Thoracic Malignancies (out of print)

Lung cancer is the leading cause of cancer mortality for males and females, and has grown into a worldwide problem over the last 50 yrs.

Cigarette smoking elicits >80% of all lung cancers. Although the prevalence of smoking is declining, the risk of lung cancer after smoking cessation persists and remains elevated in comparison to never-smokers.

Despite a rapid increase in insight into carcinogenesis, the accurate identification of high-risk groups has remained difficult; attempts to decrease lung cancer risk by preventive measures other than smoking cessation have so far been unsuccessful.

However, strategies to slow, halt or even reverse the carcinogenic process continue to gain great interest. It is very likely that further identification of the different molecular steps of carcinogenesis will finally translate into effective preventive strategies.

Bronchial dysplasia, atypical adenomatous hyperplasia and diffuse idiopathic pulmonary neuroendocrine hyperplasia are putative pre-invasive lesions for squamous cell carcinoma, adenocarcinoma and carcinoid tumours of the lung, respectively.

Recent improvements in our ability to detect and sample these lesions along with detailed histological classification schemes have led to numerous advances in our understanding of their natural history. Importantly, many molecular and genetic alterations can now be associated with the development of these lesions and, in some instances, are being related to their progression. These findings are leading to the description of biomarkers that will have applications in the early detection of pre-invasive lung lesions and can be used as indicators of their malignant potential.

In addition, new techniques and therapies are being developed for the prevention of lung cancer. The evaluation of these potential therapeutic strategies are being tested in increasingly relevant pre-clinical models of pre-invasive disease, and the findings from these studies are being used to efficiently evaluate potential preventive therapies in ongoing clinical trials.

In the present chapter, we present new findings related to the detection, molecular characterisation and evaluation of diagnostic and therapeutic intervention for pre-invasive lesions of the lung.

Lung cancer presents late in its natural history and its symptoms and signs are often nonspecific. Spread of the disease within the chest may result in pleural effusion and mediastinal involvement. Extrathoracic metastases commonly occur to bone, brain and liver. Distant effects of lung cancer, termed paraneoplastic syndromes, produce a varied constellation of symptoms and signs with musculoskeletal, endocrine and neurological abnormalities predominating. Paraneoplastic syndromes do not imply metastatic spread and may manifest prior to the discovery of the underlying tumour.

Lung cancer is the most common cancer worldwide, and remains the leading cause of death from cancer in the UK. Despite its prevalence, screening is not currently recommended, although large scale trials using computed tomography (CT) are ongoing.

Chest radiographs remain the first line of imaging investigation usually. With the advent of multislice CT scans, image acquisition times and resolution have improved. Nodule detection has been ameliorated and high quality coronal and sagittal reformats can now be constructed. Positron emission tomography (PET) scanning has revolutionised staging and has a negative predictive value for N3 disease, which is equal to that of gold standard mediastinoscopy. In the UK, the National Institute of Clinical Excellence (London, UK) has recommended that when a PET scan is negative for N2/3 disease, then biopsy is not required even if the nodes are enlarged by CT criteria. Dual modality PET-CT images are increasingly performed, which overcome the poor spatial resolution of using PET alone. Magnetic resonance imaging is still recommended for the assessment of superior sulcus tumours, and research into its value for nodal staging is ongoing at present.

Lung cancer is divided into small cell lung cancer and nonsmall cell lung cancer (NSCLC). The imaging characteristics of the different tumours vary. At present the tumour, node, metastasis staging system only applies to NSCLC.

In addition to characterising and staging lung cancer, imaging is used to guide the best site for tissue sampling. This may involve computed tomography guided percutaneous transthoracic biopsies or ultrasound guided percutaneous nodal sampling. A co-axial system is increasingly used to perform radiologically guided biopsies.

The stage of lung cancer has a key role in the management of the patient. The system classifying lung cancer based on the status of primary tumour (T), regional lymph nodes (N) and metastatic involvement (M) was originally proposed in 1946, and has been the subject of many modifications to improve its prognostic and operational roles.

In the present chapter, the 1997 classification is described, as well as the various problems reported in the literature concerning its application.

In order to improve the staging system, an international initiative, International Association for the Study of Lung Cancer staging project, was undertaken to make a huge databases and to propose a revision of the 1997 system. The proposal, which will be used as official staging classification in 2009, is presented and discussed, as well as the role of stage in prognosis. Indeed, stage is so far the main prognostic factor in lung cancer.

In the future, proposals for further TNM revisions should be based on a prospective international multicentric databases where the details of the T, N and M descriptors should be available.

