We conducted this large-scale population-based retrospective study based on NSCLC patients with chest wall invasion to investigate prognostic predictors via the national cancer registry SEER database. Besides, independent prognostic associated factors for NSCLC patients with chest wall invasion for OS and CSS were eventually confirmed. Furthermore, to predict OS and CSS conveniently, we established two prognostic nomograms with reliable accuracy and discriminative ability which were validated by ROC, calibration, K-M, and DCA curves. These nomograms can serve as a practical tool for clinicians to identify patients with a high risk of poor survival and to determine the optimal clinical treatment for NSCLC patients initially diagnosed with chest wall invasion.
The chest wall is the most common site invaded by peripheral lung cancer, and its adverse survival impact is clear because the current 8th TNM staging system classified it as an independent T3 stage for NSCLC with the tumor size less than 7 cm[17, 18]. In the past, the tumor invading the chest wall has been considered a contraindication for surgery for a long time. Surgery has been gradually accepted by thoracic surgeons since Gronquist et al published the first encouraging survival results of patients with chest wall invasion after surgery in 1947[8]. To date, With the rapid development of surgical instruments and skills, more and more studies have demonstrated that surgery with R0 resection can improve survival in NSCLC patients with chest wall invasion. For example, in a study of 104 NSCLC patients with chest wall invasion, Giancarlo et al indicated that surgery could improve the survival outcome significantly during the last 3 decades and advocated the performance of radical en bloc resection for the treatment of NSCLC with chest wall invasion[19]. Another retrospective study consisting of 135 NSCLC patients, it does not worsen the quality of life and pulmonary function of patients who underwent pulmonary resection with chest wall removal compared with patients who underwent pulmonary resection only[20]. Therefore, surgery for NSCLC patients with chest wall invasion is feasible and en bloc resection is recommended as the primary choice, even if it requires removing the partial chest wall. In our study, surgery was identified as an independent positive prognostic factor for both OS and CSS as previously reported. Additionally, our results indicated that surgery had a significant survival benefit even in NSCLC patients with lymph node metastasis and distant metastasis. Nonetheless, it requires more prospective studies to evaluate the survival impact of surgery in patients with distant metastasis.
Chest wall involvement in NSCLC patients is often categorized as locally advanced stage in which adjuvant therapy is inevitable. Chemotherapy is recommended as first-line treatment in many cancers, especially in the advanced stage like small cell lung cancer, pleural mesothelioma, and ovarian cancer[21–23]. In a large database study of 2326 eligible NSCLC patients with chest wall invasion (T3N0) constructed by Drake, they summarized that patients who were treated with adjuvant chemotherapy after en bloc resection (R0) had significantly better median survival than those without chemotherapy before and after propensity score matching[24]. Similarly, Gao et al found adjuvant chemotherapy could bring a survival benefit in NSCLC patients invading the chest wall without lymph node invasion[25]. In addition, patients with malignant pleural effusion could benefit from surgery and adjuvant chemotherapy[26] and sugemalimab combined with chemotherapy demonstrated a statistically significant and clinically meaningful progression-free survival improvement in patients with metastatic NSCLC[27]. As the same as the previous studies, our results revealed that NSCLC patients with chest wall invasion can benefit from chemotherapy. However, the benefits of radiotherapy in patients with chest wall invasion remain debatable. Magdeleinat et al revealed that radiotherapy could not improve survival even if a possibility of complete resection existed, but, they found that lymph node involvement was not a contradiction to surgery[28]. Another study demonstrated adjuvant radiation therapy had no significant benefits on local recurrence and overall survival as well[25]. Consistent with these studies, our study indicated that radiotherapy did not influence the OS and CSS in NSCLC patients with chest wall invasion. Whereas, in a prospective, multi-institutional phase II study (CJLSG0801), induction radiation plus chemotherapy followed by surgery was safe and effective with a high rate of pathologic response for patients with NSCLC invading the chest wall[29]. Largacha et al demonstrated that induction chemotherapy combined with high-dose radiation followed by surgical resection was correlated with the improvement of OS in patients with non-superior sulcus lung cancer with chest wall invasion[30]. What’s more, other studies also revealed that radiotherapy had a positive benefit on survival[25, 31]. In my opinion, those studies that considered radiotherapy useless were limited by small samples, current irradiation techniques, and incomplete resection. In the end, I would like to emphasize that in the present study, we can not distinguish neoadjuvant therapy and adjuvant therapy from the SEER database. Thus, more clinical studies are required to clarify the role of radiotherapy and chemotherapy in NSCLC patients with chest wall invasion.
