e is not related to RP quality inspection but rather to the time of taking ALK-TKI before radiotherapy. Therefore, to reduce the incidence of RP, the timing of adding TRT can be delayed to a certain extent, and consolidation treatment can be performed after the lesion shrinks. On the other hand, it is still necessary to strictly limit the V\u003csub\u003e20\u003c/sub\u003e of such patients as low as possible to reduce the risk of RP.\u003c/p\u003e \u003cp\u003eIn the latest WCLC conference, the BRIGHTSTAR trial results showed the survival benefits and better safety of local consolidation therapy in populations with oligoprogression after receiving ALK-TKI treatment. However, due to its small sample size, this study cannot be promoted as a high-level clinical application. In the future, targeted therapy combined with local consolidation therapy may become the best treatment mode for this population. However, in locally advanced NSCLC, combining TRT with targeted drugs still raises issues regarding the optimal patient population selection, dosing time interval for minimal adverse events, and protective measures against radiation damage. These issues can be addressed only through large-scale, carefully designed multicenter clinical trials explicitly targeting molecular selection populations, careful long-term safety analysis, and specific categories of the best drugs.\u003c/p\u003e \u003cp\u003eOur research also has some limitations. First, as a single institution study, all included patients were Chinese. Therefore, racial differences cannot be ruled out. Second, only 39 patients were enrolled in our study, which is too small for larger-scale statistical analysis. Finally, our focus in initiating this study is on the incidence of RP, which inevitably results in a short follow-up time and an uneven distribution of different ALK-TKI cohorts. Therefore, there is a bias in the evaluation of overall efficacy indicators (such as OS, PFS) and local control rate, which is also the reason why the 95% CI confidence interval of the crizotinib group is not shown.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, our study reported a higher incidence of grade 2 or more severe RP in patients receiving treatment with TRT and simultaneous ALK-TKI for the first time. We hope it can help make clinical doctors more aware of RP. However, the optimal combination of systemic and local therapy should not be abandoned, which requires further exploration of how to reduce the incidence of adverse events, such as the optimal dosing interval or safer combination doses of drugs and radiation. Future research should also be based on preclinical studies on the mechanism of toxicity superposition at the cellular level, exploring effective protective measures.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eTRT: thoracic radiotherapy; NSCLC: non-small cell lung cancer; PFS: progression-free survival; OS: overall survival; RP: radiation pneumonia; PTV: planning target volume; ROC: receiver operating characteristic; CT: computed tomography; PET-CT: positron emission tomography/computed tomography; ALK: anaplastic lymphoma kinase ALK-TKI: anaplastic lymphoma kinase tyrosine kinase inhibitor; PD: progressive disease; PR: partial remission\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eYang designed the study. Chen and Liu drafted the manuscript. All authors coordinated the study. Zhu checked and revised the content of the manuscript. Jing participated in imaging analysis. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China [grant number: 81972862], the CSCO Pilot Cancer Research Fund [Grant Number: Y-2019AZZD-0352], and the Key Research and Development Program of Shandong Province [Grant Number: 2018GSF118067].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this publication article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe need for informed consent was waived by the ethics committee/Institutional Review Board of The Shandong Cancer Hospital\u0026nbsp;and Institute, because of the retrospective nature of the study\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAgreed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eIkeda, S., et al., \u003cem\u003eInterstitial lung disease induced by alectinib (CH5424802/RO5424802).