Surgery remains the best option for cure in nonsmall cell lung cancer (NSCLC) and for the occasional small cell tumour. About 10–15% of NSCLC cases go to pulmonary resection, although the resection rate varies across different countries and within countries. Staging is paramount with regard to case selection for resection, and the introduction of positron emission tomography scanning and endoscopic mediastinal lymph node sampling will further refine this. The new International Association for the Study of Lung Cancer staging classification, based on a very large number of cases, has further defined prognosis by stage, and will influence selection of patients for surgery. The mortality of resection is falling and in large centres is now about 1% for lobectomy and 3–4% for pneumonectomy. Sublobar resections are becoming increasingly common as more patients are found to have stage I disease following computed tomography screening or more intensive investigation for chronic obstructive pulmonary disease. Segmentectomy appears as successful as lobectomy of patients below 71 yrs of age, with better preservation of lung function. However the non-anatomic wedge resection carries a worse long-term survival than both segmentectomy and lobectomy. Following careful case selection, older patients fare no worse than their younger counterparts. While patients presenting with stage I and II disease are suitable for curative surgery, stage IIA remains a complex constellation of presentations. Those with N1 disease can do relatively well, but for presentations such as superior sulcus tumours and chest wall tumours, if there is nodal involvement and the stage is worse than T3N0, the prognosis is much worse. The evidence for surgery after chemoradiation induction for locally advanced stage IIIA or IIIB has not yet been made, and chemoradiotherapy alone may be the treatment of choice. Trial results are awaited. In addition to age (half of lung cancer patients present aged ≥70 yrs), comorbidity remains a major reason for inoperability. For small cell lung cancer, there are only small series of patients who have undergone resection. Each case should be reviewed on its merits and if at a truly early stage after the best possible staging, resection must be considered.

Lung cancer is the leading cause of cancer death in the western world. Surgical resection remains the treatment of choice for operable nonsmall cell lung cancer (NSCLC). Even after complete resection, systemic relapse is common and hence there is a role for adjuvant and neoadjuvant treatment.

Adjuvant chemotherapy is feasible and improves overall survival in completely resected NSCLC, with cisplatin chemotherapy offering survival advantage of 5% at 5 yrs. Use of alkylating agents is not recommended as they are detrimental to survival. There is a small increase in noncancer-related death with cisplatin chemotherapy; hence, only patients at high risk of systemic relapse should be offered adjuvant treatment. At present, adjuvant chemotherapy is not recommended for stage IA patients and its benefits in stage IB patients are debatable. Adjuvant uracil-tegafur has no confirmatory trials in the western population and, thus, it is not recommended outside the context of a clinical trial. There has been an ongoing debate about neoadjuvant versus adjuvant chemotherapy. Neoadjuvant chemotherapy is feasible, with no increase in post-operative complications. It has so far failed to show improvement in overall survival and it is likely that the standard of care is towards adjuvant chemotherapy.

In the adjuvant setting, where the aim is cure, cisplatin-based regimes are preferred over carboplatin-based regimes. One of the main toxicities of cisplatin is nausea and vomiting but, with the use of new anti-emetics, this may be less of an issue. There should be no scepticism about chemotherapy in elderly patients. Patients under the age of 70 yrs with a good performance status benefit from adjuvant chemotherapy, but there is paucity of data for those over 70.

New knowledge of mechanisms of oncogenesis has allowed us to identify new molecular targets for cancer treatment. So far, no molecular targets have been shown conclusively to have a significant relationship with clinical outcome, particularly survival in NSCLC. Newer targeted agents, including including epidermal growth factor receptor and vascular endothelial growth factor inhibitors, are still under evaluation in phase III clinical trials.

There is no dispute that chemotherapy is the standard treatment for advanced stage (IIIB (wet) and IV) nonsmall cell lung cancer.

The best chemotherapy regimen for patients with performance status (PS) 0–1, no renal or cardiac insufficiency is a platin-based doublet. The drug combined with platin salt maybe any of the new generation drugs (vinorelbine, taxotere, taxol, gemcitabine, pemetrexed) with similar results regarding survival benefit, the differences being essentially the toxicity profiles. Carboplatin, which is less toxic than cisplatin, may be used instead of cisplatin, with a slightly less efficacy (probably not clinically important). Tailored treatment approach is a new concept with adaptation of platin-based doublets to the histology of the tumour (gemcitabine is no more recommended for adenocarcinoma and pemetrexed is not recommended for squamous cell carcinoma). Also gene expression (ERCC1, RRM1, β-tubulin class III, etc.) might become of primary importance for customised chemotherapy.

The recommended number of cycles is four to six for stable or responding patients. At the current time there is no indication in favour of any maintenance therapy.

For patients with PS 2, a combination of carboplatin and paclitaxel is feasible, but there is no direct comparison with single agent therapy and thus no clear-cut recommendation.

In elderly patients the recommended first-line chemotherapy is a single agent, the most extensively studied being vinorelbine and gemcitabine.

Second-line therapy is now well established, with docetaxel or pemetrexed being the recommended choices. Targeted therapies can be used either as second-line therapy (female, nonsmokers, adenocarcinomas) or third-line therapy.

