Lung cancer is a common malignant tumor with poor therapeutic effect.. Now comprehensive treatment is recommended as an effective strategy for lung cancer patients11. However, the high recurrence rate one year after lung cancer surgery is still a challenge in clinical treatment. Most studies have focused more on risk factors for overall survival after lung cancer resection. And there is a lack of real-world data available to predict and evaluate the clinical risk of lung cancer recurrence in the first year after surgery. Currently, the FDA attaches importance to the real-world evidence including electronic health records which can add and evaluate information on how factors such as clinical setting and health system characteristics affect the therapeutic effect and even guide the outcomes(12). And this is the first research to provide some real-world evidence to assess the recurrence of cancer within one year after lung cancer resection. Studies suggest that the first local recurrence rate after lung cancer resection is 27%-36%(14). In this retrospective review, we found that the incidence of LRO reached 29.22%, which was consistent with previous reports. This study has shown a close link between the occurrence of PPST and LRO development with a distinct warning role for PPFS. The PPFS-associated risk for LRO development was independent of preoperative pulmonary conditions and PPOT. PPFS is an important and ongoing clinical turning point, which could be an important time window for critical interventions to modify disease deterioration and progression.
In our analyses, PPFS significantly increased the risk of development of LRO, regardless of the existing of preoperative pneumonia and PPT. Although the preoperative pneumonia and PPT groups had higher prevalence of PPFS than the preoperative non-pneumonia and non-PPT groups, the risk of preoperative pneumonia and PPT on the development of LRO did not differ with regards to patients without preoperative pneumonia and PPT. Poor early recovery of postoperative pneumonia was not associated with the incidence of PPST and PPFS. Although one study found a close link between PPT and the prognosis of lung cancer resection, it focused on overall survival within five years after surgery(5). It did not assess the actual progression of LRO, which limits further direct comparisons to our study. Here, we found that PPOT patients had 3-times higher risk of progression to PPST than non- PPOT patients, whereas there is no increased risk in developing LRO. The risk of PPST and LRO were increased up to 8-times and 3-times higher in PPFS patients, respectively.
The association of the history of chemotherapy and targeted therapy and the occurrence of PPFS and PPST was well-demonstrated. The PPFS and PPST groups with the history of postoperative chemotherapy and targeted therapy had the higher incidence than the non-history groups. The history of chemotherapy and targeted therapy was an independent risk factor for the progress of PPFS and PPST. A previous study has showed that adjuvant chemotherapy after surgery was a high risk factor for postoperative pneumonia(15). Chemotherapy played an important part after lung cancer surgery. Previous studies mainly suggested that chemotherapy was related to the mechanism of alveolar injury and immune function. Chemotherapy increased the presence of inflammatory cell and interleukines in bronchoalveolar lavage systemic inflammatory response in chemotherapy patients is increased, as compared to patients not undergoing neoadjuvant treatment (16). Higenbottam T et al. also reported that the reason chemotherapy agents affect lungs. The drug directly acts on alveolar cells in the metabolic process and induces an immune response to produce many kinds of biochemical substances. Lung damage is not only directly related to the dose of the drug, but also affected by drug-drug, drug-diet, and drug-environment interactions(17).
In addition, relevant clinical studies also showed that the commonly used chemotherapy drugs for lung cancer such as docetaxel, paclitaxel, gemcitabine, and vinorelbine can cause alveolar epithelial cell damage(18, 19). There is research that showed that small-molecule agents that target EGFR are potential cause of pneumonitis in patients with lung cancer. The occurrence of drug-induced pneumonitis associated with gefitinib and erlotinib is 1.2%-1.6%, with a relatively mortality of 22.8%(20). Furthermore, a post-marketing study of crizotinib found that it was associated with pneumonitis in 5.77% of ALK-positive NSCLC patients, of which 3.45% were pneumonitis of at least grade 3(21). Oshima et al.(22)also reported that there was an increased pneumonia incidence after treatment with EGFR-targeted drugs in patients receiving nilumab. However, the exact underlying mechanism of pneumonia caused by targeted agents is unclear. Some studies believed that the mechanism of lung infection caused by targeted agents is direct toxicity and immune-mediated injury on alveolar epithelial cells and pulmonary capillary endothelial cells, which leads to pneumonia(23). Namba T et al. (24) also reported that targeted drug-related pneumonia may be associated with its inhibition on the expression of heat shock protein 70 ,or may be linked with the release of large amounts of tumor necrosis factor from tumor necrosis. Therefore, we hypothesize that chemotherapy and targeted therapy lead to weakened immune system function in a period of time. Our study found that patients with a history of chemotherapy and targeted therapy are directly related to the incidence of PPFS, but the history of chemotherapy and targeted therapy is not a risk factor for the occurrence of LRO. As many as 48.49% of patients in our study did not have history of chemotherapy or targeted therapy. Therefore, PPFS patients without history of chemotherapy or targeted therapy should be treated with caution to prevent the occurrence of LRO.
