Lung Cancer

Lung cancer CT screening has the potential to save many lives if implemented in Europe. The National Lung Screening Trial (NLST) found a 20% reduction in lung cancer mortality following three annual CT screenings, with a cost per quality-adjusted life year of US$81 000 in the USA. The European trials have provided evidence for: 1) the use of a risk prediction model to select high-risk individuals; 2) the use of volumetric analysis and volume doubling time to determine the care pathway for CT-detected nodules; 3) the potential for undertaking biennial screening after 2 years of scans with no evidence of disease; 4) the importance of integrated smoking cessation, which uses the CT screen as a way to augment quit rates. The NELSON (Dutch–Belgian Randomised Lung Cancer Screening Trial) and the pooled European trial data will be available in 2016, so it is imperative we start planning for the implementation of lung cancer screening now.

Epidemiological and case–control studies have shown that COPD is an independent risk factor for lung cancer. The presence of airway obstruction and/or emphysema increases the risk of having lung cancer by two to three fold. Recent research has highlighted several potential common pathways that may explain this deadly association. These include chronic retention of airborne carcinogens, the presence of chronic inflammation, and common genetic and epigenetic risk factors.

Smoking prevention and smoking cessation are the most important measures for primary prevention of both COPD and lung cancer. Recent data suggest that lung cancer screening in patients with COPD, especially those with mild-to-moderate disease, could potentially decrease lung cancer mortality, one of the most common causes of death.

The association between COPD and lung cancer means that the clinical management of these patients requires a multidisciplinary team that includes a respiratory medicine physician. The pulmonologist's role ranges from determining preoperative risk to handling the consequences of oncologic treatments, such as COPD exacerbations.

Contemporary management of patients with lung cancer requires a comprehensive diagnosis embracing anatomical, morphological and molecular features of the tumours. Accurate, consistent histological diagnosis also provides invaluable epidemiological information and contributes to our understanding of the pathogenesis of the disease. The World Health Organization (WHO) histological classification is fundamental, combined with TNM staging, to proper diagnosis of surgically resected cases and has recently been revised. Most patients, however, have only small biopsy or cytology specimens for diagnosis, where the WHO classification cannot be applied in full, and where IHC has become a key factor in refining the likely diagnosis. The increasing diversity of treatments offered to patients with all types of lung cancer and the recognition of therapeutically important biological differences between tumour subtypes has placed accurate pathological diagnosis in the spotlight. Subtyping of NSCLC and appropriate pathological assessment are required to follow current guidelines for the triage of cases for molecular pathology testing.

The discovery of druggable molecular targets in NSCLC has led to a shift from the former “one size fits all” chemotherapy approach to treatment selection based on tumour biology. Recent work has demonstrated that most known driving mutations are homogeneously distributed in NSCLCs, allowing meaningful molecular analysis and therapy based on small tissue samples. Although currently, a mix of methods is necessary to analyse NSCLCs, NGS techniques will allow the simultaneous analysis of most relevant mutations and translocations in NSCLCs in the near future. At the moment, approved drugs are available for patients with tumours revealing EGFR mutations and ALK translocations, although there are ongoing clinical trials for many more targets and patients showing secondary resistance mechanisms. Thus, comprehensive profiling of all NSCLCs before and during treatment will become the standard of care for NSCLC patients.

Lobectomy with lymphadenectomy is the standard of care for patients with early stage NSCLC and the use of minimally invasive approaches are associated with reduced morbidity when compared with thoracotomy. Segmentectomy with lymphadenectomy seems to provide a curative effect equivalent to that of lobectomy for stage IA tumours of ≤2 cm and for pure or predominant ground glass opacities. The combination of lung sparing resections with minimally invasive approaches results in preserved pulmonary function, improved quality of life and very low morbidity. This benefit persists in so-called high-risk patients. Among patients with clinical stage IA managed with sublobar resections, more than 25% are proved to have a more advanced pathologic stage at surgery, suggesting that alternative ablative therapies would result in an incomplete resection in a similar proportion. Moreover, resection samples tumour tissue that is adequate in quantity and quality, and provides material for “research biopsies” to consolidate tissue availability for clinical trials, translational research, and in biobanks.

