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Lung cancer poses a serious threat to public health due to its high morbidity and mortality. Nevertheless, little attention has been paid to multiple primary cancers (MPC) involving lung cancer. With the advancement of medical technology and the extension of survival time of cancer patients, more and more cancer patients develop one or more new primary malignant tumors in the same or other organs during follow-up. MPC involving lung cancer is common clinically. Depending on incomplete statistics, the incidence of MPC involving lung cancer ranges from 0.9% to 26.3% (1–4). However, research on MPC involving lung cancer is still limited. People still do not have a clear idea of these patients. When patients have multiple primary malignancies at the same time, it is complicated for clinicians to judge the prognosis of these patients. Although the TNM staging system is the most widely used method for evaluating prognosis, it still has some limitations, especially for patients with multiple primary malignancies (they tend to have special biological characteristics different from single primary malignancy). Thus, it is necessary to learn more about this particular disease and seek more refined methods to predict the survival of these patients. Nomogram, which has been widely used to evaluate the prognosis of cancer patients in recent years owing to its convenience and accuracy (5, 6), may be a good choice for this purpose. This study is to conduct a retrospective analysis based on the clinical information of LCSPM patients to understand the common site distribution of the first primary cancer (FPC) and time interval between two primary malignancies and to determine the prognostic factors and to develop a nomogram that can predict the survival in order to provide certain evidence for guiding clinical practice.

In recent years, with the continuous advancement of medical technology and the improvement of patient compliance, many cancer patients have been diagnosed with new primary malignant tumors in their lungs. In the past, a large number of studies have focused on single primary lung cancer or multiple primary lung cancer (MPLC), but there are few studies on lung cancer patients with other primary malignancies. To date, little is known about the regularity of the time interval between two primary malignancies and the prognosis of dual primary cancer patients with LCSPM. Thus, this study retrospectively analyzed the clinical characteristics of 3465 dual primary cancer patients with LCSPM extracted from the SEER database between 2010 and 2015, intending to improve the understanding of these diseases and provide a certain reference for future clinical work.

During the follow-up of cancer patients, clinicians tend to focus more on the organ where the primary tumor is located and other organs where the tumor is more likely to metastasize, which will inadvertently ignore the risk of developing a primary malignancy in other organs. Lung cancer, a malignant tumor with a high incidence rate and mortality rate, poses a serious threat to public health. Thus, it is of great clinical significance to clarify the common sites of FPC in LCSPM patients to improve the effectiveness of follow-up and vigilance of cancer patients. Through analysis of 185 patients with MPC involving lung cancer from Guangdong Lung Cancer Research Institute from 2005 to 2013, Li et al. found that colorectal cancer, esophageal cancer, and thyroid cancer were the tumors that most frequently accompanied lung cancer (10). Liu et al. also reported that the most common tumors associated with lung cancer were upper aerodigestive tract cancer, colorectal cancer, and cervical cancer (1). In this study, we found that, in 3465 dual primary cancer patients with LCSPM, the most common organ of FPC was prostate, followed by female breast, and urinary bladder, accounting for 20.8%, 13.4%, and 11.0%, respectively. Obviously, the findings of these studies were significantly different. We believe that, in addition to the different sample size, the reasons for this phenomenon might also be related to geographical environment (China/American), ethnic differences, and research design (different from them, the cases with FPC in the lung and bronchus were excluded in our study). Despite the differences, all the findings suggest that cancer patients were still at risk of developing new primary malignant tumors in their lungs. Thus, cancer patients, as well as clinicians, should pay close attention to the changes of the lung or other organs and be alert to the occurrence of lung cancer or other malignant tumors during follow-up. Of course, we should also note that periodic follow-up to find a new primary tumor in the lung is a kind of cancer screening for high-risk populations. These patients usually have a long history of smoking, exposure to chemicals, family history of lung cancer, etc.

Definitely, understanding the time interval between two primary cancers can assist clinicians to develop better follow-up strategies for cancer patients. Li and his colleagues found that the median interval between two primary cancers in MPC patients was 41.2 months (10). Liu et al. also observed that, when lung cancer was the second primary cancer, the interval time between the two primary malignancies was 46 months (1). The findings were longer than that of our study (the median interval was 21 months in our study), which may be related to the inclusion criteria and sample size of the study. Because there was no recognized diagnostic criteria for MPLC, our study excluded the cases with lung cancer as FPC and included 3465 dual primary cancer patients with LCSPM from the SEER database with significantly more cases than other studies (there were only 185 cases in Li’s study and 142 cases in Liu’s study). To the best of our knowledge, this is one of the largest studies on this topic. In daily clinical practice, how long and how often to follow up after the diagnosis of FPC is a matter in hand. Our study found that the median interval between the FPCs (prostate cancer, female breast cancer, and urinary bladder cancer) and lung cancer (the second primary cancer) were 26 months, 52 months, and 24 months, respectively. Additionally, for the entire study cohort, the median interval between the FPC and second primary cancer (lung cancer) was 21 months, the shortest interval was 2 months, and the longest was 81 months. This indicates that patients with cancer are still at the risk of developing another new primary malignancy in the lungs. Close, lifelong follow-up was recommended for all cancer patients not only to detect recurrence or metastasis, but also to detect early-stage primary tumors in the lungs or other organs.

