As the most lethal cancer worldwide, there are approximately 1.8 million new patients with lung cancer (LC) diagnosed each year (1, 2). Bone is the most common and the earliest site of metastases from LC, and 30%–40% of patients with LC already have bone metastases (BMs) upon initial diagnosis, which is usually associated with a poor prognosis (3–5). The therapy for patients with lung cancer with bone metastasis (LCBM) is diverse, including primary tumor resection, metastatic surgery, chemotherapy, and radiotherapy. However, in many cases, the survival of patients with LCBM could not be accurately assessed, and individualized therapeutic scheme could not be provided, which leads to additional distress and poorer prognosis of patients.

In LCBM, tumor cells release cytokines and chemical mediators to stimulate the periosteum and bone, combined with the mechanical stress caused by tumor tissue in the osteolytic lesions, causing serious bone pain. Moreover, it increases the risk of complications referred to as skeletal-related events (SREs), including pathologic fracture, spinal cord compression, and hypercalcemia of malignancy. The main therapeutic options for treating LCBM are chemotherapy and radiotherapy. The therapy for BM from solid tumors has been revolutionized over the last few decades. Since the 1990s, bisphosphonates were introduced to treat BM and became a mainstay of the management of BM. Until around the year 2000, the appearance of denosumab challenged this dominance. Based on existing studies, denosumab was found to be more effective in reducing SREs. However, aforementioned treatment development in BM was mainly dedicated to reducing SREs and bone pain, and the increase of overall survival (OS) was still limited. Data are still limited on the epidemiology, signatures, and prognostic factors of LCBM in general (6–8).

For data visualization, nomograms can increase the accuracy of prognostic prediction in cancer, using the tumor size. The chart integration predicts the probability of events. In previous studies, nomograms have demonstrated its superior predictive ability to the TNM staging system (9–12). As far as we know, the current study is the first that developed nomograms based on a large-size number of patients, which was verified by internal and external validation sets to guarantee the reliability of the results.

The Surveillance, Epidemiology, and End Results (SEER) Program’s registry is maintained by the National Cancer Institute (NCI), which collects a large number of cancer-related survival data from 1973 based on the US population. The cancer-related data in the SEER Program were obtained from 18 population-based registries, covering approximately 26% of the US population. Compared with any single institution, the SEER database encompasses much more population-level cancer data based on the largest sample size worldwide (13–16).

In this study, we analyzed the data extracted from the SEER database to identify risk factors associated with prognosis. Then, we subsequently created nomograms as a comprehensive prognostic assessment system. Both internal and external validation cohorts were employed to ensure the nomogram’s accuracy and reliability.

Commonly, the symptoms associated with patients with LCBM are pain, occasional fractures, or interference with daily activities (20). BM accounts for approximately 350,000 deaths in the United States every year and nearly three times this number if patients in the European countries and Japan are also included (21). In the retrospective analysis of Swedish national inpatient data involving 21,169 patients with LC, by Riihimaki et al., BM conferred the worst prognosis compared with other frequent metastatic sites, which was one of the most frequent metastatic sites as well (22). In another study based on the nationwide Korean health insurance database, SREs most commonly occurred in patients with LC among the 1,849 patients with BM (23). The condition of patients with LCBM can rapidly progress to an advanced stage after initial diagnosis and display metastasis, which often renders the treatment difficult. Therefore, there is an urgent need for the development of more clinically applied risk predictors as well as novel tools for prediction of survival of patients with LCBM in the clinic. Based on the data extracted from the SEER database, we analyzed the survival of patients with LCBM. The prognostic factors associated with OS and CSS were also identified to accurately predict the prognosis of patients. As far as we know, this was the first multicenter population-based study that includes internal and external validation.