In the absence of distant metastasis, accurate mediastinal nodal staging is the most important prognostic factor for lung cancer. Contrast enhanced CT is an imperfect means of staging the mediastinum, but it provides information on lymph node size and anatomical borders of the nodal stations. An integrated PET-CT, guides clinicians in the next step, i.e. either tissue verification of mediastinal nodes or direct to surgery.

Linear endosonography has become the preferred invasive procedure to perform mediastinal nodal staging of lung cancer. A combined EBUS and oesophageal EUS approach enables systematic mediastinal nodal sampling of at least nodal stations 4R, 4L and 7.

A low threshold for considering a confirmatory video-assisted mediastinoscopy (VAM) should be maintained after a negative combined endosonography. The role of VAM has been redefined: it lowers the post-test probability after a negative endosonography to approximately 5%, and allows bimanual nodal dissection of stations 2L and 4L, which are rarely dissected at the time of lung resection.

The backbone of treatment for locally advanced NSCLC should be chemotherapy in all suitable patients.

In fit patients with resectable disease, concurrent chemotherapy and radiotherapy, intensive chemotherapy followed by resection, chemotherapy followed by intensive (i.e. accelerated) radiotherapy or concurrent chemoradiotherapy followed by resection are all viable options with none proven to be superior over the other. Across all trials, tri-modality therapy was shown to be the best way to achieve local tumour control; however, no randomised trial has been large enough to show a possible overall survival benefit. Bi-modality therapy thus remains the standard, except in situations where local tumour control is a prerequisite, e.g. in exemplary cases with Pancoast tumours.

In nonresectable locally advanced NSCLC, concurrent chemoradiotherapy is the standard of care with doses of 60–66 Gy in 2 Gy fractions. In patients who are unsuitable for concurrent schedules, induction chemotherapy followed by accelerated radiotherapy is an alternative treatment with curative intent.

Lung cancer incidence increases with age, with a median age at diagnosis between 63 and 72 years depending on the country and the diagnostic procedures performed.

The treatment of elderly patients, and especially systemic treatment, is of utmost importance. However, treating elderly patients has some caveats: geriatric syndromes, comorbidities and polypharmacy interfering with the metabolism of the drugs are frequent; and renal function may necessitate an adaptation of the doses. Finally, haematopoietic reserves are often reduced, needing more extensive use of granulocyte colony stimulating factors. Thus, there has been quite a long period of therapeutic nihilism regarding these patients, but studies dedicated to elderly patients have increased in number in the last 15 years, allowing for the development of recommendations regarding some clinical situations. For example, whereas there are no specific recommendations for peri-operative chemotherapy or locally advanced NSCLC, they do exist for metastatic-stage NSCLC and for first-line systemic treatment of SCLC.

The success of cancer genomics research in transforming the clinical care of patients with advanced ADC of the lung has been a powerful incentive to identify molecular abnormalities in SCLC that can be treated with targeted agents. A considerable number of drugs have already been tried in SCLC clinical trials without notable success. Efforts to identify molecular targets for SCLC have been impeded by a paucity of adequate tissue for translational research in a disease in which resections are uncommon. Molecular abnormalities are extremely complex in this tobacco hyper-mutated tumour. Additionally, the circumstances for clinical research are difficult where patients with recurrent disease are frequently in rapid decline during the window of opportunity for biopsies, genomic studies, identification of a suitable target, and administration of novel agents. Despite these challenges, interesting work is moving forward with newly identified molecular targets emerging from comprehensive genomic profiling efforts. There is also the intriguing possibility that a high antigenic load from many mutations may be an asset for immunotherapy studies.