What Are the Survival Factors in Surgically Resected Synchronous Multiple Primary Lung Cancers: A Retrospective Study

Background With the popularization of high-resolution computed tomography (HRCT), the detection rate of synchronous multiple primary lung cancer (SMPLC) is increasing. We retrospectively analyzed the surgical results of SMPLC patients in our hospital to determine the best treatment, surgical prognosis and survival analysis. Methods the relationship between and tumor location, metastasis, TNM surgical frequency, histopathologic types, vascular inltration, visceral pleural invasion and postoperative therapy. Third, TNM stage of the largest tumor (II:HR=7.40,III:9.01,p=0.002) was an independent risk factor for DFS. Smoking history (HR=4.34,p=0.039) and TNM stage of the largest tumor (II:HR=9.38,III:9.42,p=0.003) were independent risk factors for overall survival. CT, scintigraphy, electrocardiogram, ultrasonography,


Introduction
According to global cancer statistics, lung cancer is one of the malignant tumors with the highest morbidity and mortality in the world [1]. With the popularization of high-resolution computed tomography (HRCT), the detection rate of synchronous multiple primary lung cancer (SMPLC) is increasing but there is no clear clinical stage and clinical guidelines for SMPLC. And the latest 8 th (2015) edition TNM classi cation for lung cancer [2] still classi ed separate tumor nodules in the same lobe as T3, in the ipsilateral lung but different lobes as T4 and in the contralateral lung as M1a. Obviously, SMPLC is still regarded as intrapulmonary metastasis. However, according to related studies, the prognosis of SMPLC surgery is better than that of patients with high-stage lung cancer [2][3][4][5][6][7]. So such classi cation and stage still need to be further studied. In this study, the clinical data of 78 patients with SMPLC who underwent thoracic surgery in the Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University from January 2013 to November 2018 were collected retrospectively in order to evaluate the surgical effect and related prognosis of SMPLC and to provide reference for clinical practice.

Materials And Methods
Patient selection: All the medical records of SMPLC who underwent thoracic surgery in the Department of Thoracic Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University from January 2013 to November 2018 were collected retrospectively. All patients had postoperative pathology as the basis for diagnosis. Informed consent was waived because this was a retrospectively study.
Diagnostic criteria: All patients met the new improved standard of SMPLC [8][9]. The subjects of this study were SMPLC, with more than 2 independent cancers in the lung at the same time. They were also considered after multi-disciplinary discussion and met at least one of the following criteria: (1) tumors with different histology; (2) tumors with similar histology requires that the tumor was located in different lobes or segments of the lung, without common lymph node metastasis and extrapulmonary metastasis; (3) tumors originated from different primary cancers; (4) tumors with different histologic subtypes (such as acinar cell or papillary cell is the main part of the adenocarcinomas, etc.); (5) tumors with different molecular genetic characteristics (such as epidermal growth factor receptor [EGFR], k-ras, etc.) [10,11].
Preoperative evaluation: All patients with lung cancer in our hospital underwent relevant preoperative examinations, including thoracic and abdominal Computed Tomography (CT), cranial magnetic resonance image (MRI) or CT, bone scintigraphy, electrocardiogram, cardiac ultrasonography, pulmonary function and so on. Some patients were examined by PET/CT scan. The appropriate operation method was chosen carefully according to the preoperative examination, the patient's physical condition and the situation during the operation.
Surgical strategy: The principle of surgery was to remove the tumor as thoroughly as possible and preserve lung function as much as possible. And the following strategies should be followed: (1) when pulmonary function permits, the lobes of all lesions should be removed; (2) when pulmonary function did not allow multi lobectomy, the lobe of major lesion (the tumor with central type or the highest TNM stage) should be removed, then the secondary lesions should be removed locally, otherwise local resection of multiple lesions should be performed; (3) when the lesions were on different sides, if the patient's physical quality permits, the tumors should be removed at the same time. If the physical quality of the patient was not allowed, the main lesions should be removed rst and then remove the secondary lesions in another time. According to the preoperative discussion and intraoperative conditions, thoracotomy or video-assisted thoracoscopic surgery (VATS) was selected. No matter which operation method was chosen, all patients underwent radical pneumonectomy and lymph node dissection or sampling.
Postoperative pathological stages We staged every lesion independently using the 8 th edition TNM classi cation [2] for each patient. Each tumor was staged and the highest stage was taken as the nal stage of the patient.
Postoperative follow-up: The patients were checked every 3 months within 2 years, every 6 months within 2-5 years, and every 1 year after 5 years. The follow-up items included tumor markers, thoracic CT, abdominal ultrasound, cranial MRI, and bone scintigraphy (if necessary).
Statistical analysis: Disease-free survival (DFS) was de ned as the time from the rst operation to postoperative recurrence or distant metastasis or the last follow-up. Overall survival (OS) was de ned as the time from the rst operation to death or the last follow-up. The follow-up time at the end of this study was August 4, 2020. The Kaplan-Meier method was used to estimate the survival curve, and log-rank test was used to compare the survival curve of each group. The cox proportional hazard regression model was used to analyze the prognostic factors for survival. The data were analyzed by SPSS20.0 statistical software, and the value of P < 0.05 was considered statistically signi cant.
The results of univariate analysis of prognostic factors related to OS and DFS were showed in Table 1.