In this study, we observed that age, sex, histology, stage, and surgery were all closely related to the prognosis of these patients. Advanced age (> 65 years old) and being male were independent risk factors for patients. Compared with nonsurgical treatment, lung cancer-directed surgery could significantly improve OS of these patients, with 3-year OS rates of 18.0% and 66.0%, respectively. SCLC had the worst prognosis. The later the stage of lung cancer, the worse the prognosis. This was also in line with the findings of other studies (11, 12). Massard et al. (11) reported that the survival of LCSPM patients was associated with the stage of lung cancer. Kim et al. (12) also found advanced lung cancer stage was a poor prognostic factor for patients with MPC involving lung cancer. In addition, some retrospective research has demonstrated that patients with MPC involving lung cancer tended to have the better long-term survival than ordinary lung cancer population (1, 4, 13). However, so far there are few studies on whether the prognosis of LCSPM is related to another primary malignancy. This study found that the 3-year OS of LCSPM patients with urinary bladder cancer as FPC was significantly lower than that of patients with other primary malignancies as FPC. It should be noted that lung cancer here referred only to NSCLC, and the prognosis of dual primary cancer patients with SCLC as a second primary malignancy had no relation to the FPC. Kim et al. (12) observed that cancer patients with another primary malignancy in the head and neck tended to have a worse prognosis than these patients with another primary malignancy elsewhere. Unfortunately, due to so few cases (less than 1.3%) with FPC in the head and neck, our study did not separately compare the prognosis of these patients with those of other patients, which may result in different results.

Additionally, our study found that, since 2010, more and more cancer patients were diagnosed with another new primary tumor in their lungs. This trend was mainly related to the following points. First, the age of the population was prolonged. Second, more and more chemicals were coming into contact. The third was the influence of bad habits, such as cigarettes. The fourth were the advances in imaging technology and the increasing pace of life. Finally, an important factor was the increasing awareness of early lung cancer screening. Several studies (14, 15) have demonstrated that cancer patients, compared to the general population, had a higher risk to develop new primary tumors. Therefore, we believe that, even if the primary tumor has undergone radical surgery, the cancer patient still needs long-term close follow-up. In addition to paying attention to changes in the organ where the primary tumor is located, changes in other organs should not be ignored.

Good prognosis evaluation is of great significance for the treatment and follow-up of cancer patients. Clinically, due to the lack of a relatively perfect scoring system, clinicians often make empirical judgments based on the patients’ age, AJCC stage and pathological results. As an emerging tool widely used in some clinical research (5, 6, 16), a nomogram can integrate the influence of various prognostic factors in the clinic and present the results visually. Compared with traditional methods, it can make predictions more quickly and accurately, and its predictive value has been considered superior to other evaluation systems (17, 18). Thus, a prognosis nomogram was also applied in this study. From the established nomogram, we could intuitively see the influence of each independent prognostic factor on score points. Considering the good prediction performance and clinical utility of this nomogram were fully proven in both internal and external validation sets, this clinical nomogram is expected to be routinely applied to the survival prediction of such patients in the future.

Our study has the following advantages. First, we used the large sample size of the SEER database to determine the common sites of FPC and the median interval between the two primary malignancies in dual primary cancer patients with LCSPM, which was of great significance in improving the effectiveness of follow-up in cancer patients. Second, our study was the first attempt to use a nomogram to predict the survival of dual primary cancer patients with LCSPM, which included 2285 patients from the SEER database, and its data accuracy was up to 95% (19). Third, our preliminary findings can help clinicians understand this disease better and serve as a basis for future, larger multicenter studies.

Admittedly, our study also has some shortcomings. First, the limitations of the SEER database widely discussed in previous studies (20, 21). Second, research on MPC involving lung cancer is still lacking, and thus, the understanding of this special population remains limited. Although this is a multicenter study with a large sample size, this SEER-based study can still not provide important survey information on the risk of multiple primary cancer due to the limitations of the SEER database, including smoking status, genetic conditions (such as gene mutation), family history, exposure history (chemicals), organ transplantation, or chronic immunosuppression to name a few. In the end, this study, as a retrospective analysis, inevitably leads to selective bias. Taking into account the deficiencies of retrospective research, prospective analysis is recommended to proceed further.

In summary, dual primary cancer patients with LCSPM have approximately 59.3% of 1-year OS, 34.7% of 3-year OS, and 25.2% of 5-year OS, respectively. Systematic and periodic follow-up is recommended for all cancer patients, and other organs should not be ignored in the follow-up of cancer patients. Early detection for surgical treatment will significantly improve the prognosis of these patients.

Publicly available datasets were analyzed in this study. This data can be found here: http://seer.cancer.gov/data/.

The present study was approved by the Institutional Research Committee of Zhongnan Hospital of Wuhan University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

CS, WH, and SL: designed the study. CS, SL, and WH: reviewed relevant literature and drafted the manuscript. CS, QW, and YW conducted all statistical analyses. All authors contributed to the article and approved the submitted version.

This work was supported by Key Projects of Hubei Provincial Health and Family Planning Commission (WJ2017Z006) and Zhongnan Hospital of Wuhan University Science Technology and Innovation Cultivating Fund (cxpy2017041) and the 351 Talent Project of Wuhan University (Luojia Yong Scholars: SL).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.