We searched PubMed with the following keywords used in various combinations: “carcinoma”, “small cell lung”, “epidemiology”, “pathology”, “biology”, “diagnosis”, “staging”, “treatment”, “management”, “antineoplastic agents”, “targeted agent”, “radiotherapy”, and “surgery”. The search was limited to articles published in peer-reviewed, journals published from 2005 onwards. For the management section we searched all publications and for the other sections we only searched journals published in
SeminarSmall-cell lung cancer
Introduction
Small-cell lung cancer (SCLC) is a distinct clinical and histological entity within the range of lung cancers. Its management has followed the major developments of modern cancer treatment through the integration of biology, imaging, chemotherapy, and radiotherapy.
SCLC was originally thought to originate from the lymphatic system because of microscopic similarities between SCLC and lymphoma cells. In 1879, Härting and Hesse1 described an arsenic-induced lymphosarcoma in miners. The term SCLC was first coined in 1926, when its epithelial origin was recognised.2 In this and ensuing classifications, phenotypical variants were described as oat cell or mixed subtypes. These terms are no longer used in WHO's classification.3
Here we address the scientific advances that have been made in defining the biology of SCLC and that have increased our ability to manage this cancer. We also consolidate the evidence on the usefulness of current therapeutic and prophylactic methods, and suggest ways they can be further improved by new developments in targeted therapy.
Section snippets
Epidemiology
Lung cancer accounts for 12% of all new cases of cancers worldwide, it is the second most common cancer in men and women, and it is the leading cause of cancer-related death in the USA.4 SCLC represents 13% of all newly diagnosed cases of lung cancer worldwide, or more than 180 000 cases per year. More than 90% of patients with SCLC are elderly current or past heavy smokers, and risk rises with increasing duration and intensity of smoking.5 Although rare cases have been reported in people who
Diagnosis
SCLC is defined as “a malignant epithelial tumour consisting of small cells with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli” (figure 1).3 Typical SCLC involves only small cells and accounts for around 90% of cases. The remaining cases are classified as combined disease, in which the tumour contains large-cell components.3, 9
Presentation
Watson and Berg13 were the first to describe distinct clinical features of SCLC, especially the predominantly central and bulky location on chest radiography, the tendency for early dissemination, the high initial response rates to chemotherapy, and the high frequency of metastases at autopsy. Patients are typically men older than 70 years who are heavy current or ex-smokers and have various pulmonary, cardiovascular, and metabolic comorbidities.14 Onset of symptoms is rapid, with the duration
Management
Early treatments for SCLC were nitrogen mustard,50 surgery (which was first used in 1948), radical radiotherapy,51 and cyclophosphamide; treatment with cyclophosphamide significantly favoured survival.52 In the mid-1970s, the possibility of cure seemed feasible as new drugs were developed and combination chemotherapy became possible and led to better results than did single-agent treatments.53 Although no cure has emerged, combined chemotherapy remains the cornerstone for all stages of SCLC.54
Prophylactic cranial irradiation
The response rate and a median survival after whole-brain radiotherapy in SCLC patients with recurrence in the brain alone are 50% and 4–5 months, respectively.97 Several randomised studies have been done, therefore, to investigate the usefulness of prophylactic cranial irradiation against microscopic brain involvement in limited-stage disease. Prophylactic cranial irradiation could indeed kill small tumour deposits with low radiation doses, thus resulting in increased long-term survival if all
Novel biological targets
Evasion of apoptosis is a hallmark of cancer and is a major factor underlying drug resistance in SCLC. The mechanisms are complex and incompletely understood, but, similarly to other cancers, SCLC cells seem to suppress apoptosis by at least three mechanisms: increase in stimulation of antiapoptopic pathways via extracellular signals, desensitisation of the intrinsic cell death machinery via addiction to antiapoptosis proteins, and mutational burden leading to the loss of proapoptotic tumour
Conclusions and additional issues
SCLC remains a frustrating disease to research and to treat. In extensive-stage disease new drug combinations and approaches have made little difference to overall survival. Improved survival remains the ultimate goal as, unlike in other chemosensitive cancers, second-line treatment is not an option for most patients.
Although most patients with limited-stage SCLC will also succumb, long-term survival has been improved by good integration of chemotherapy with early, accelerated chest
Search strategy and selection criteria
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