Radical Resection With Contralateral Lymph Node Dissection for Clinical N3 NSCLC

1. Background Lung cancer is one of the most common malignant tumors worldwide and a leading cause of cancer-related mortality. According to cancer statistics, approximately 1.8 million people die from lung cancer annually worldwide. In China, the incidence and mortality rates of lung cancer are on the rise, particularly for non-small cell lung cancer (NSCLC), which accounts for approximately 85% of all lung cancer cases. Many lung cancer patients already present with contralateral mediastinal or hilar lymph node metastasis at the time of diagnosis, which corresponds to N3 stage in lymph node staging. N3 stage lung cancer is classified as locally advanced or metastatic disease. Due to its aggressive progression and extensive invasiveness, clinical diagnosis and treatment of N3 stage lung cancer pose significant challenges. Therefore, effectively assessing lymph node metastasis in lung cancer patients and developing personalized treatment strategies for those with contralateral thoracic lymph node metastasis has become a central topic in clinical research.

The staging system for lung cancer is based on tumor size, lymph node involvement, and the presence of distant metastasis. According to the eighth edition of the TNM staging system released by the International Association for the Study of Lung Cancer (IASLC), lymph node metastasis (N stage) is a core factor in determining prognosis and treatment decisions. N stage not only assesses whether the tumor has spread to adjacent lymph nodes, but also includes the specific location and number of affected nodes. N0 indicates no lymph node metastasis, N1 indicates metastasis to proximal hilar lymph nodes, N2 indicates metastasis to mediastinal lymph nodes, and N3 indicates distant lymph node metastasis, which typically involves contralateral thoracic lymph nodes and cervical lymph nodes. N3 stage lung cancer is usually considered as locally advanced or metastatic disease, with a poor prognosis. The 1-year, 3-year, and 5-year overall survival rates are 35.8%, 6.8%, and 1.7%, respectively, while the corresponding cancer-specific survival rates are 36.6%, 6.9%, and 1.8%. Contralateral thoracic lymph node metastasis is a specific type of N3 stage lymph node metastasis, indicating that cancer cells have spread from the primary tumor to the contralateral thoracic lymph nodes through the lymphatic system. The presence of contralateral thoracic lymph node metastasis usually signifies that cancer has crossed the midline of the thoracic cavity, increasing the cancer's invasiveness and the complexity of surgical treatment. For clinically staged N3 NSCLC patients, treatment strategies often require a combination of surgery, radiotherapy, chemotherapy, and chemoradiotherapy to improve survival and control symptoms. However, due to the presence of contralateral thoracic lymph node metastasis, surgical resection alone is often insufficient for achieving optimal cure, and lymph node dissection becomes an indispensable part of the treatment plan.

Currently, treatment strategies for N3 stage lung cancer with contralateral thoracic lymph node metastasis emphasize multimodal approaches. Traditional treatment options include surgery, chemotherapy, radiotherapy, and chemoradiotherapy combinations, aiming to improve survival rates and control symptoms. In recent years, targeted therapies and immunotherapies have also been increasingly applied in the treatment of N3 stage lung cancer, offering new hope for patients who were previously considered unsuitable for surgery or with limited treatment options. Immunotherapy, particularly immune checkpoint inhibitors, has been used as a first-line treatment for metastatic disease and as consolidation therapy after chemoradiotherapy for unresectable locally advanced disease. Targeted therapies have improved prognosis for patients with specific genetic mutations (e.g., EGFR mutations and ALK rearrangements). These therapies are personalized based on the tumor's molecular characteristics, representing a more individualized approach to treatment. However, the development of resistance to these therapies by tumor cells remains an unresolved issue. The combination of immunotherapy in N3 stage NSCLC has improved surgical success rates and reduced postoperative recurrence. However, the side effects of immunotherapy significantly limit its widespread application in lung cancer. Surgery remains the primary treatment for early-stage lung cancer, but due to the extensive lymph node metastasis in N3 stage patients, the difficulty of lymph node dissection increases, and guidelines do not recommend primary surgery for N3 stage lung cancer patients.

Management of N3 stage NSCLC remains controversial due to the heterogeneity of the disease and the limited efficacy of current treatment methods. For patients with contralateral thoracic lymph node metastasis, the suitability of surgery remains a topic of debate. On one hand, surgical resection can significantly improve local control rates, particularly in patients who are amenable to resection. A retrospective analysis of N3 stage lung cancer patients found that lobectomy combined with lymph node dissection could improve overall survival and local control rates compared to non-surgical treatments. Additionally, Bott et al. reported that N3 stage lung cancer patients who underwent surgical resection had a higher median overall survival (OS) compared to those who did not undergo surgery. On the other hand, the widespread and multifocal nature of lymph node metastasis in N3 stage patients requires an expanded surgical resection to achieve complete removal of the tumor and affected lymph nodes, significantly increasing the complexity and risk of surgery.