There is no recommendation beyond third-line regarding any chemotherapy/targeted therapy scheme and this remains an unmet need.

Limited disease small cell lung cancer (LD-SCLC) is a heterogeneous disease, not only for its clinical behaviour, but also for its anatomical extension. In very rare, early cases, LD-SCLC might be treated with surgery and chemotherapy, but as the overwhelming majority of patients present with locally advanced disease, the standard of care is concurrent chest radiotherapy with cisplatin and etoposide chemotherapy followed by prophylactic cranial irradiation (PCI). Newer chemotherapeutic drugs as well as targeted agents have not improved the outcome thus far.

Given concurrently with chest irradiation, cisplatin combined with etoposide, administered every 21 days for 4–5 cycles, have frequently been used.

Thoracic radiotherapy should begin as early as possible during the first chemotherapy cycle. A total radiation dose of 45 Gy is recommended, delivered in a short overall treatment time (<4 weeks). Accelerated therapy increases absolute 5-yr survival rates by 10% compared with longer treatment times, at the expense of an incidence of severe oesophagitis of ∼30% that is reversible within a few weeks. Haematological complications and late pulmonary damage may occur but are not more frequent than with less intensive schedules yielding inferior long-term survival. Obviously, only fit patients (World Health Organisation performance status 0–2) with adequate organ function can tolerate this treatment.

As the tumour remission status is difficult to assess due to radiographic changes induced by chemoradiation therapy, patients that show no tumour progression are suitable for PCI. The recommended dose is 25 Gy, given in 10 daily fractions of 2.5 Gy. PCI reduces the risk of brain metastases by ∼50%. When delivered after chemotherapy and at the recommended doses and fractionation, PCI did not lead to persistent neurocognitive function decline.

With this treatment strategy, 5-yr survival rates of 25% can be achieved in patients with LD-SCLC.

Malignant pleural disease is common in patients with lung cancer. Establishing malignant pleural involvement in lung cancer patients often alters management and significantly impacts on staging and prognosis.

Histocytological confirmation should be obtained for suspected malignant pleural effusions to differentiate them from paramalignant effusions. If cytology is negative, imaging-guided biopsy or thoracoscopy should be considered.

Relieving dyspnoea and improving quality of life are the goals of management of malignant effusions. Pleurodesis should be considered in suitable patients. Long-term indwelling pleural catheters are recommended in patients with trapped lung or in whom pleurodesis has failed.

In the USA, lung cancer remains the leading cause of cancer death in both males and females, even though an extensive list of modifiable risk factors has long been identified. The predominant cause of lung cancer is exposure to tobacco smoke, with active smoking causing most cases but passive smoking also contributing to the lung cancer burden. The reductions in smoking prevalence in males that occurred in the late 1960s until the 1980s will continue to drive lung cancer mortality rates downward in males during the first portion of this century, but rates in females have not yet begun to decrease. Asbestos has been identified as responsible for the great majority of mesothelioma cases. Fortunately, exposures to major occupational respiratory carcinogens have largely been controlled, but the population is still exposed to environmental causes of lung cancer, including radon, the second leading cause of lung cancer death. Mesothelioma incidence has begun to reflect limitations on use of asbestos implemented decades ago and should continue to fall if asbestos use is limited and workers are protected.

Over the past 10 yrs, there have been several achievements in the management of malignant pleural mesothelioma (MPM), including a better insight into the tumour biology, more effective chemotherapy with pemetrexed or gemcitabine in combination with cisplatin, and extrapleural pneumonectomy (EPP) within a multimodality treatment. Nevertheless, the choice of the best treatment remains a matter of debate. A systematic review of the value of surgery remains highly critical as to the quality of the studies and the lack of randomised studies. Pleurectomy/decortication (P/D) has proven its effectiveness as a palliative procedure for symptom control such as relief of dyspnoea due to control of pleural effusion and freeing a tumour-entrapped lung but it is limited to good performance status patients. P/D provides the advantage of avoiding a pneumonectomy and may be indicated for patients with reduced cardiopulmonary capacity or mesotheliomas located mainly at the parietal pleura. However, P/D is, by intent, less radical than EPP. Furthermore, the application of full adjuvant hemithoracic radiotherapy is not possible because of the risk of damage to the remaining lung. The best long-term results may be achieved by multidisciplinary concepts including EPP together with neo- or adjuvant chemotherapy and a median survival time of about 2 yrs has been reported by several studies. Hemithoracic radiotherapy after EPP has been suggested to decrease the rate of local relapse; however, it is a complex procedure associated with additional morbidity and mortality.

Diagnosis and treatment of MPM remains a challenge and is best performed in a specialised centre by a multidisciplinary team, in order to balance treatment related morbidity with potential treatment benefit. Proper randomised trials are still needed to answer these basic questions.