\u003c/em\u003e Japanese Journal of Clinical Oncology, 2015. \u003cstrong\u003e45\u003c/strong\u003e(2): p. 221-224.\u003c/li\u003e\n\u003cli\u003ePellegrino, B., et al., \u003cem\u003eLung Toxicity in Non-Small-Cell Lung Cancer Patients Exposed to ALK Inhibitors: Report of a Peculiar Case and Systematic Review of the Literature.\u003c/em\u003e Clinical Lung Cancer, 2018. \u003cstrong\u003e19\u003c/strong\u003e(2): p. E151-E161.\u003c/li\u003e\n\u003cli\u003eWatanabe, N., et al., \u003cem\u003eCrizotinib-induced acute interstitial lung disease in a patient with EML4-ALK positive non-small cell lung cancer and chronic interstitial pneumonia.\u003c/em\u003e Acta Oncologica, 2014. \u003cstrong\u003e53\u003c/strong\u003e(1): p. 158-160.\u003c/li\u003e\n\u003cli\u003eAl-Halabi, H., et al., \u003cem\u003ePattern of Failure Analysis in Metastatic EGFR-Mutant Lung Cancer Treated with Tyrosine Kinase Inhibitors to Identify Candidates for Consolidation Stereotactic Body Radiation Therapy.\u003c/em\u003e Journal of Thoracic Oncology, 2015. \u003cstrong\u003e10\u003c/strong\u003e(11): p. 1601-1607.\u003c/li\u003e\n\u003cli\u003eChen, Y., et al., \u003cem\u003eLocal consolidative therapy for synchronous oligometastatic non-small cell lung cancer treated with first-line pembrolizumab: A retrospective observational study.\u003c/em\u003e Thoracic Cancer, 2022. \u003cstrong\u003e13\u003c/strong\u003e(5): p. 732-741.\u003c/li\u003e\n\u003cli\u003eHu, F., et al., \u003cem\u003eAdditional local consolidative therapy has survival benefit over EGFR tyrosine kinase inhibitors alone in bone oligometastatic lung adenocarcinoma patients.\u003c/em\u003e Lung Cancer, 2019. \u003cstrong\u003e135\u003c/strong\u003e: p. 138-144.\u003c/li\u003e\n\u003cli\u003eArrieta, O., et al., \u003cem\u003eRadical consolidative treatment provides a clinical benefit and long-term survival in patients with synchronous oligometastatic non-small cell lung cancer: A phase II study.\u003c/em\u003e Lung Cancer, 2019. \u003cstrong\u003e130\u003c/strong\u003e: p. 67-75.\u003c/li\u003e\n\u003cli\u003eZhu, H., et al., \u003cem\u003eSevere Pulmonary Toxicity With Concurrent Anlotinib and Chemoradiotherapy in Stage III NSCLC: The ALTER-L042 Phase 1 Clinical Trial.\u003c/em\u003e JTO Clin Res Rep, 2022. \u003cstrong\u003e3\u003c/strong\u003e(6): p. 100339.\u003c/li\u003e\n\u003cli\u003eJia, W.X., et al., \u003cem\u003eAn especially high rate of radiation pneumonitis observed in patients treated with thoracic radiotherapy and simultaneous osimertinib.\u003c/em\u003e Radiotherapy and Oncology, 2020. \u003cstrong\u003e152\u003c/strong\u003e: p. 96-100.\u003c/li\u003e\n\u003cli\u003eZhuang, H.Q., et al., \u003cem\u003ePreliminary analysis of the risk factors for radiation pneumonitis in patients with non-small-cell lung cancer treated with concurrent erlotinib and thoracic radiotherapy.\u003c/em\u003e Oncotargets and Therapy, 2014. \u003cstrong\u003e7\u003c/strong\u003e: p. 807-813.\u003c/li\u003e\n\u003cli\u003eGan, G.N., et al., \u003cem\u003eStereotactic Radiation Therapy can Safely and Durably Control Sites of Extra-Central Nervous System Oligoprogressive Disease in Anaplastic Lymphoma Kinase-Positive Lung Cancer Patients Receiving Crizotinib.\u003c/em\u003e International Journal of Radiation Oncology Biology Physics, 2014. \u003cstrong\u003e88\u003c/strong\u003e(4): p. 892-898.\u003c/li\u003e\n\u003cli\u003eZhuang, H.Q., et al., \u003cem\u003eRadiation Pneumonitis in Patients with Non-Small-Cell Lung Cancer Treated with Erlotinib Concurrent with Thoracic Radiotherapy.\u003c/em\u003e Journal of Thoracic Oncology, 2014. \u003cstrong\u003e9\u003c/strong\u003e(6): p. 882-885.\u003c/li\u003e\n\u003cli\u003eRodriques, G., et al., \u003cem\u003ePrediction of radiation pneumonitis by dose-volume histogram parameters in lung cancer - A systematic review.\u003c/em\u003e Radiotherapy and Oncology, 2004. \u003cstrong\u003e73\u003c/strong\u003e: p. S26-S26.