Elsevier

The Lancet

Volume 378, Issue 9804, 12–18 November 2011, Pages 1741-1755
The Lancet

Seminar
Small-cell lung cancer

https://doi.org/10.1016/S0140-6736(11)60165-7Get rights and content

Summary

The incidence and mortality of small-cell lung cancer worldwide make this disease a notable health-care issue. Diagnosis relies on histology, with the use of immunohistochemical studies to confirm difficult cases. Typical patients are men older than 70 years who are current or past heavy smokers and who have pulmonary and cardiovascular comorbidities. Patients often present with rapid-onset symptoms due to local intrathoracic tumour growth, extrapulmonary distant spread, paraneoplastic syndromes, or a combination of these features. Staging aims ultimately to define disease as metastatic or non-metastatic. Combination chemotherapy, generally platinum-based plus etoposide or irinotecan, is the mainstay first-line treatment for metastatic small-cell lung cancer. For non-metastatic disease, evidence supports early concurrent thoracic radiotherapy. Prophylactic cranial irradiation should be considered for patients with or without metastases whose disease does not progress after induction chemotherapy and radiotherapy. Despite high initial response rates, most patients eventually relapse. Except for topotecan, few treatment options then remain. Signalling pathways have been identified that might yield new drug targets.

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

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

References (152)

  • JP Sculier et al.

    The impact of additional prognostic factors on survival and their relationship with the anatomical extent of disease expressed by the 6th edition of the TNM classification of malignant tumours and the proposals for the 7th edition

    J Thorac Oncol

    (2008)
  • M Sørensen et al.

    Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

    Ann Oncol

    (2010)
  • GR Simon et al.

    Management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition)

    Chest

    (2007)
  • J van Loon et al.

    Selective nodal irradiation on basis of 18FDG-PET scans in limited-disease small-cell lung cancer: a prospective study

    Int J Radiat Oncol Biol Phys

    (2010)
  • RA Green et al.

    Alkylating agents in bronchogenic carcinoma

    Am J Med

    (1969)
  • KF Giordano et al.

    Ramifications of severe organ dysfunction in newly diagnosed patients with small cell lung cancer: contemporary experience from a single institution

    Lung Cancer

    (2005)
  • C Mascaux et al.

    A systematic review of the role of etoposide and cisplatin in the chemotherapy of small cell lung cancer with methodology assessment and meta-analysis

    Lung Cancer

    (2000)
  • J Jiang et al.

    A meta-analysis of randomized controlled trials comparing irinotecan/platinum with etoposide/platinum in patients with previously untreated extensive-stage small cell lung cancer

    J Thorac Oncol

    (2010)
  • A Inoue et al.

    A phase II study of amrubicin combined with carboplatin for elderly patents with small-cell lung cancer: North Japan Lung Cancer Study Group Trial 0405

    Ann Oncol

    (2010)
  • G Robinet et al.

    Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Français de Pneumo-Cancérologie (GFPC) Protocol 95-1

    Ann Oncol

    (2001)
  • T Lad et al.

    A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy

    Chest

    (1994)
  • E Lim et al.

    The role of surgery in the treatment of limited disease small cell lung cancer: time to reevaluate

    J Thorac Oncol

    (2008)
  • JB Yu et al.

    Surveillance epidemiology and end results evaluation of the role of surgery for stage I small cell lung cancer

    J Thorac Oncol

    (2010)
  • FS Shepherd

    Surgery for limited stage small cell lung cancer. Time to fish or cut bait

    J Thorac Oncol

    (2010)
  • N Hanna et al.

    Etoposide, ifosfamide and cisplatin (VIP) plus concurrent radiation therapy for previously untreated limited small cell lung cancer (SCLC): a Hoosier Oncology Group (HOG) phase II study

    Lung Cancer

    (2002)
  • D De Ruysscher et al.

    Chest radiotherapy in limited-stage small cell lung cancer: facts, questions, prospects

    Radiother Oncol

    (2000)
  • D De Ruysscher et al.

    Omission of elective node irradiation on basis of CT-scans in patients with limited disease small cell lung cancer: a phase II trial

    Radiother Oncol

    (2006)
  • M Pijls-Johannesma et al.

    Timing of chest radiotherapy in patients with limited stage small cell lung cancer: a systematic review and meta-analysis of randomised controlled trials

    Cancer Treat Rev

    (2007)
  • PE Postmus et al.

    Brain-only metastases of small cell lung cancer; efficacy of whole brain radiotherapy. An EORTC phase II study

    Radiother Oncol

    (1998)
  • C Le Péchoux et al.

    Standard-dose versus higher-dose prophylactic cranial irradiation (PCI) in patients with limited-stage small-cell lung cancer in complete remission after chemotherapy and thoracic radiotherapy (PCI 99-01, EORTC 22003-08004, RTOG 0212, and IFCT 99-01): a randomised clinical trial

    Lancet Oncol

    (2009)
  • FH Härting et al.

    Der Lungenkrebs, die Bergkrankheit in den Schneeberger Gruben

    Vjschr gerichtl Med offen Sanitats

    (1879)
  • W Barnard

    The nature of the ‘oat-celled sarcoma’ of the mediastinum

    J Pathol

    (1926)
  • SEER Cancer Statistics Review, 1975–2006

  • SS Devesa et al.

    International lung cancer trends by histologic type: male:female differences diminishing and adenocarcinoma rising

    Int J Cancer

    (2005)
  • CM Rudin et al.

    Lung cancer in never smokers: molecular profiles and therapeutic implications

    Clin Cancer Res

    (2009)
  • JK Field et al.

    Lung cancer screening: the way forward

    Br J Cancer

    (2008)
  • WF Franklin et al.

    Molecular and cellular pathology of lung cancer

  • BP Coe et al.

    Gain of a region on 7p22.3, containing MAD1L1, is the most frequent event in small-cell lung cancer cell lines

    Genes Chromosomes Cancer

    (2006)
  • WL Watson et al.

    Oat cell lung cancer

    Cancer

    (1962)
  • GA Masters

    Clinical presentation of small cell lung cancer

  • LD Wilson et al.

    Superior Vena cava syndrome with malignant causes

    N Engl J Med

    (2007)
  • DH Ellison et al.

    The syndrome of inappropriate antidiuresis

    N Engl J Med

    (2007)
  • JP Chute et al.

    A metabolic study of patients with lung cancer and hyponatremia of malignancy

    Clin Cancer Res

    (2006)
  • M Boscaro et al.

    Approach to the patient with possible Cushing's syndrome

    J Clin Endocrinol Metab

    (2009)
  • RB Darnell et al.

    Paraneoplastic syndromes involving the nervous system

    N Engl J Med

    (2003)
  • SH Gultekin et al.

    Paraneoplastic limbic encephalitis: neurological symptoms, immunological findings and tumour association in 50 patients

    Brain

    (2000)
  • SE Monstad et al.

    Hu and voltage-gated calcium channel (VGCC) antibodies related to the prognosis of small-cell lung cancer

    J Clin Oncol

    (2004)
  • L Gandhi et al.

    Paraneoplastic syndromes associated with small cell lung cancer

    J Natl Compr Canc Netw

    (2006)
  • MJ Titulaer et al.

    SOX Antibodies in small-cell lung cancer and Lambert-Eaton myasthenic syndrome: frequency and relation with survival

    J Clin Oncol

    (2009)
  • Cited by (902)

    View all citing articles on Scopus
    View full text