ReviewWhen is surgery indicated for small-cell lung cancer?
Introduction
Lung cancer is the leading cause of cancer-related death in the world, accounting for more deaths than breast, prostate, pancreatic, and colon cancer combined [1]. Over 1.6 million cases of lung cancer were diagnosed worldwide in 2008 [2]. Small-cell lung cancer (SCLC) accounts for 13–20% of all lung cancers, and is the fifth leading cause of cancer death when considered independently of non-small-cell lung cancer (NSCLC) [3], [4].
SCLC is a malignant epithelial neoplasm usually consisting of small cells with scant cytoplasm, ill-defined cell borders, granular nuclear chromatin, and absent or inconspicuous nucleoli. The cells can be round, oval, or spindle-shaped. Nevertheless, it can be difficult to distinguish SCLC from other lung malignancies and, in addition to morphology, immunohistochemistry to detect cytokeratins (epithelial marker) and neuroendocrine markers is often useful to distinguish SCLC from other lung cancers.
Notwithstanding improvements in treatment and earlier diagnosis, leading to small survival improvements [5], five-year relative survival for SCLC was only 5–7% in the last decade of the last century (latest available data) [5], making it the most aggressive lung cancer subtype. The aggressive, rapidly fatal natural history of SCLC may be due to the large number of mutations present, usually including TP53 mutations [6], [7] in turn probably related to the fact that around 98% of SCLC patients have a history of heavy smoking [3]. Both smoking intensity (cigarettes/day) and number of years of smoking increase the risk of developing SCLC [4].
Approximately two-thirds of SCLC patients have clinical evidence of metastasis at diagnosis; most of the remaining third have clinical evidence of extensive involvement of hilar, mediastinal, and sometimes supraclavicular lymph nodes. Typical local symptoms are cough, shortness of breath, and chest pain. Weight loss and weakness suggest metastatic disease.
About 80% of patients die within 1–2 years of diagnosis [5]. Without treatment, patients with limited disease typically die within 3–6 months and those with extensive disease die within 1–2 months [5]. As yet no specific molecular markers to facilitate early diagnosis of SCLC have been identified [8]. However, evidence suggests that CT can identify SCLC at an earlier stage than usual with favorable impact on survival [9].
Section snippets
Staging
The first SCLC staging system was introduced by the Veterans Administration Lung Cancer Study Group (VALSG) in 1973 for use in clinical trials [10]. It divided patients into those with ‘limited stage’ (LS) disease, confined to the hemithorax, and those with ‘extensive stage’ disease (ES) at sites beyond those included in LS. In 1989 [11] the International Association for the Study of Lung Cancer (IASLC) recommended that the VALSG staging system be modified to include all non-metastatic patients
Chemoradiotherapy for limited SCLC
SCLC was found highly sensitive to various chemotherapeutic agents in the 1960s. The cyclophosphamide, doxorubicin, vincristine combination (CAV) came to be widely used in the 1970s as it was effective and had good tolerability [18]. However, the benefit to patients was short-lived, and more effective treatments were required. Chemotherapy was soon combined with thoracic radiotherapy. A 1984 study [19] reported on CAV in combination with thoracic radiotherapy and prophylactic cranial
Newer chemotherapeutic agents
While for NSCLC there have been significant improvements in diagnosis, treatment and survival in recent years [42], little has changed in the management of SCLC since the platinum-etoposide doublet was introduced nearly forty years ago. In fact, although numerous new cytotoxic agents and combinations have been investigated, especially in ES SCLC, most have not proven effective [43].
It is also the case that disease biomarkers and molecular subtypes (that can be targeted by specific agents) have
Role of surgery
Up to the early 1970s, surgery was standard treatment for operable SCLC [48], [49]. After 1973 the standard of care gradually switched to thoracic radiotherapy as local treatment, with chemotherapy as systemic treatment. This change was ushered in by the ten-year findings of the MRC trial, which, as noted previously, reported better survival with radical radiotherapy than with surgery [21]. The Lung Cancer Study Group trial, published in 1994, was also important in consolidating radiotherapy:
Population-based analyses of the role of surgery
A 2014 analysis of 359,873 lung cancer patients from the population-based English National Cancer Data Repository identified a large group of 465 SCLC patients whose tumors were resected surgically [89]. SCLCs constituted 14% of all lung cancers and 2% of surgically resected cancers. Surgically resected SCLC cases had 31% five-year survival, compared to 45% for surgically resected NSCLC cases, and 3% for cases of either subtype that were not resected (Fig. 1). Survival was better for SCLC cases
Treatment and prognosis of SCLC detected in screening programs
CT screening has improved the stage distribution of diagnosed lung cancers and reduced lung cancer deaths. [93], [94] However few studies have been specifically concerned with stage distribution and prognosis in screening-detected SCLC [9]. Austin et al. [95] carried out a multinational study of baseline and annual repeat CT screenings of 48,037 volunteers at risk for lung cancer. They found 48 SCLC cases, 92% of which were asymptomatic at diagnosis and 8% of which developed symptoms between
Conclusions
The current guidelines of the National Comprehensive Cancer Network (NCCN) [96] and the American College of Chest Physicians (ACCP) [97] are not identical but both recommend that only patients with clinical stage I disease (T1-T2 N0) should be considered for surgery. The NCCN emphasizes that complete staging, including total body CT, PET, mediastinoscopy or endobronchial ultrasound-guided trans-bronchial needle aspiration biopsy (or trans-esophageal endoscopic ultrasound with biopsy) is
Acknowledgment
We thanks Don Ward for his help in the language editing.
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2018, Cancer LettersCitation Excerpt :Small cell lung cancer (SCLC) accounts for 15–20% of all lung cancer cases, and approximately two-thirds of SCLC patients have extrathoracic metastases at the time of diagnosis. Furthermore, the median survival of patients with SCLC without treatment is 2–4 months, and the five-year overall survival rate is only 5–7% [3–6]. SCLC is a malignancy that exhibits rapid tumor growth and the early development of widespread metastases, which makes it the most aggressive subtype of lung cancer [7,8].
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2018, Clinical Lung CancerCitation Excerpt :Even in patients who present with limited-stage disease, surgery has been avoided largely on the basis of one randomized controlled trial published more than 20 years ago that showed no improvement with the use of surgery in addition to chemoradiation.8 In the modern era of computed tomography (CT) screening of high-risk patients with smoking histories, however, patients are more frequently presenting with very localized limited-stage SCLC compared with historical cohorts.9 In one analysis by Austin et al, CT screening led to a significant shift in the percentage of patients diagnosed with stage IA or IB SCLC (33% of all SCLC cases diagnosed) compared with historical controls (7% of all SCLC cases diagnosed).10
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2016, Clinical Lung CancerCitation Excerpt :Accordingly, a curative therapy approach is only available to a few patients. Patients with stage I or II disease, peripherally located tumor, and certain exclusion from mediastinal lymph node metastases may, in some centers, receive a primary surgery, if they are in a good functional condition, followed by 4 to 6 cycles of adjuvant chemotherapy.54,55 In most centers, a primary, in parts hyperfractionated, radio-(chemo)therapy is performed.