Tumor size has already been a T descriptor in TNM staging system and its influence on direct tumor extension and survival is widely accepted. In a study conducted by Lee, tumor size (> 5 cm) and lymph node involvement were negatively related to OS[32]. To explore the impact of the depth of the chest wall invasion on survival, Wu et al suggested that compared with pT4, rib invasion has a poorer prognosis, and patients with parietal pleura invasion and tumor size ranging from 5.1cm to 7.0cm could be up-classified from pT3 to pT4[33]. A larger tumor size led to worse OS and CSS in our study as the previous conclusion. Chest wall invasion tends to involve mediastinal lymph nodes and distant organs which exhibit adverse impact on survival. Recently, Jones said that pathological nodal status and higher pathological stage were associated with poor OS in locally advanced NSCLC with chest wall invasion[11]. Similarly, Burkhart et al identified that node-positive and male were related to poor survival[34]. And beyond that, a deep learning model demonstrated that node-positive and distant metastasis had a negative survival benefit[35]. Our multivariate analysis concluded that tumor size, lymph node invasion, and distant metastasis were independent negative predictors for OS and CSS, which was in line with current opinions. As for histology, Burkhart et al indicated that no significant difference in impact on survival was observed between adenocarcinoma and squamous cell carcinoma[34], as well as Facciolo, reported[10]. Our analyses indicated that there was also no significant difference between adenocarcinoma and squamous cell carcinoma while others were a significant risk factor for OS and CSS. It requires more studies concentrating on histopathology to clarify its survival impact. Older age was associated with poor survival in many cancers[36–40], which was consistent with our results. The reason why older age can worse survival may be that patients with older age have a poor physical condition, have a high risk of metastasis and are more likely to die from other diseases. In a pan-cancer analysis, the incidence and survival of cancers vary significantly by sex which indicates males generally have lower incidence and survival compared to females[41]. Other studies demonstrated that compared with men, women had better survival in metastatic pancreatic cancer[42], esophageal cancer[43], and large cell lung cancer[44]. Male was an independent risk factor for OS while not for CSS in our study which needs further studies to illustrate. Increasing tobacco use, increasing exposure to oncogenic agents, engaging in high-risk behaviors, and fewer health care services for males may attribute to the difference in survival between males and females.
Nomograms can predict prognosis efficiently and accurately in other tumors. Mo et al combined age, CEA, perineural invasion, circumferential resection margin status, grade, lymph nodes harvested, mismatch repair deficiency status, and T stage to predict survival in stage II colorectal cancer [45]. In germ cell testicular cancer, a nomogram for CSS was established based on age, race, AJCC stage, TM stage, SEER stage, and radiotherapy[46]. To date, there are many studies on the prognosis and nomograms of NSCLC, nonetheless, there is still no study concentrated on the prognosis in NSCLC patients with chest wall invasion based on the clinical characteristics, which leads to worse cancer prognosis. In the present study, two novel prognostic nomograms were established with good performance in accuracy, discrimination, and predictive benefits.
However, there are still some limitations in this study. First, prospective randomized controlled studies are required to confirm our results because of the selection bias of the retrospective study. Second, due to the lack of external validation in the present study, an inherent bias can not avoid. Third, we don’t include complete information on surgery such as R0 resection or not, chest wall reconstruction or not, and so on, which may affect survival outcomes. Finally, the depth of chest wall invasion is not described in detail which may confound the survival impact of chest wall invasion.