Lung cancer continues to be the leading contributor to cancer-related mortality worldwide.1 In Australia lung cancer is the fourth most commonly diagnosed cancer, but the leading cause of cancer death, with non-small cell lung cancer (NSCLC) making up the vast majority of cases.2 Despite public health policies and tobacco control legislation, smoking continues to be the main risk factor in Australia and worldwide.2 While the incidence rate for lung cancer in men has been decreasing, there has been an increase in the incidence rate in women, paralleling smoking trends.2 In Australia, the absolute number of lung cancer cases will continue to increase as the population ages.3 Lung cancer in never smokers is also a significant health problem, accounting for greater than 12 per cent of lung cancer deaths.4 Unfortunately, the large proportion of patients with lung cancer present late with advanced/metastatic disease, resulting in the high observed mortality rate that has improved only slightly over the last two decades (from 1982-1987 to 2000-2007 five-year relative survival increased from 8% to 11% for males and 10% to 15% for females).2 Malignant pleural mesothelioma, the asbestos related malignancy of the pleura, also continues to be a problem in Australia with its high per capita incidence.5 Despite the nationwide ban on importing and using all forms of asbestos from 31 December 2003, mesothelioma incidence continues to rise, with 612 new cases reported in Australia in 2011.6
This edition of Cancer Forum coincides with the 15th World Conference of Lung Cancer and is focused on lung cancer and mesothelioma management. It highlights current practice and recent developments in lung cancer screening, drug therapy, surgery, radiotherapy and ongoing developments in the molecular pathology of NSCLC.
The last five years has seen a paradigm shift in the treatment of metastatic NSCLC, led by improvements in the understanding of the molecular biology of this disease. Historically, all patients with NSCLC were treated empirically with chemotherapy. Recent practice changing advances include the recognition of greater efficacy with certain chemotherapy regimens according to histologic sub-type. Different subtypes benefit from maintenance therapies in non-progressing patients after first-line chemotherapy and the identification of molecular subgroups of adenocarcinoma that benefit from specific targeted therapies. These advances have seen the practical application of histologic sub-classification of NSCLC into two groups, squamous cell carcinoma and adenocarcinoma, where further molecular phenotyping to identify underlying ‘driving’ mutations has led to the use of specific targeted therapy, leading to more substantial clinical benefit than historically observed with empirical chemotherapy. These advances have recognised that lung cancer cannot be considered one disease and that where possible, effort should be made to tailor drug therapy in order to maximise therapeutic benefit for individual patients. The collective evidence for the management of lung cancer was recently reviewed by Cancer Council Australia to produce its new Clinical Practice Guidelines for the management of lung cancer (http://wiki.cancer.org.au/australia/Guidelines:Lung_cancer). A novel approach used in the preparation of these guidelines was the use of a wiki platform, making it much easier to update the guidelines as new high-level evidence emerges for future change of practice.
While the majority of lung cancer patients present with largely incurable locally advanced or metastatic disease, those patients fortunate enough to have early disease at diagnosis can receive potentially curative treatment. Marshall and Fong review the development of lung cancer screening to date, extending from the historical failures of chest radiography screening through to the more promising approach of low dose computed screening as evaluated in the landmark National Lung Cancer Screening Trial.7 The potential benefits in terms of detection of early stage disease, the potential for harm through false positives and adverse effects, and the cost-effectiveness of screening are reviewed together with the challenges of implementing screening programs.
Vrtik and Alam provide an overview of the role of surgery in the various stages of NSCLC.8 The mediastinum remains an important area to accurately stage pre-operatively. Approaches to accurately stage the mediastinum are reviewed, including mediastinoscopy and endobronchial ultrasound guided trans-bronchial needle aspiration, with the increasing availability and accuracy of endobronchial ultrasound greatly reducing the need for mediastinoscopy. In operable patients, surgery remains the treatment of choice for patients with Stage I, II and IIIA (T3N0, 1, T4 N0, 1) disease,9 alone or as part of a multimodality treatment regimen. Complete surgical resection can be achieved by either lobectomy or pneumonectomy, whereas in high-risk surgical patients (those with significant medical co-morbidities or poor pre-existing lung function), lesser surgery can be performed. The greatest recent advance in surgery for lung cancer – video-assisted thoracoscopic surgery (VATS) – is reviewed, revealing how VATS lobectomy is increasingly considered the procedure of choice for patients with early stage lung cancer.