\u003c/li\u003e\n\u003cli\u003eHayashi, H., et al., \u003cem\u003eClinical Outcomes of Thoracic Radiotherapy for Locally Advanced NSCLC with \u003c/em\u003e\u003cem\u003eMutations or \u003c/em\u003e\u003cem\u003eRearrangement.\u003c/em\u003e Anticancer Research, 2012. \u003cstrong\u003e32\u003c/strong\u003e(10): p. 4533-4537.\u003c/li\u003e\n\u003cli\u003eDe Bacco, F., et al., \u003cem\u003eInduction of MET by Ionizing Radiation and Its Role in Radioresistance and Invasive Growth of Cancer.\u003c/em\u003e Journal of the National Cancer Institute, 2011. \u003cstrong\u003e103\u003c/strong\u003e(8): p. 645-661.\u003c/li\u003e\n\u003cli\u003eJost, T., et al., \u003cem\u003eInfluence of alectinib and crizotinib on ionizing radiation - \u003c/em\u003e\u003cem\u003eanalysis of ALK/ROS1-wildtype lung tissue cells.\u003c/em\u003e Neoplasia, 2022. \u003cstrong\u003e27\u003c/strong\u003e.\u003c/li\u003e\n\u003cli\u003eShrestha, N., et al., \u003cem\u003eMechanisms of suppression of cell growth by dual inhibition of ALK and MEK in ALK-positive non-small cell lung cancer.\u003c/em\u003e Scientific Reports, 2019. \u003cstrong\u003e9\u003c/strong\u003e.\u003c/li\u003e\n\u003cli\u003eWood, G.E., et al., \u003cem\u003eThe role of MET in chemotherapy resistance.\u003c/em\u003e Oncogene, 2021. \u003cstrong\u003e40\u003c/strong\u003e(11): p. 1927-1941.\u003c/li\u003e\n\u003cli\u003eSinclair, W.K., \u003cem\u003eCyclic X-Ray Responses in Mammalian Cells.\u003c/em\u003e Radiation Research, 2012. \u003cstrong\u003e178\u003c/strong\u003e(2): p. Av112-Av124.\u003c/li\u003e\n\u003cli\u003eDai, Y., et al., \u003cem\u003eSynergistic effects of crizotinib and radiotherapy in experimental \u003c/em\u003e\u003cem\u003efusion positive lung cancer.\u003c/em\u003e Radiotherapy and Oncology, 2015. \u003cstrong\u003e114\u003c/strong\u003e(2): p. 173-181.\u003c/li\u003e\n\u003cli\u003eSun, Y.G., et al., \u003cem\u003eALK Inhibitor PF02341066 (Crizotinib) Increases Sensitivity to Radiation in Non-Small Cell Lung Cancer Expressing EML4-ALK.\u003c/em\u003e Molecular Cancer Therapeutics, 2013. \u003cstrong\u003e12\u003c/strong\u003e(5): p. 696-704.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u0026nbsp;\u003c/strong\u003eBaseline characteristics\u0026nbsp;of patients\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"633\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 67.4121%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.5879%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal (%) (n=39)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 67.4121%;\"\u003e\n \u003cp\u003eGender\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Male\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Female\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.5879%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18 (46.1)\u003c/p\u003e\n \u003cp\u003e21 (53.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 67.4121%;\"\u003e\n \u003cp\u003eAge (y)\u003c/p\u003e\n \u003cp\u003e(Median, range)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;65\u003c/p\u003e\n \u003cp\u003e\u0026ge;65\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.5879%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e54(36-80)\u003c/p\u003e\n \u003cp\u003e31 (79.5)\u003c/p\u003e\n \u003cp\u003e8 (20.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 67.4121%;\"\u003e\n \u003cp\u003eSmoking history\u003c/p\u003e\n \u003cp\u003eNo\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.5879%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e29 (74.3)\u003c/p\u003e\n \u003cp\u003e10 (25.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 67.4121%;\"\u003e\n \u003cp\u003eKPS score\u003c/p\u003e\n \u003cp\u003e\u0026lt;80\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026ge;80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.5879%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1 (2.5)\u003c/p\u003e\n \u003cp\u003e38 (97.