Lung cancer
Dr Seamus Linnane
Dr Olga Mikulich
Lung cancer is fourth most common cancer diagnosed in Ireland after breast, colorectal and prostate cancers, but kills more patients than all three combined.
Trends in Epidemology:
The trends report from the National Irish Cancer Registry on lung cancer showed in 2015 that incidence rates were falling for men (-0.8% per year 1994 to 2013) but rising for women (+2.0% per year over the same period), in whom it is projected to increase by 136% by 2040. In both sexes, incidence rates of adenocarcinoma continue to rise.
Mortality rates for men have also been declining, by about 2.0% annually since the mid-1980s, but increasing for women at 0.5% annually. This put Irish women at the top of the European league of lung cancer mortality. Female lung cancer mortality is 34% higher than the EU average and accounts for 18% of all female cancer deaths, probably reflecting smoking prevalence trends.
The overall 5-year survival from lung cancer improved from 10% in 2000 to 15% in 2013. For those with earliest stage of disease (non-small cell cancer, stage Ia) 5-years survival is highest at 77%. Regrettably, almost 40% of all newly diagnosed lung cancers are already stage IV. So, early diagnosis remains a key goal.
Classification:
Although lung cancer can be divided into many subtypes, historically the most important distinction was between small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) which is further divided into adenocarcinoma, squamous cell carcinoma and large cell carcinoma. This difference is reflected in major clinical variation of presentation, metastatic spread and response to therapy. However, there has been a major shift toward more precise lung cancer classification based on histological confirmation, in particular for NSCLC patients, as this guides the choice of therapies. Therefore the rate of NSCLC not otherwise specified (NOS) is falling as improvements in immunohistochemical analysis allows for more accurate characterisation and typing.
Gene analysis has also revolutionised the diagnosis and management of a cohort of lung cancer patients. One example is the EGFR mutation. 10% to 15% of Irish patients with adenocarcinoma have this mutation. Patients with adenocarcinoma and specific EGFR mutations have significant increases in response rates and survival when treated with the tyrosine kinase inhibitors group of drugs. To date, three molecular targets have been validated in the treatment of advanced NSCLC: Epidermal Growth Factor Receptor (EGFR), Anaplastic Lymphoma Kinase (ALK) and Vascular Endothelial Growth Factor (VEGF).
Developments in Screening:
The earlier the stage of lung cancer at diagnosis – the longer the survival. The difficulty is that early stages are often clinically silent. Furthermore despite intensive ongoing effors and some promising early results there are no relevant blood or sputum markers of the disease. The National Lung Cancer Screening Study offered hope by demonstrating that screening patients with low-dose computed tomography (CT) can reduce lung cancer-related mortality by 20% compared to screening with routine chest x-ray. The benefits were as a result of earlier cancer detection leading to higher surgical rates and therefore improved survival for patients. However, it was also shown in this study that for every patient diagnosed with lung cancer by CT screening there will be 24 patients with a false positive exam, resulting in more tests, complications from biopsies and significant anxiety. At present CT screening is recommended for high risk patients by the US Preventative Services Task Force. Adults aged between 55 to 75 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years are advised to have a low dose CT chest annually. The guidelines recommend beginning screening at age 50 until they are 15 years free of cigarettes or develop a disease that would otherwise reduce life expectancy. They also recommend lowering the threshold to at least a 20 pack-year smoking history when a patient has one of the following additional risk factors:
Radon exposure (documented sustained and substantially elevated)
Occupational exposure to carcinogens (eg, silica, cadmium, asbestos, arsenic, beryllium, chromium, diesel fumes, nickel, coal smoke, soot)
Cancer history (eg, lymphomas, head and neck cancer)
Family history of lung cancer in first-degree relatives
Disease history (chronic obstructive pulmonary disease [COPD] or pulmonary fibrosis)
Europe continues to struggle with the logistical and health economic impacts of such advice. There are a number of European screening studies but no national program is likely to be seen until the implications assessed.