Our study found that some prognostic factors of LCBM were in accordance with previously published reports, including a male predominance, older age, and a propensity for high-grade tumors and more patients who were diagnosed with advanced stage III/IV disease (20, 24, 25). In addition to this, T, N, and M stages were correlated with shortened survival time. The effect of primary location of LC on prognosis after BM could not be defined, in accordance with our findings; the primary site was a factor associated with survival. We found that patients with main bronchial neoplasm had worse prognosis compared with other locations. Although there has been a previous study that confirmed that T3 centrally located early non–small cell LC (NSCLC) has a better survival than other types, more research studies obtained similar results with the present study (26, 27). This conclusion could be explained as the technical limitations of tumor resection involved in the main bronchus due to its anatomy. On the other hand, the main bronchus neoplasm had a high rate of lymph node metastasis, which was associated with worse outcomes (28).

As one of the most common metastatic sites, the bone is a unique microenvironment that appears to promote tumor growth. Our results revealed that liver and brain metastases were independent predictors of survival in LCBM. According to the theory of “seed and soil hypothesis,” metastatic cancer cells can dynamically interact with particular organ microenvironment and lead to different patterns of metastatic spread. Several studies found that the site of metastasis did not significantly influence patients’ survivals. However, our findings were supported by other researchers (20, 29). Tamura et al. reported a 1.55-fold increase in mortality in patients with liver metastasis compared with those with other metastasis (30). Most patients with LC with liver metastasis had multiple nodules morphologically and biliary tract obstruction may have been caused by LC metastatic to the lymph nodes in the porta hepatis or the hepatic parenchyma lesion. Patients would be jaundiced and would have a progressive divergence of hepatic synthetic and coagulation function. Meanwhile, the activation or metabolism of several cytotoxic drugs commonly used in various procedures for chemotherapy could be affected, in turn, leading to the limitation of chemotherapy’s administration. There were several cases reporting that patients with liver metastases could not receive conventional chemotherapy for liver dysfunction (31, 32). As one of the most common sites of metastasis in patients with LC, brain metastasis was regarded as one of the unfavorable prognostic factors in previous research studies. In one study, based on the SEER database, the cancer-specific case fatality was 91.01% after a median follow-up of 52 months in 5,974 patients with LC and with brain metastasis (33, 34). This study also revealed that patients with additional sites of metastasis (like BM) were related to worse survival. Thus, patients with LCBM combined with brain metastasis tend to exhibit poor prognosis. In the case of brain metastasis, the daily living activities of patients could be limited significantly and they could develop severe neurological symptoms, which may lead to reduced willingness of patients and doctors to pursue aggressive therapy. In addition, the use of chemotherapy for brain metastasis patients could be limited by poor efficacy and high toxicity. In the case of LCBM with brain metastasis, surgical treatment is not recommended because it has no significant impact on the long-term prognosis (32). In comparison, intracranial tumor biopsy is the gold standard for the diagnosis, which can determine not only the nature of intracranial lesions but also their source.

We found that radiotherapy, chemotherapy, and surgery of primary lesions were of prognostic significance in LCBM. Among them, chemotherapy contributed most significantly to prognosis in accordance with the nomogram. As is well known, chemotherapy remains the cornerstone of therapy in the management of advanced LC. First-line chemotherapy, maintenance chemotherapy, and second-line therapy were considered as regular therapeutic regimen to advanced NSCLC for many years (35, 36). Platinum-based doublets were used for the standard first-line chemotherapy, which could achieve symptoms remission and increased median survival by 1.5 months and the 1-year survival rate by 9%. Radiotherapy could relieve pain at the site of skeletal metastasis, reduce the incident of SRE, and could be used as an alternative treatment option for medically inoperable LC with high local control rates and with low toxicity (37). The technology of stereotactic body radiotherapy (SBRT) improved the accuracy and safety of radiotherapy for patients with LCBM, especially for those with spinal metastasis, which optimized radiation dose delivery to the BM while sparing the spinal cord.