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 67.4121%;\"\u003e\n \u003cp\u003ePTV-dose (Gy)\u003c/p\u003e\n \u003cp\u003e(Median, range)\u003c/p\u003e\n \u003cp\u003e50-60\u003c/p\u003e\n \u003cp\u003e60\u003c/p\u003e\n \u003cp\u003e\u0026gt;60\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.5879%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e60 (50-66)\u003c/p\u003e\n \u003cp\u003e11 (28.2)\u003c/p\u003e\n \u003cp\u003e22 (56.4)\u003c/p\u003e\n \u003cp\u003e6 (15.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 67.4121%;\"\u003e\n \u003cp\u003eFraction\u0026nbsp;dose (Gy)\u003c/p\u003e\n \u003cp\u003e(Median, range)\u003c/p\u003e\n \u003cp\u003e\u0026le;3\u003c/p\u003e\n \u003cp\u003e\u0026gt;3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.5879%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2 (1.8-8)\u003c/p\u003e\n \u003cp\u003e36 (92.3)\u003c/p\u003e\n \u003cp\u003e3 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 67.4121%;\"\u003e\n \u003cp\u003eTime of taking ALK-TKI before radiotherapy\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e(Median, range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.5879%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.5 (0-35.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 67.4121%;\"\u003e\n \u003cp\u003e\u0026le;1.4\u003c/p\u003e\n \u003cp\u003e\u0026gt;1.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.5879%;\"\u003e\n \u003cp\u003e18 (46.2)\u003c/p\u003e\n \u003cp\u003e21 (53.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 67.4121%;\"\u003e\n \u003cp\u003ePTV-volume (cm\u0026sup3;)\u003c/p\u003e\n \u003cp\u003e(Median, range)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026le;\u0026thinsp;223.05\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026gt;223.05\u003c/p\u003e\n \u003cp\u003eV\u003csub\u003e20\u003c/sub\u003e total (%)\u003c/p\u003e\n \u003cp\u003e(Median, range)\u003c/p\u003e\n \u003cp\u003e\u0026le;20.23\u003c/p\u003e\n \u003cp\u003e\u0026gt;20.23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.5879%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e159.7(13-980.1)\u003c/p\u003e\n \u003cp\u003e28 (62.2)\u003c/p\u003e\n \u003cp\u003e11 (37.8)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13(3.5-28.7)\u003c/p\u003e\n \u003cp\u003e28 (71.8)\u003c/p\u003e\n \u003cp\u003e11 (28.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 67.4121%;\"\u003e\n \u003cp\u003eV\u003csub\u003e5\u003c/sub\u003e total (%)\u003c/p\u003e\n \u003cp\u003e(Median, range)\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026le;35.63\u003c/p\u003e\n \u003cp\u003e\u0026gt;35.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.5879%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e30.51 (14.3-83.95)\u003c/p\u003e\n \u003cp\u003e22 (56.4)\u003c/p\u003e\n \u003cp\u003e17 (43.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 67.4121%;\"\u003e\n \u003cp\u003eTiming of radiotherapy addition\u003c/p\u003e\n \u003cp\u003econsolidation\u003c/p\u003e\n \u003cp\u003esalvage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.5879%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e29 (74.3)\u003c/p\u003e\n \u003cp\u003e10 (25.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 67.4121%;\"\u003e\n \u003cp\u003eALK-TKI\u003c/p\u003e\n \u003cp\u003ealectinib\u003c/p\u003e\n \u003cp\u003ecrizotinib\u003c/p\u003e\n \u003cp\u003eiruplinalkib\u003c/p\u003e\n \u003cp\u003ebrigatinib\u003c/p\u003e\n \u003cp\u003eceritinib\u003c/p\u003e\n \u003cp\u003eThe treatment line of ALK-TKI\u003c/p\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 32.5879%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e26 (66.6)\u003c/p\u003e\n \u003cp\u003e7 (17.9)\u003c/p\u003e\n \u003cp\u003e3 (7.6)\u003c/p\u003e\n \u003cp\u003e1 (2.5)\u003c/p\u003e\n \u003cp\u003e2 (5.1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e26 (66.6)\u003c/p\u003e\n \u003cp\u003e8 (20.5)\u003c/p\u003e\n \u003cp\u003e5 (12.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations:\u0026nbsp;KPS: Karnofsky performance status. PTV: plan tumor volume.