Staging Systems:
The prognosis of lung cancer is directly related to the stage at presentation. Staging is based on the TNM system, where T stands for tumour size, N – for nodal involvement and M – for presence of metastases. There have been regular updates on TNM nomenclature as a result of a global staging project organized through the International Association for the Study of Lung Cancer (IASLC), with a major focus on tumour size, as even small differences in tumour size are known to affect survival and recurrence after surgical tumour resection.
The TNM descriptors are clustered into stages for ease of discussion. There are 4 stages of lung cancer though each can be subdivided into subcategories:
Stage I: The cancer is located only in the lungs and has not spread to any lymph nodes.
Stage II: The cancer is in the lung and nearby lymph nodes.
Stage III: Cancer is found in the lung and in the mediastinal lymph nodes, also described as locally advanced disease.
Stage IV: When metastases are present.
Imaging:
Positron emission tomography (PET) scaning is now established as a standard of care in the evaluation of patients with lung cancer. The technique has multiple applications; characterizing lung nodules, staging the mediastinum, identifying occult distant metastases, determining prognosis and treatment response, guiding targets for radiation therapy, restaging during and after treatment, and selecting targets for tissue sampling.
Advances in Biopsy Techniques:
For patients with a solitary lung lesion which can not be reached by bronchoscopy, tissue confirmation is recommended either by CT guided fine needle aspiration or Video-Assisted Thoracoscopic Surgery (VATS) lung biopsy.
Accurate mediastinal lymph nodes sampling remains one of the most important factors in diagnosis and staging of lung cancer that affects patient’s outcome as it determines the most suitable treatment plan and prognosis. Mediastinoscopy is still the gold standard for mediastinal lymph node staging. However, it requires general anaesthesia and is used in fewer patients undergoing lung resection. Endoscopic ultrasound techniques provide a minimally invasive alternative to that and have been increasingly popular in lung cancer work up since their introduction in 1990s. The convex probe of the miniature curvilinear ultrasound transducer attached to the bronchoscope allows real-time vizualisation of needle aspiration. Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) and transoesophageal endoscopic ultrasound guided fine needle aspiration (EUS-FNA) can both be performed in outpatient settings without need for general sedation.
Treatment:
Surgery can be performed via conventional thoracotomy and open lobectomy, or increasingly via a minimally invasive thoracoscopic approach (VATS). Robotic Thoracic Surgery has been introduced in practice in 2011, and when combined with a minimally invasive VATS approach was shown to result in less blood loss, less air leaks and faster post-operative recovery with shorter ICU and hospital stay, especially in patients older than 75 years of age.
Although surgical resection remains the treatment of choice for early stage non-small cell lung cancer, a significant subset of patients are considered medically ineligible for surgery due to poor cardiopulmonary reserve, or other medical comorbidities. Stereotactic radiotherapy has emerged as an effective treatment alternative for these patients with localized early-stage disease.
For the past 30 years, chemotherapy has been the mainstay of treatment for advanced and recurrent lung cancer patients who do not directly access palliative care services. However, regardless of drug combination used, tumours eventually develop resistance to these agents and the duration of remission from each subsequent line of therapy is often shorter than the preceding one. As alluded to above identifying specific genetic mutations can help in the selection of specific agents which will be targeted against specific biologic processes unique to the lung cancer cell. For example tyrosine kinase inhibitors can increase response rates and survival by over 50% in patients with certain EGFR mutations. Immunotherapy is well established in appropriate cases to harness the power of the innate immune system to limit growth and spread of lung cancer cells.
Such a targeted or personalised approach to the management of lung cancer can change prognosis dramatically and is likely to be an increasing aspect of practice in the future.
Conclusion:
The overall prognosis for patients with lung cancer is historically poor. However, the last 15 years has seen a substantial number of advances in the diagnosis and treatment of lung cancer with the main focus being early detection and a tailored approach to treatment.