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Lung cancer — treatment and diagnosis

The latest trends report from the National Cancer Registry Ireland (NCRI) on lung cancer shows that incidence rates have been falling for men (-0.8 per cent per year from 1994 to 2013) but rising for women (+2 per cent per year over the same period), for whom it is projected to increase by 136 per cent by 2040. In both sexes, incidence rates of adenocarcinoma continue to rise.

Lung cancer mortality rates for men have also been declining by about 2 per cent annually since the mid-1980s, but increasing for women at 0.5 per cent annually. This puts Irish women at the top of the European league of lung cancer mortality. Female lung cancer mortality is 34 per cent higher than the EU average and accounts for 18 per cent of all female cancer deaths, probably reflecting smoking prevalence trends.

The overall five-year survival from lung cancer has improved from 10 per cent 15 years ago to 15 per cent in 2013. For those with the earliest stage of disease (non-small cell cancer, stage Ia), five-year survival is highest at 77 per cent. Regrettably, almost 40 per cent of all newly-diagnosed lung cancers are already stage IV. Therefore, early diagnosis remains a key goal.

Improvements in classification

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, in the past decade, 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 allow 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 epidermal growth factor receptor (EGFR) mutation — 10-to-15 per cent 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 inhibitor group of drugs.

To date, three molecular targets have been validated in the treatment of advanced NSCLC: EGFR; anaplastic lymphoma kinase (ALK); and vascular endothelial growth factor (VEGF).

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Figure 1: Overall lung cancer mortality for patients presenting to Beaumont Hospital, Dublin

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 efforts and some promising early results, there are no relevant blood or sputum markers of the disease.

The recent National Lung Cancer Screening Study offered hope by demonstrating that screening patients with low-dose CT can reduce lung cancer-related mortality by 20 per cent 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 would 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 scan annually. The guidelines recommend beginning screening at age 50 years 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 ongoing European screening studies and no national programme is likely to be seen until these are fully reported and the implications assessed.

New 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 recent updates on TNM nomenclature as a result of a global staging project organised 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 four stages of lung cancer, though each can be subdivided into A and B categories:

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 IIIA if ipsilateral lymph nodes involved, and stage IIIB if cancer has spread to contralateral lymph nodes.

Stage IV: When metastases are present.

Advances in imaging

PET scanning is now established as a standard of care in the evaluation of patients with lung cancer. The technique has multiple applications: characterising 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 cannot be reached by bronchoscopy, tissue confirmation is recommended either by CT-guided fine needle aspiration or video-assisted thoracoscopic surgery (VATS) lung biopsy. Electromagnetic navigational bronchoscopy is a new alternative in such situations, which provides a way to extend the utility of bronchoscopy into the small peripheral airways beyond the reach of the standard bronchoscope.

Using the patient’s own CT scan, this method allows the creation of a three-dimensional map, which is linked to the patient’s airways in real time. The operator then navigates to the target using augmented reality feedback. This increases sensitivity of sampling and improves the diagnostic yield, while avoiding the complications of more invasive techniques.

Accurate mediastinal lymph node sampling remains one of the most important factors in diagnosis and staging of lung cancer that affects a 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 than 30 per cent of patients undergoing lung resection.

Endoscopic ultrasound techniques provide a minimally-invasive alternative and have been increasingly popular in lung cancer work-up since their introduction in the 1990s. The convex probe of the miniature curvilinear ultrasound transducer attached to the bronchoscope allows real-time visualisation 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.

Advances in treatment

Surgery can be performed via conventional thoracotomy and open lobectomy, or increasingly via a minimally-invasive thoracoscopic approach (VATS). Robotic thoracic surgery was 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.

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 localised early-stage disease.

Radiofrequency ablation, microwave ablation and cryoablation are the three primary thermal ablative modalities for the treatment of inoperable lung cancer, utilising thermal energy to destroy tumour cells. Each of these techniques involves the use of percutaneous applicators that are placed directly into tumours under imaging guidance.

These techniques, in particular radiofrequency ablation, have been shown to be safe and are associated with promising long-term survival and local tumour progression outcomes in carefully-selected patients. Although efficacy data lags far behind that of stereotactic radiotherapy, they remain novel and innovative treatment options, which may increase the treatment options for patients with lung cancer as evidence accumulates.

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 the 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 that 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 per cent in patients with certain EGFR mutations.

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 extremely 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.

Acknowledgements

Beaumont Hospital, Dublin, is a designated cancer centre for the diagnosis and treatment of lung cancer. We are grateful to the multidisciplinary team who collect and review all activity data prospectively.

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