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. univariate and multivariate analysis of risk of developing RP\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cimg 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\" width=\"670\" height=\"738\"\u003e\u003cbr\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"radiation pneumonitis, anaplastic lymphoma kinase tyrosine kinase inhibitor, thoracic radiotherapy, non-small cell lung cancer","lastPublishedDoi":"10.21203/rs.3.rs-5340433/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5340433/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnaplastic lymphoma kinase tyrosine kinase inhibitor(ALK-TKI) is a first-line treatment regimen for patients with advanced non-small cell lung cancer harboring anaplastic lymphoma kinase-positive. For non-small cell lung cancer patients with slow progression, thoracic radiotherapy can provide significant local control and survival benefits as an effective local consolidation therapy. Radiation pneumonia, one of the typical adverse reactions to radiation therapy, has not yet been reported in studies on the incidence of radiation pneumonia when ALK is combined with thoracic radiotherapy. Therefore, in this study, we aimed to evaluate the incidence and risk factors for radiation pneumonia in such patients and provide a reference for clinical practice.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients and methods:\u003c/strong\u003e All medical records of patients with NSCLC who had ALK fusion between January 2016 and May 2023 at Shandong Cancer Hospital and Institute were reviewed using an institutional query system. All patients underwent intensity-modulated radiotherapy and 3-dimensional conformal radiation therapy with photon therapy. Radiation pneumonia was diagnosed via computed tomography and was classified according to the RTOG toxicity scoring system. The risk factors for radiation pneumonia were identified using univariate and multivariate analyses. The Kaplan–Meier method calculates progression-free survival (PFS) and overall survival (OS).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Ultimately, 39 patients were included; 14 (35.8%) had grade 2 or above radiation pneumonia, and 6 out of 39 patients (12.8%) had grade 3 or above radiation pneumonia. The median time interval between the onset of radiation pneumonia and thoracic radiotherapy was 1.7 months. In univariate analysis, V\u003csub\u003e20\u003c/sub\u003e ≥ 20.23%, V\u003csub\u003e5\u003c/sub\u003e≥35.63%, and PTV-volume ≥ 223.05 cm\u003csup\u003e3\u003c/sup\u003e were associated with the occurrence of RP. In the multivariate analysis, V\u003csub\u003e20\u003c/sub\u003e ≥ 20.23% and PTV-volume ≥ 223.05 cm\u003csup\u003e3\u003c/sup\u003e was considered an independent predictor of radiation pneumonia occurrence. Crizotinib is also a risk factor for radiation pneumonia. The mPFS of all patients was 27.7 months. The mOS of all patients was 49.3 months.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions:\u003c/strong\u003e In summary, our study reports for the first time that the incidence of grade 2 or more severe radiation pneumonia is slightly higher in patients receiving combined treatment with thoracic radiotherapy and anaplastic lymphoma kinase tyrosine kinase inhibitors. Simultaneously, whole-lung V\u003csub\u003e20\u003c/sub\u003e and PTV volume are risk factors for radiation pneumonia.\u003c/p\u003e","manuscriptTitle":"The incidence and risk factors for radiation pneumonia in anaplastic lymphoma kinase- positive non-small cell lung cancer patients treated with thoracic radiotherapy and simultaneous anaplastic lymphoma kinase tyrosine kinase inhibitor","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-11-20 10:46:53","doi":"10.21203/rs.3.rs-5340433/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3ca60cd8-7199-432a-86b4-eb3f6a57d28f","owner":[],"postedDate":"November 20th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-01-15T14:23:54+00:00","versionOfRecord":[],"versionCreatedAt":"2024-11-20 10:46:53","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5340433","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5340433","identity":"rs-5340433","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}