Previous studies have shown that smoking and lymphatic metastasis are associated with the recurrence of lung cancer (25–28). We found that the LRO group had a higher incidence of smoking and lymphatic metastasis than the non-LRO group. Our study was consistent with previous reports. Accordingly, it was suggested that smoking and lymphatic metastasis may be the risk factors of the development of LRO. The combination of surgery and radiotherapy was the important treatment for patients with lung cancer after surgery. Notably, our study found that patients with postoperative radiotherapy had a significantly higher incidence of lung cancer recurrence than patients without radiotherapy. This association suggests that radiotherapy was the independent risk factor for the development of LRO, which was differ from several previous studies(29–31).However, recent studies have shown patients who were determined to need radiotherapy had already cancer that had spread to the lymph nodes(32). Some other studies have shown that adjuvant radiotherapy may increase the risk of radiation pneumonia, especially in combination with chemotherapy(33, 34). Considering the interaction between adjuvant radiotherapy and postoperative pneumonia, individuals with adjuvant radiotherapy may exhibit an increased incidence of PPFS, which predisposes patients with lung cancer surgery to develop LRO. The number of patients with adjuvant radiotherapy in this study was too small, and the study did not analyze adjuvant chemotherapy or target therapy combined with radiotherapy. Although our study concluded that postoperative radiotherapy was a risk factor for LRO, a larger sample size should still be conducted for revalidation analysis. In this study, the intraoperative blood loss was also an independent risk factor for the development of LRO. G Ma et al. reported a significant correlation between intraoperative blood loss and postoperative survival in lung cancer patients(35). Studies have shown that massive blood loss during the perioperative period can lead to postoperative hemorrhagic stress response, which may lead to infectious complications(36). Shuang-jiang Li et al. also reported that blood loss can inhibit the cell-mediated immune response by inducing the mitotic response of T lymphocytes and the antigen presentation ability of macrophages(37). Therefore, we hypothesized that large intraoperative blood loss may increase the incidence of LRO by influencing immune system.
There are two possible explanations as to why PPFS is associated with LRO. The first explanation is that t systemic inflammation can accelerate the adhesion of circulating tumor cells to the vascular endothelium of distant organs, which is the first step of forming distant metastases. This was confirmed in a mouse model of the early stages of hematogenous metastasis(38). Numerous studies have demonstrated that these two status of postoperative inflammatory and lung cancer metastasis are inter-related (39–42).The inflammatory status of PPOT may be related to the postoperative wound repair or the prognosis of lung tumors. So, PPOT is not risk factor for predicting LRO. In the absence of PPOT, the recurrence of PPFS combined with the continuous attack state of PPST would form the inflammatory environment, which may cause the accelerated spread of tumor cells and further induce the development of LRO. The second explanation is that when the cause of inflammation persists that is, when the PPOT persists, acute inflammation can be converted into chronic inflammation. Inflammatory cells can release chemicals such as ROS that promote carcinogenic evolution, and many factors released by inflammatory cells may lead to significant inhibition of immune response(43, 44).As an important time window after lung cancer resection, PPFS played an warning role during the chronic inflammation of the development of LRO. Thus, PPFS, which was associated with inflammatory environment, may be a predictive factor for LRO.
In addition to avoiding further LRO, identifying risk factors for lung cancer recurrence in the early stage could guide timely follow-up and application of therapeutic measures in patients at risk for PPST progression after lung cancer surgery-associated PPFS. In this regard, our study has several strengths. This is the first study to encompass comprehensive data sets of real-world evidence of serially assessed lung inflammation and recurrence during the postoperative 12 months in a cohort of lung cancer surgery patients. We describe a detailed overview of the factors associated with the occurrence of PPFS. In addition,our study provides primary evidence that PPFS, regardless of the existing of PPOT, is associated with LRO development, and concomitantly demonstrates the importance of an warning role for PPFS and the intermediary role for PPST, connecting these two diseases. Lastly, we reaffirmed well-known risk factors for LRO, including smoking, lymphatic metastasis, blood loss and radiotherapy. Chemotherapy or targeted therapy was risk factors for PPFS and PPST. These findings may be helpful for identifying patients without treating chemotherapy or targeted therapy who may benefit from close post-surgery follow-up because 40.99%和19.88% of these patients in our study developed PPST and LRO, respectively. Future studies are warranted to confirm whether identifying and treating PPFS may improve LRO and overall prognosis outcomes.