Lung cancer is a major global health issue and will remain so for decades to come. Lung cancer screening has the potential to reduce mortality from this disease and represents one of the most exciting developments in recent years. Screening appears to have taken hold in the US, yet has received a more cautious reception in other countries, probably due to a lack of accurate cost-effectiveness data and implementation capacity uncertainties. Refinement of screening using risk prediction to select the highest risk candidates is the next challenge and, coupled with an integrated smoking cessation program, could substantially improve cost-effectiveness. Future research will determine if biomarkers in biological samples will offer a low cost and minimally invasive method of screening and early detection. In this paper we review the development of lung cancer screening to date, the current state of the art and future directions for research.
Lung cancer remains the leading cause of cancer related deaths in Australia and worldwide. Despite recent advances in screening, diagnosis and treatment, long-term overall survival of lung cancer remains poor. Surgery, either alone or as part of a multimodality treatment regimen, plays an important role in the management of patients with non-small cell lung cancer. Complete surgical resection of early stage disease can be achieved by either lobectomy or pneumonectomy. Probably the greatest recent change in surgery for lung cancer is video assisted thoracic surgery. Controversy remains around the treatment of non-small cell lung cancer with mediastinal lymph node involvement (Stage IIIA – T1-3 N2). The potential role of surgery in the palliation of lung cancer patients is also addressed.
Radiotherapy is an important modality in the treatment of lung cancer. In Australia, up to 76% of patients have an indication for radiotherapy at diagnosis. This includes curative radiotherapy for patients with inoperable stage I and II non-small cell lung cancer, and in combination with chemotherapy, for patients with stage III non-small cell lung cancer and limited stage small cell lung cancer. There are challenges in delivering curative radiotherapy to this group of patients, many of whom have smoking-related comorbidities. However, newer technologies allow selection of appropriate patients for treatment, improve identification of the tumour, individualise radiotherapy treatment according to patient specific motion and reduce normal tissue toxicities. Image guided radiotherapy is increasingly becoming the standard of care, whereby the tumour position is confirmed on cone-beam CT performed on the linear accelerator prior to treatment. Intensity modulated radiotherapy is improving dose conformality and avoidance of normal tissue structures. Stereotactic ablative radiotherapy is currently being evaluated as a treatment option for patients with inoperable stage I non-small cell lung cancer. Radiotherapy is also an important palliative treatment for lung cancer, with well-established indications for palliation of thoracic symptoms such as airway obstruction, chest pain, cough and haemoptysis. Bone and brain metastases are common in lung cancer and radiotherapy remains the prime modality for alleviating symptoms from these. Multidisciplinary discussion of lung cancer patients is essential to ensure that appropriate patients receive the evidence-based benefits of radiotherapy.
Increasing understanding of genomic changes in cancer is transforming the diagnosis and treatment of a subset of lung cancers. A significant proportion of lung adenocarcinomas harbour biologically relevant or targetable somatic genetic changes such as mutations, amplifications or translocations in a range of genes, including KRAS, EGFR, ALK, ROS1, MET and BRAF. This review highlights the key actionable somatic changes seen in lung cancer, with particular emphasis on epidermal growth factor receptor mutations and ALK gene rearrangements in adenocarcinoma, as well as identifying promising new targets in squamous cell carcinoma of the lung. Accurate and sensitive molecular testing is essential to ensure patients with this poor prognosis disease receive the correct therapy, but mutation testing in lung cancer poses particular challenges. As the majority of patients with lung cancer present with advanced disease that is unsuitable for resection, many biopsies submitted for molecular testing are small biopsies such as core biopsies and fine needle aspirate biopsies, often with only a very small amount of diagnostic material available for mutation analysis. This paper highlights the need for good communication between clinicians, radiologists and pathologists to ensure optimal samples for molecular testing and the benefits of testing for multiple genes in one assay.
The management of non-small cell lung cancer is undergoing a paradigm shift from empirically-selected treatment to personalised therapy, based on the clinical characteristics of patients and the histological and molecular features of their tumours. This has been driven by the identification of oncogenic ‘drivers’ responsible for cancer cell growth and survival, and the development of specific therapy targeting these. The pivotal discovery was the identification of mutations in the epidermal growth factor receptor and recognition of their exquisite sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors. Defining this molecular cohort and instituting targeted therapy has led to significantly improved clinical outcomes over empirical chemotherapy. However, the development of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors therapy appears universal, and strategies to delay or overcome the emergence of this resistance remain to be defined.
Identification and inhibition of molecular pathways that drive malignant cells have led to improved outcomes in the understanding and management of non-small cell lung cancer. This has been illustrated by the effective use of the EGFR-tyrosine kinase inhibitors erlotinib, gefitinib and afatinib, which have been major steps forward in targeted therapy for advanced and metastatic lung cancer in patients who harbour specific epithelial growth factor receptor mutations. This success continues to drive ongoing research in identifying other novel molecular pathways in malignant cells that may be exploited for targeted therapy. Some of the other current advances in identifying targetable genetic mutations and the development of therapies that may have a potential clinical impact on the management of both adenocarcinoma and squamous cell lung cancer are reviewed.
Small cell lung cancer remains a highly lethal form of cancer, with few advances made in treatment over the last two decades. The use of platinum-containing doublet chemotherapy, and concurrent chemotherapy and thoracic irradiation in limited stage disease, remains the standard of care. To date, a number of trials have been conducted to assess the impact of newer chemotherapy agents, either for single agent activity or combined with standard chemotherapy, but with limited success. Many of the recent benefits seen in other forms of cancer (including non-small cell lung cancer) arise from the identification and targeting of specific molecular abnormalities that promote cancer growth and spread. However, although a range of targeted therapies have also been trialled in small cell lung cancer, and despite promising in-vitro data, these have not as yet produced major breakthroughs in clinical management. Further elucidation of the molecular mechanisms in small cell lung cancer and therapies directed at these abnormalities holds the key to improving outcomes in this condition, but requires significant ongoing work.
Malignant pleural mesothelioma is a relatively uncommon disease associated with asbestos exposure. Its incidence increased markedly following the widespread mining and use of asbestos in many industries. The legal aspects regarding compensation cases for those who have developed this disease has raised its profile in the media, but also compounds the stress of diagnosis for patients. It has an insidious onset and may clinically and pathologically mimic other benign or malignant processes, complicating diagnosis. Radical surgery may be used for a highly selected population of malignant pleural mesothelioma patients in the context of multimodality treatment in an experienced thoracic surgical centre, but there is no randomised evidence to support its benefit. In most cases surgery is used to treat symptoms or obtain tissue for diagnosis. Combination of a platinum agent and pemetrexed is now widely used and shown to prolong life. Other treatments including radiotherapy, analgesics and supportive interventions are an integral part of the treatment of this disease. Further research is being undertaken on promising novel therapies for use in this disease, which will be discussed in this review.