The important role of radiation therapy in the multidisciplinary management of lung cancer is discussed by Vinod and Ball.10 Its importance as a potentially curative treatment modality in patients with inoperable early stage or locally advanced NSCLC, or in limited stage small cell lung cancer, and in palliating symptoms in patients with advanced disease, is reviewed. Recent technological advances that assist patient selection, improve identification of the tumour, individualise radiotherapy treatment according to patient specific motion and reduce normal tissue toxicities are highlighted, including the use of stereotactic ablative radiotherapy. While many of these changes have already been incorporated into clinical practice, Vinod and Ball also describe clinical trials evaluating these approaches.
Cooper and O’Toole discuss the recent advances in the molecular pathology of lung cancer, highlighting the key actionable somatic changes seen in lung cancer, with particular emphasis on EGFR mutations and ALK gene rearrangements in adenocarcinoma, as well as identifying promising new targets in squamous cell carcinoma of the lung.11 Swaying the interest in this key ongoing area of research has been the identification that tumours harbouring driver mutations are ‘addicted’ to the effects of these molecular changes in an oncogene, making them key targets for inhibition, with large clinical benefits observed with targeted drugs. The first major discovery leading to practice change was in the identification of activating mutations in the gene for the epidermal growth factor receptor (EGFR or HER1). These activating mutations in the EGFR gene are found in approximately 10-15% of NSCLC patients, while in Asian populations, the frequency is higher (30-40%), especially in young women who have never smoked.10 Adenocarcinomas harbouring activating EGFR mutations were shown in 2004 to be very sensitive to targeted EGFR-tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib.12
Cooper and O‘Toole also review the available molecular genetic techniques used to identify EGFR (and other mutations) in lung cancer, highlighting their strengths and weakness, demonstrating how today, both tissue based biopsies and cytology specimens are adequate for mutation analysis. KRAS mutations are also discussed as a poor prognostic marker, occurring in nearly 40% of adenocarcinomas and predicting for insensitivity to EGFR-TKIs. More recently identified key molecular changes in adenocarcinomas include ALK gene rearrangements, occurring in up to four per cent of cases. The molecular features of these are discussed, including the techniques used to identify them, such as fluorescence in situ hybridisation and the potential value of immunohistochemistry to identify ALK over-expression in lung adenocarcinomas. Other rare, but potentially targetable mutations in lung adenocarcinomas, include MET gene amplifications, BRAF mutations and ROS1 gene rearrangements. Promising new targetable oncogenes in squamous cell carcinoma are also highlighted.
The clinical results of the use of EGFR targeted therapies in patients with metastatic NSCLC with EGFR mutations and those with wild-type EGFR are discussed by Hasovits and Pavlakis.13 The first clinical trials with EGFR-TKIs such as gefitinib and erlotinib, were designed to follow the traditional paradigm of empirical chemotherapy of ‘one size its fall’. Disappointingly, the trials investigating the addition of erlotinib or gefitinib in unselected patients receiving standard chemotherapy failed to show a benefit, while trials investigating monotherapy with the EGFR-TKIs showed only modest response rates, with only erlotinib statistically proven to prolong survival compared with placebo in the 2nd/3rd line setting.14 In a pivotal Asian study of selected patients (never smokers) with adenocarcinoma, substantial clinical benefit was observed using gefitinib in patients with sensitising EGFR mutations, resulting in significantly prolonged progression free survival and much higher response rates compared with chemotherapy.15 Six studies have now confirmed similar benefits in response rates and progression free survival with first-generation EGFR-TKIs (gefitinib or erlotinib) in patients with sensitising EGFR mutations, compared with chemotherapy. This has resulted in a practice shift in patients with known sensitising EGFR mutations. Newer EGFR-TKIs have also been developed, with afatinib also showing superiority to first line chemotherapy in patients with EGFR mutations.
