Description of the condition
In 2012, there were 1.8 million new cases of lung cancer and 1.59 million deaths from the disease worldwide (International Agency for Research on Cancer 2012). Lung cancer is the most common cancer among men (1.2 million new cases), with the highest incidence rates in Central and Eastern Europe and Eastern Asia in 2012 (International Agency for Research on Cancer 2012). Among women, the incidence rates of lung cancer are lower (0.6 million new cases), and the highest incidence rates are in Northern America and Northern Europe in 2012 (International Agency for Research on Cancer 2012).
The World Health Organization classifies lung cancers into two major groups: non-small cell lung cancer (NSCLC) and small cell lung cancer (Travis 2015). More than 80% of all lung cancer cases are NSCLC. There are two major types of NSCLC: non-squamous carcinoma (e.g. adenocarcinoma, large cell carcinoma) and squamous cell carcinoma. Adenocarcinoma is the most common type of lung cancer.
Twenty per cent of all lung and bronchial cancers are diagnosed when the cancer has spread to regional lymph nodes or beyond the primary site (Howlader 2017). The majority of the lung cancer cases (57%) are diagnosed when the disease has metastasised (spread) to distant sites. The Tumor, Node, Metastasis (TNM) staging system, proposed by the American Joint Committee on Cancer (AJCC), is a widely accepted system to characterize the extent of NSCLC.The TNM staging staging system is based on the extent of tumour (T), extent of spread to the lymph nodes (N) and the presence of metastases (M).The numbers after each letter give more details about the cancer. For example, a higher number after the T indicates a larger tumor while a higher number after the N suggests more lymph nodes are involved by the cancer.The TNM system has undergone several changes over the last 40 years.
The first edition of the AJCC TNM system, published in 1977, defined Stage III disease as T3 with any N or M, N2 with any T or M and M1 with any T or N (Beahrs 1977).
The second edition, published in 1983, broadened the Stage III disease definition by including N1 disease with any T or M (Beahrs 1983).
The third edition, published in 1988, first introduced the category of Stage IIIA disease which is defined by T1 N2, T2 N2, T3 N0-2 (Beahrs 1988).
The fifth edition, published in 1997, modified the category of Stage IIIA disease slightly by removing T3N0 disease (Fleming 1997).
The seventh edition, published in 2010, broadened the definition of Stage IIIA disease slightly by including T4N0-1 disease (Edge 2010).
The eighth edition, published in 2017, modified the Stage IIIA disease category even further to include only T1-2N2, T3N1, T4N0-1 (Amin 2017).
The prognostic significance of multi-station N2 disease was highlighted in the eighth edition of the AJCC TNM staging system, in which an exploratory subclassification of pathologic N2 disease was introduced. Presence of multi-station N2 disease is classified as pN2b disease whereas single N2 disease can be categorized as pN2a1 or N2a2 depending on the presence of concurrent N1 involvement. The overall survival rate for people with pN2b disease is significantly lower than for those with pN2a disease,and five-year overall survival rate of 38% (pN2b) versus 49% (pN2a) (Amin 2017).
Pearson and colleagues reported a series of 141 N2 patients who had undergone mediastinal lymph node examination and subsequent thoracotomy (an operation to allow the surgeon to access the chest cavity). They demonstrated that for patients who had a negative mediastinal lymph node evaluation, but had N2 disease identified at subsequent thoracotomy, there were higher rates of five-year overall survival compared with patients who had N2 disease at both mediastinal lymph node evaluation and subsequent thoracotomy (24% versus 9%) (Pearson 1982).
The location and definition of thoracic lymph nodes has changed over the years. Naruke and colleagues first proposed the thoracic lymph node map in the 1960s and it was widely adopted in the North America, Europe and Japan (Naruke 1967; Naruke 1978). The map was further refined by the American Thoracic Society (Tisi 1983), and by Mountain et al (Mountain 1997), and was subsequently adopted in the fourth to sixth editions of the TNM staging system. There were important differences between the maps by Naruke (Naruke 1967; Naruke 1978), and by Mountain (Mountain 1997). The level 7 subcarinal lymph nodes in the Mountain map corresponded to the levels 7 and 10 in the Naruke map. This resulted in some tumours being staged as N2 disease according to the Mountain map but as N1 disease according to Naruke map.
To reconcile the differences between the maps by Naruke (Naruke 1967; Naruke 1978), and Mountain (Mountain 1997), the members of the International Association for the Study of Lung Cancer (IASLC) developed a revised lymph node map which was adopted in the seventh (Edge 2010), and eighth (Amin 2017), editions of the TNM staging system. It is important to note that the definition of lymph node stations was changed in the seventh edition of the TNM staging system (Edge 2010). For example, the lymph node station 4R below the azygos vein — considered as N2 disease in the sixth edition of the TNM staging system (Greene 2002) — is now N1 disease (station 10) based on the seventh edition of the TNM staging system (Edge 2010).
Complete resection is a major prognostic factor for patients undergoing lung cancer surgery (Osarogiagbon 2012; Osarogiagbon 2013). Rami-Porta and colleagues have proposed clear definitions of what is considered a complete resection, incomplete resection or uncertain resection (Rami-Porta 2005). These definitions are consistent with the residual tumor classification , i.e. R0 for no identifiable tumour remaining, negative surgical margins; R1 for microscopic residual disease; and R2 for gross residual disease. Initially there was a subdivision named Run, indicating that a complete resection was probably achieved but not all criteria were fulfilled, which was proposed but not adopted. Examples of Run include incomplete nodal dissection when less than the required three hilar/intrapulmonary nodal stations, or less than three mediastinal nodal stations, were removed. Recently, the eighth edition of the TNM staging system has formally adopted the Run category (Amin 2017) (Appendix 1).