Discussion
At present, according to the latest t 8 th (2015) edition TNM classi cation for lung cancer [2], same as the 7 th edition [12], SMPLC is still regarded as intrapulmonary metastasis in T and M stages. Multiple tumor nodules in the same lobe were classi ed as T3, in the different lobe but ipsilateral as T4 and in the bilateral lobe were classi ed as M1a (8 th and 7 th edition). In our study, the 1-,2-,3-,4-and 5-year disease free survival (DFS) rates were 93.42%, 86.84%, 77.78%, 62.96%, and 60.00%, respectively, while the 1-,2-,3-,4-and 5-year overall survival (OS) rates were 94.73%, 92.11%, 82.22%, 77.78%, and 65.00%, respectively. These were basically consistent with other researches [2][3][4][5][6][7]. The research of Shintani, T. et al [13] and Chang JY.et al [14]found that in SMPLC patients only treated with stereotactic body radiotherapy (SBRT), The 2-year and 4-year OS rates were 73.2% and 47.5%, respectively; DFS rates were 67% and 58%, far lower than the surgical-based comprehensive therapy. Other studies also supported this conclusion [15][16].Comprehensive studies had shown that the prognosis of patients with SMPLC was better than that of patients with lung cancer recurrence or metastasis [2][3][4][5][6][7]. Therefore, whether to treat multiple primary lung cancer as intrapulmonary metastasis for clinical staging remains to be further studied and discussed. At present, there is no systematic and authoritative treatment guideline for SMPLC, but our study showed that surgery can bring a great survival bene t. Therefore, for patients with SMPLC, it should never treat them as lung cancer recurrence or metastasis and give up surgery. Further research and discussion of clinical guidelines for SMPLC are still needed.
In the choice of surgical methods, the principle was radical resection of tumor and maximum preservation of pulmonary function at the same time. In our study, there was no signi cant difference in prognosis among patients who underwent multi lobectomy, lobectomy + sublobectomy and sublobectomy alone. The results may be due to the popularity of early screening in recent years, the early diagnosis and treatment of SMPLC make the prognosis difference small. Some literatures [17][18] suggested that sublobectomy was acceptable for patients with SMPLC at an early stage, with the equivalent prognosis to the standard resection and better pulmonary function preservation. While the study of Ishikawa, Y. et al [19] suggested that lobectomy was an independent risk factor for poor prognosis. In our study, there were 32 patients who underwent lobectomy only. Their 2-, 4-, and 5-year DFS survival rates were 84.38%, 61.54%, and 60.00%, and 2-, 4-, and 5-year OS survival rates were 84.38%. , 69.23% and 70.00%. Another 46 patients underwent sublobectomy (sublobectomy and lobectomy + sublobectomy), their 2-, 4-, and 5-year DFS rates were 86.63%, 64.29%, and 60.00% and the 2-year, 4-year and 5-year OS rates were 97.73%, 85.71%, and 70.00%, which were all higher than the above-mentioned stereotactic radiotherapy (2-year and 4-year OS rates were 73.2% and 47.5%, respectively, and DFS rates were 67% and 58%, respectively). Although the survival rate of sublobectomy is higher than the rate after simple lobectomy, the latter has more patients in the middle and late stages, so more samples and evenly staged patients were still needed to compare the two surgical methods impact on the prognosis, but for patients who cannot tolerate simple lobectomy, sublobectomy (simple sublobectomy and lobectomy + sublobectomy) can bring a signi cant prognosis. In order to study the impact of surgical methods on patients with the same TNM stage, the author analyzed the stage I patients in this sample separately, but the surgical method had not been found to be an independent prognostic risk factor.
It was also found that the number of operations was not an adverse factor for DFS and OS in SMPLC patients. In our study, most of the unilateral tumors were removed with a single operation, and 5 of the 9 bilateral tumors were operated in different time. The treatment method was to rst remove the tumor which was large, central, quick-progressing or with positive lymph node metastasis, and then remove the tumor which was small, peripheral, slow-progressing or no positive lymph node metastasis. The general principle was to deal with the main lesions with late stage and high malignancy rst. And the remaining lesions of the patients were closely followed up and treated in time for the second-stage operation. The study of Peng Y. et al [4] showed that simultaneous operation of bilateral lesions was feasible. There was no signi cant statistical difference in postoperative hospital stay between synchronous surgery and nonsynchronous surgery. However, the study did not mention other postoperative conditions, such as extubation time and postoperative complications and the study was more based on clinical experience with no more signi cant statistical studies.
For DFS, the TNM stage of largest tumor was the only independent risk factor. For OS, smoking history and the TNM stage of largest tumor were independent risk factors. This study found that the 3-year survival rate of DFS and OS in patients whose largest tumor was TNM stage I were 84.85% and 87.88%, which were signi cantly higher than those of patients whose largest tumor was TNM stage > I (50.00% and 64.29%, respectively ). In univariate analysis, T stage, N stage and TNM stage were all risk factors for DFS and OS. However, in multivariate analysis, only TNM stage was an independent risk factor for prognosis. Considering that TNM stage includes T stage and N stage, they were still closely related to the prognosis of patients, which is basically consistent with the results of other studies [3,[6][7][20][21].
Smoking history was one of the independent prognostic risk factors for OS. Among 21 patients in our study, 18 were heavy smokers (smoker index>400). The 5-year DFS rate and 5-year OS rate of heavy sMPLC smokers were only 33.3% and 44.44%, which were much lower than the overall 5-year rate of the patients in this study (DFS: 60.00%, OS: 65.00%). For patients with mild to moderate smoking, whether smoking history was an independent prognostic factor remained to be studied, but the existing study showed that smoking did harm to the human health, especially the lungs, and it was inseparable from the occurrence of lung cancer. Tobacco smoke can lead to gene mutations, DNA damage, DNA adduct formation,abnormal DNA methylation, lung in ammation, oxidative stress, abnormal differentiation, abnormal proliferation, epithelial-mesenchymal transition (EMT) and so on [22][23][24][25][26].
In univariate analysis, postoperative adjuvant therapy was not conducive to the patients' DFS and OS. This should be due to the synergy with the independent risk factor TNM stage. Obviously, the prognosis of patients with high TNM stage was bad to the patients with low TNM stage and all the patients with high TNM stage in our study had adjuvant treatment after surgery, so in the univariate analysis, postoperative adjuvant therapy was a risk factor but not in the multivariate analysis. Some literatures showed that postoperative adjuvant chemotherapy can bring survival bene ts [6,[27][28]. Based on the relevant research subjects, we found that it may be bene cial to the patients with late TNM stage and positive lymph node metastasis.
In clinical practice, there was no uni ed opinion on whether adjuvant therapy should be given to sMPLC patients whose largest tumor was TNM stage I. In order to study whether postoperative adjuvant therapy affects the prognosis of those patients, we separated them to carry out survival analysis. The univariate survival analysis found that smoking history and postoperative adjuvant therapy were risk factors for DFS. Gender, smoking history and postoperative adjuvant therapy were risk factors for OS. However, in multivariate analysis, no independent survival risk factors were found in DFS and OS (P>0.05).
Considering that in the univariate analysis, postoperative adjuvant therapy in patients with TNM stage I of the largest tumor was a risk factor for DFS and OS, whether postoperative adjuvant therapy increased recurrence or death and whether it prolonged prognostic survival rate remained to be further studied. However, it was certain that during the operation, the relevant lymph nodes should be removed as radically as possible so that accurate lymph node staging can guide the follow-up treatment.
This study had found that age, preoperative symptomatic, family history of cancer, preoperative tumor markers, tumor laterality, tumor location, surgical type, surgical frequency, pathological types, vascular in ltration, and visceral pleural invasion had no signi cant impact on the prognosis of sMPLC, which still need further study.
Limitations: First of all, the sample size was insu cient, and there was a bias in the selection of patients.
Patients with high pT stage and high pN stage were not enough in the study. Secondly, we did not include patients who only received non-surgical treatment (such as chemotherapy, radiotherapy, targeted therapy, etc.) and no rigorous comparison was operated. Thirdly, there was still a need for more sample sizes and evenly staged patients to compare the in uence of surgical method and times on prognosis. Finally, no independent prognostic risk factors were found in SMPLC patients whose largest tumor was TNM stage I.