We found that surgery of primary lesions was beneficial for prolonging both the OS and CSS of patients with LCBM. Although it is the standard treatment for patients with advanced LC, surgeons have performed curative resection in those who present with oligometastases. In the retrospective study by Takahashi et al., patients with NSCLC and synchronous isolated BMs achieved longer survival rates following primary lung tumor resection (38). However, other studies had different opinions. Patrini et al. suggested that there was no case in which BM was considered as an oligometastatic for the infaust prognosis (39). Considering quite the low number of patients who underwent surgery of the primary site, we speculated that they received surgery for oligometastases. The role of surgery in LCBM has not been effectively identified yet, especially for those with polymetastasis.

In addition to the previously mentioned treatments, bone-targeted pharmacological treatments including bisphosphonates and denosumab were widely used clinically to reduce pain and avoid SREs. In the last 30 years, bisphosphonate has been considered a key player in the therapy of BM from various cancers. Among bisphosphonates, zoledronic acid’s clinical effectiveness was validated in multiple studies (40). Compared with bisphosphonates, denosumab was found to be associated with delayed first and subsequent SREs and lower incidence of renal toxicity but higher incidence of hypocalcemia in several meta-analyses. However, we failed to consider the bone-targeted pharmacological treatments as the information in this regard was not provided by the SEER data center. In recent years, the application of next-generation sequencing technology has been widely used in the auxiliary diagnosis and target therapy of cancers (40). Epidermal growth factor receptor (EGFR) is the most widely used driving gene for the targeted treatment of LC and responds well to EGFR tyrosine kinase inhibitors (41). Previous studies have shown that microRNA, Dickkopf1, and insulin-like growth factor binding protein 3 are potential therapeutic targets for LCBM (40). Mukai et al. reported a high expression of mesenchymal-to-epithelial transition (MET) in both the primary metastasis and BM of patients with LC and suggested that drugs targeted at MET amplification, such as crizotinib and cabotinib, would have a certain effect on patients with LCBM (42). Recently, the study by Huang et al. found a high consistency of mutation patterns between primary LC lesions and matched BM, which indicated that the effective treatment of primary LC may also be suitable for matched LCBM, such as the EGFR-TKI treatment for LCBM with sensitive EGFR mutations (43). Unfortunately, the data of molecular alterations were not available in the SEER database, and our nomogram failed to include relevant factors.

Our study also has significant advantages. Compared with the previous studies, we identified the risk factors for BM in patients with LC and the prognostic factors of patients with LCBM. Meanwhile, we created a nomogram containing identified independent factors as a convenient and intuitive visual tool for prognostic prediction, which was verified by internal and external validation sets to guarantee the reliability of the results. As a retrospective cohort analysis with a large sample size, we point out that the validated results of current study can provide guidance to clinicians in daily routine practice and decision-making. However, some limitations are present. First, this was a retrospective study in which selection bias existed inevitably. Our study was limited by the data available in the SEER database. Second, in the process of patient screening, many failed to be enrolled to the SEER database for lack of detailed information like insurance and details on treatment. Missing data of these patients may mildly affect the accuracy of the research result. Third, the SEER database is based on the US population. The nomograms that we constructed may be limited by geographic constraints and may only be considered as a reference in the Chinese LCBM population. In the future, large multicenter studies should be performed in Chinese patients to develop a model to demonstrate its clinical validity for the Chinese population.

In conclusion, the findings of this study based on a population level identified several factors that affect the OS and CSS of patients with LCBM, namely, age, sex, T stage, N stage, grade, histology, radiation therapy, chemotherapy, primary site, primary surgery, liver metastasis, and brain metastasis. We also found that metastatic surgery was beneficial for prolonging the CSS of patients with LCBM. Moreover, nomograms were developed to objectively predict 1-, 3, and 5-year OS and CSS of patients with this devastating disease. The result indicated that the nomogram had favorable discrimination, good consistency, and clinical benefits in patients with LCBM. For LCBM’s extremely poor prognosis, the development of the prediction models was important for patients and meant a lot to them. We point out that nomograms could help oncologists to make better clinical decisions and provide personalized treatment plans for patients.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding authors.

All authors were responsible for the study concept and design. MY, SG, XD, and RZ are co-first authors. JX and WM are co-response authors. All authors contributed to the article and approved the submitted version.