Description of the intervention
Surgery-based treatment approaches for Stage IIIA disease involve surgery with other treatment modalities such as chemotherapy and radiotherapy (National Comprehensive Cancer Network 2018). Surgical intervention entails anatomic pulmonary resection, such as lobectomy (excision of a lobe) or pneumonectomy (complete removal of a lung), as well as N1 and N2 lymph node resection and mapping with a minimum of three N2 stations sampled or complete lymph node dissection. In anatomically appropriate situations where margin-negative resection can be achieved, lung sparing anatomic resection (sleeve lobectomy) is preferred to pneumonectomy. Video assisted thoracic surgery (VATS) should be considered in patients with no anatomic contraindications as it has been shown to be associated with fewer complications and shorter time in hospital compared with lobectomy by thoracotomy (Cao 2013). The addition of chemotherapy, either preoperatively or postoperatively, has been shown to improve overall survival in patients with Stage IB to Stage IIIA NSCLC. An individual patient data meta-analysis, including 2385 patients, demonstrated that adding preoperative chemotherapy improved overall survival by five per cent at five years, from 40% to 45% in Stage IB-IIIA NSCLC (NSCLC Collaborative Group 2014). A Cochrane individual patient data meta-analysis, including 11,107 patients, reported that there was a clear absolute survival benefit of four per cent at five years from the addition of adjuvant chemotherapy, regardless of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy for Stage IB to IIIA NSCLC (Burdett 2015).The role of adding radiotherapy to surgery for Stage IIIA NSCLC is unclear. A Cochrane individual patient data meta-analysis, including 2343 patients, showed that postoperative radiotherapy is detrimental to those with completely resected NSCLC and should not be used in the routine treatment of such patients (Burdett 2016). However, these trials employed now outdated radiotherapy techniques. Randomized trials are awaited to determine the effects of modern post-operative radiotherapy in patients with N2 disease. The role of adding radiotherapy to preoperative chemotherapy for NSCLC is unclear. A randomized trial comparing sequential neoadjuvant chemo-radiotherapy with neoadjuvant chemotherapy in Stage IIIA/N2 NSCLC showed that radiotherapy did not add any benefit to induction chemotherapy followed by surgery (Pless 2015). As this trial only compared preoperative sequential chemo-radiotherapy with preoperative chemotherapy, it is unclear if there will be a benefit with preoperative concurrent chemo-radiotherapy over chemotherapy alone for this group of patients.
Non-surgical treatment includes combined chemo-radiotherapy treatment. A randomized trial from 1968 involving 800 patients with locally advanced NSCLC, which compared radiotherapy alone and placebo, showed that the use of radiotherapy was associated with a small improvement in survival (18% at one year versus 14% in the control group) (Roswit 1968). A Cochrane review using individual patient data from 22 trials comparing radical radiotherapy with radical radiotherapy plus chemotherapy showed that there was a 10% reduction in the risk of death (corresponding to absolute benefits of 3% at two years and 2% at five years) with the use of radical radiotherapy plus chemotherapy (NSCLC Collaborative Group 2000). An individual patient data meta-analysis of six trials (1205 patients) showed that concurrent chemo-radiotherapy improved overall survival (4.5% absolute benefit at five years) compared with sequential chemo-radiotherapy in unresectable NSCLC (Auperin 2010).
How the intervention might work
Surgery, radiotherapy and chemotherapy are the three modalities used to treat patients with NSCLC according to the National Comprehensive Cancer Network (NCCN) guidelines (National Comprehensive Cancer Network 2018). They can be used alone or in combination depending on the stage of the disease, patients' performance status, comorbidities and pulmonary function. A patient can have resectable lung cancer by virtue of having a surgically removable NSCLC, but may not be operable due to poor pulmonary function or multiple comorbities.
For resectable and operable Stage I or II NSCLC, surgical resection should be used whenever possible. Postoperative chemotherapy can be given in pathologic Stage II NSCLC to reduce disease recurrence and improve survival. Patients with Stage I or II NSCLC who are inoperable or who refuse surgery may be candidates for definitive radiotherapy treatment, delivered using stereotactic or conventional techniques (National Comprehensive Cancer Network 2018).
For Stage III disease, a combined modality approach is used. When surgical resection is clearly feasible, surgery followed by postoperative chemotherapy with or without radiotherapy depending on the findings at surgery is an option. For N2 disease, options include preoperative chemotherapy or chemo-radiotherapy, possibly followed by surgery. When surgical resection is not feasible, the options include combinations of radiotherapy with sequential or preferentially concurrent chemotherapy (National Comprehensive Cancer Network 2018).
Why it is important to do this review
The optimal management of patients with resectable Stage IIIA NSCLC is unclear. The NCCN guidelines recommend a surgery-based approach for patients with resectable T1-3, N0-1 disease, and definitive concurrent chemo-radiotherapy for N2 disease (National Comprehensive Cancer Network 2018). The European Society for Medical Oncology (ESMO) guidelines also recommend surgery-based treatment for patients with N0-1 disease. However, for patients with potentially resectable N2 disease, the ESMO guidelines recognise that both surgery- and non-surgery-based treatment approaches are reasonable options (Eberhardt 2015).