Conclusion
First, SMPLC is different from intrapulmonary metastasis and its clinical stage is also different from the 8 th (2015) edition TNM classi cation for lung cancer. Second, when pulmonary function permits, surgery (R0 resection and lymph node dissection) is a signi cantly bene cial treatment for patients with SMPLC. Third, heavy smoking and high TNM stage are not conducive to the prognosis of SMPLC patients Abbreviations SMPLC: synchronous multiple primary lung cancer; HRCT: high-resolution computed tomography; pT: tumor. pN: lymph node.; d: maximum diameter; HR, Hazard ratio; CI, con dence interval.

Declarations
Ethics approval and consent to participate This study was reviewed and approved by the Ethics Committee of Qilu Hospital, Cheeloo College of Medicine, Shandong University (KYLL-202008-179). Informed consent was waived because this was a retrospectively study. We obtained patient data from the Medical Records and Statistics Room. We analyzed the data anonymously and would abide by the con dentiality agreement. The use of the raw data was permitted by the Ethics Committee of Qilu Hospital, Cheeloo College of Medicine, Shandong University.

Consent for publication
Not applicable; no personal information is presented in this article.

Availability of data and materials
The data supporting our ndings can be found by contacting us (zhaojianjn@sdu.edu.cn).

Competing interests
The authors declare that they have no competing interests.

Authors' contributions
Haichao Li was majored in the study design, data extraction, data analysis, statistical analysis and was the major author of writing the manuscript. Kai Wang, Xingxing Zhang, Rong Chen and Jian Zhao all contributed to the study and the manuscript. All authors read and approved the nal manuscript.