Although surgical treatment for N3 stage lung cancer with contralateral thoracic lymph node metastasis has been relatively rare, bilateral lymph node dissection has been consistently regarded as an important component of surgery for N3 stage patients, especially those with contralateral thoracic lymph node metastasis. Bilateral lymph node dissection not only helps to remove the tumor and its metastases more thoroughly but also improves the lymph node clearance rate, thereby reducing the risk of postoperative recurrence. Riquet et al. retrospectively analyzed 11 pN3 patients, all of whom underwent complete resection of the primary tumor and ipsilateral mediastinal lymph node dissection. Seven of them also underwent additional N3 lymph node dissection, and four of these patients were alive at five years of follow-up with good survival outcomes. Another retrospective study analyzed 11 N3 stage lung cancer patients who underwent bilateral lymph node dissection. Among those with left-sided lung cancer, six patients had a 100% five-year survival rate, while five right-sided lung cancer patients had a 30% three-year survival rate. Hata et al. reported a high five-year survival rate (62.5%) with conventional thoracotomy combined with bilateral lymph node dissection in eight N3 stage lung cancer patients. Furthermore, Watanabe et al. employed median sternotomy to perform extensive bilateral hilar, mediastinal, and supraclavicular lymph node dissection in 19 N3 stage lung cancer patients, with six patients still alive at the end of the study, and the longest survival time was 23 months, although the longest follow-up period in this study was less than five years.

Currently, research on the application of primary surgical interventions in clinically staged N3 NSCLC patients remains limited, with most studies being retrospective analyses with small sample sizes. The existing studies show significant heterogeneity in surgical techniques and lymph node dissection strategies, making it difficult to discern the specific differences in efficacy between different surgical approaches and lymph node dissection methods for N3 stage lung cancer. Additionally, many related studies are relatively old, with lymph node dissection techniques mainly involving median sternotomy for bilateral thoracic lymph node dissection. This technique, being more invasive, may adversely affect postoperative recovery and survival outcomes for patients.

In recent years, with the rapid development of thoracoscopic technology, the invasiveness of lung cancer surgery has been significantly reduced, leading to improved postoperative recovery, reduced complications, and better quality of life for patients. Thoracoscopic surgery not only achieves higher R0 resection rates but also effectively improves local tumor control, especially in handling N3 stage lymph node metastasis. Therefore, with ongoing advancements in surgical techniques and postoperative care, the treatment approach of primary tumor resection combined with bilateral lymph node dissection may offer less surgical trauma, higher complete resection rates, and significant improvements in local control and survival for patients with locally advanced lung cancer.

N3 stage lung cancer with contralateral thoracic lymph node metastasis presents a complex and challenging clinical problem. Although bilateral lymph node dissection has shown positive results in some patients, its high-risk profile and complications in previous studies raise questions about whether primary surgical intervention can be expanded to more N3 stage patients. Minimally invasive lung tumor resection surgery offers a promising approach to controlling locally advanced lung cancer and improving patient survival. 2. Purpose

Primary Purpose:

\- Evaluate the efficacy of primary tumor resection combined with bilateral lymph node dissection in non-small cell lung cancer (NSCLC) patients with contralateral thoracic lymph node metastasis detected by PET: The primary objective is to assess the clinical efficacy of primary tumor resection combined with bilateral lymph node dissection in terms of postoperative survival rates (such as overall survival and disease-free survival).

Secondary Purpose:

\- Investigate the impact of primary tumor resection combined with bilateral lymph node dissection on postoperative complications: This objective aims to evaluate the potential complications arising from the surgical procedure, including postoperative infection, lymphatic leakage, respiratory dysfunction, and atrial fibrillation, as well as analyze the safety of this combined surgical approach.

\- Assess the extent of surgical trauma caused by primary tumor resection combined with bilateral lymph node dissection: The study will examine key indicators of surgical trauma, such as intraoperative blood loss, postoperative pain scores, and length of hospital stay, to provide evidence for the safety and feasibility of this combined treatment approach and offer guidance for postoperative management and patient recovery optimization. * Analyze the impact of neoadjuvant therapy on the efficacy of primary tumor resection combined with bilateral lymph node dissection: This objective aims to explore the effects of neoadjuvant therapy (or the lack thereof) and different neoadjuvant treatment regimens on patient survival, recurrence rates, and postoperative complications, in order to identify key factors that may influence treatment outcomes. * Evaluate the impact of lymph node metastasis during lymph node dissection and its prognostic predictive value: This objective will analyze the effect of the number and location of lymph node metastases on patient prognosis, as well as assess the benefit-risk ratio of applying this combined therapy in patients who are pathologically classified as non-N3 (i.e., those without contralateral thoracic lymph node metastasis). 3. Study Design

\- Study Type This study is a single-center, prospective, single-arm trial. The primary objective of the study is to evaluate the efficacy of primary tumor resection combined with bilateral lymph node dissection in non-small cell lung cancer (NSCLC) patients with

• Evaluation of intra-operative blood loss [Срок оценки: Perioperative]
• Evaluation of post-operative pain [Срок оценки: Perioperative]
• Evaluation of incidence of post-operative complications [Срок оценки: Perioperative]
• Evaluation of chest tube retention time [Срок оценки: Perioperative]
• Evaluation of chest tube drainage output [Срок оценки: Perioperative]
• The impact of neoadjuvant therapy on the safety of surgery [Срок оценки: Perioperative/Periprocedural]
• The impact of neoadjuvant therapy on the efficacy of surgery [Срок оценки: Disease-free survival rate at 12 months post operative for the analyzation of patient survival and recurrence rates.]
• Evaluation of the impact of lymph node metastasis on surgical outcomes [Срок оценки: 12 months for disease-free survival]