Despite the marked improvements in progression free survival with EGFR-TKIs in the first line setting compared with chemotherapy (increases in median progression free survival by 1.7-8.5 months),13 tumour progression eventually develops due to drug resistance. The different clinical scenarios at progression, the proposed mechanisms for resistance and related treatments are discussed.
Cruikshank and Hughes review recent advances in identifying molecular targets beyond the EGFR.16 Rapid progress in this area is exemplified by the identification of ALK gene rearrangements in a subset of NSCLC in 2007 and the subsequent phase I, II, and III clinical trials with the ALK inhibitor crizotinib, leading to approval by the US Food and Drug Administration in 2010 and subsequently by regulatory authorities in over 50 countries worldwide. ALK gene rearrangements now represent the second validated actionable genetic alteration in lung cancer after EGFR mutations. Progress in this area continues with characterisation of mechanisms of resistance to crizotinib and with clinical trials of novel, more potent ALK inhibitors, such as LDK378 and CH5424802. Numerous other targets have been identified in both adenocarcinoma (eg. ROS1, MET and B-Raf ) and in squamous cell carcinoma (eg. FGFR1, PI3Kinase and DDR2) which are currently being evaluated in clinical trials.
Small cell lung cancer accounts for about 11% of lung cancers in Australia. In contrast to the dramatic progress in non-small cell lung cancer, there have been few advances in small cell lung cancer over the last two decades. Ferraro and Millward provide a concise overview regarding the current state of the art with respect to staging and management of small cell lung cancer, including recent advances such as the use of prophylactic cranial irradiation in patients with advanced disease.17 They detail attempts to target molecular abnormalities identified in small cell lung cancer, which to date have been largely unsuccessful, indicating the need for further basic and translational research into this aggressive and highly lethal variant of lung cancer.
Honeyball, Boyer and colleagues review the current treatment strategies for malignant pleural mesothelioma, with discussion of novel systemic therapies.18 Unfortunately, the pleural origin of this tumour and its insidious onset leading to presentation with advanced disease, means that traditional paradigms of curative tumour resection and additional therapies are restricted to highly selected patients in specialist centres, with uncertainty over benefit due to lack of randomised evidence. Thus the mainstay of treatment is supportive, including palliative surgery for recurrent effusions, radiotherapy and palliative care with chemotherapy, with platinum and pemetrexed used in fit patients to prolong survival and improve quality of life since 2003. Despite efforts over the last decade, targeted therapy for patients with MPM has proven to be elusive. Trials of maintenance therapy with thalidomide and second line therapy with vorinostat, a histone deacetylase inhibitor, have also been unsuccessful. New directions carrying hope for positive outcomes are discussed, such as the mammalian target of rapamycin (mTOR) inhibitors, and focal adhesion kinase (FAK) inhibitors.
As in most other cancers, the greatest therapeutic progress in advanced or metastatic lung cancer has come from the greater understanding of the molecular pathogenesis of the disease and the identification of targeted therapies, resulting in much greater clinical benefit than historical empirical chemotherapy. In NSCLC, cure is achievable through early detection and surgery (or radiotherapy), with or without additional therapy. For the majority of patients with relapse or metastatic disease, the way forward is by identifying their cancer’s molecular signature, hoping to find one predictive for greater benefit from targeted therapies. And yet, drug resistance to such targeted therapies, as it was for chemotherapy, will result in treatment failure, requiring ongoing work to unravel the biology of this disease. In mesothelioma and small cell lung cancer, the search continues for the elusive molecular signatures that may leap frog outcomes achieved using our current standard chemotherapy approaches. In all the diseases discussed here, it is clear that overall progress will depend on a co-operative multi-disciplinary effort.