Elsevier

Lung Cancer

Volume 90, Issue 3, December 2015, Pages 582-589
Lung Cancer

Review
When is surgery indicated for small-cell lung cancer?

https://doi.org/10.1016/j.lungcan.2015.10.019Get rights and content

Highlights

  • SCLC prognosis is poor and has hardly changed over the last 30 years.

  • Recent studies indicate that surgery has a role in early SCLC.

  • Lobectomy + nodal dissection is OK for SCLC/mixed histology found intraoperatively.

  • Postoperative chemotherapy is indicated after surgical removal of early SCLC.

  • Surgery may improve local control/survival after chemotherapy in stage I/II SCLC.

  • CT screening identifies SCLC at an earlier stage promising to increase survival.

Abstract

Small-cell lung cancer (SCLC) comprises 13–20% of all lung cancers but is the fifth leading cause of cancer death worldwide. SCLC prognosis remains poor despite improvements in diagnosis and therapy over the last 30 years. Current treatment is systemic chemotherapy, flanked by thoracic irradiation for limited stage disease; however, about two-thirds of patients are diagnosed with extensive stage disease when thoracic irradiation is not worthwhile. Randomized trials on surgical resection in patients with limited stage disease conducted in the pre-PET era, when both staging and treatment were inadequate, did not support a role for surgery in disease management. However recent retrospective and population-based studies indicate that outcomes after surgery in patients with very early SCLC are comparable to those in patients with non-SCLC, and that survival is better than in SCLC patients not given surgery. CT screening identifies SCLC at an earlier stage – with better survival – than usual care, and offers the hope that more SCLC patients may become long-term survivors. However, cases must be exhaustively staged to identify those likely to benefit from surgery. Finding a specific SCLC marker to facilitate early diagnosis remains a priority.

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.

References (100)

  • 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)
  • J.A. Bogart et al.

    70Gy thoracic radiotherapy is feasible concurrent with chemotherapy for limited-stage small-cell lung cancer: analysis of Cancer and Leukemia Group B study 39808

    Int. J. Radiat. Oncol. Biol. Phys.

    (2004)
  • R. Komaki et al.

    Phase I study of thoracic radiation dose escalation with concurrent chemotherapy for patients with limited small-cell lung cancer: report of radiation therapy oncology group (RTOG) protocol 97-12

    Int. J. Radiat. Oncol. Biol. Phys.

    (2005)
  • R. Catane et al.

    Follow-up neurological evaluation in patients with small cell lung carcinoma treated with prophylactic cranial irradiation and chemotherapy

    Int. J. Radiat. Oncol. Biol. Phys.

    (1981)
  • J.S. Lee et al.

    Neurotoxicity in long-term survivors of small cell lung cancer

    Int. J. Radiat. Oncol. Biol. Phys.

    (1986)
  • M. Reck et al.

    Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, multicenter phase 2 trial

    Ann. Oncol.

    (2013)
  • S.C. Lennox et al.

    Results of resection for oat cell carcinoma of the lung

    Lancet

    (1968)
  • F.A. Shepherd et al.

    Is there ever a role for salvage operations in limited small-cell lung cancer?

    J. Thorac. Cardiovasc. Surg.

    (1991)
  • J.A. Meyer et al.

    The prospect of disease control by surgery combined with chemotherapy in stage I and stage II small cell carcinoma of the lung

    Ann. Thorac. Surg.

    (1983)
  • J.A. Meyer et al.

    Adverse prognostic effect of N2 disease in treated small cell carcinoma of the lung

    J. Thorac. Cardiovasc. Surg.

    (1984)
  • G. Veronesi et al.

    Adjuvant surgery after carboplatin and VP16 in resectable small cell lung cancer

    J. Thorac. Oncol.

    (2007)
  • H. Kreisman et al.

    Small-cell lung cancer presenting as a solitary pulmonary nodule

    Chest

    (1992)
  • K. Osterlind et al.

    Influence of surgical resection prior to chemotherapy on the long-term results in small cell lung cancer. A study of 250 operable patients

    Eur. J. Cancer Clin. Oncol.

    (1986)
  • R.L. Prager et al.

    The feasibility of adjuvant surgery in limited-stage small cell carcinoma: a prospective evaluation

    Ann. Thorac. Surg.

    (1984)
  • D.H. Johnson et al.

    Post chemotherapyresection of residual tumor in limited stage small cell lung cancer

    Chest

    (1987)
  • H. Wada et al.

    Surgical treatment of small cell carcinoma of the lung: advantage of preoperative CT

    Lung Cancer

    (1995)
  • K. Fujimori et al.

    A pilot phase 2 study of surgical treatment after induction CT for resectable stage I to IIIA small cell lung cancer

    Chest

    (1997)
  • F.A. Shepherd et al.

    A prospective study of adjuvant surgical resection after chemotherapy for limited small cell lung cancer. A University of Toronto Lung Oncology Group study

    J. Thorac. Cardiovasc. Surg.

    (1989)
  • T. Takenaka et al.

    Role of surgical resection for patients with limited disease-small small cell lung cancer

    Cancer

    (2015)
  • B. Weksler et al.

    Surgical resection should be considered for stage I and II small cell carcinoma of the lung

    Ann. Thorac. Surg.

    (2012)
  • J.B. Yu et al.

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

    J. Thorac. Oncol.

    (2010)
  • S.E. Combs et al.

    Bolstering the case for lobectomy in stages I, II, and IIIA small-cell lung cancer using the National Cancer Data Base

    J. Thorac. Oncol.

    (2015)
  • J.H. Austin et al.

    International early lung cancer action program investigators. Small-cell carcinoma of the lung detected by CT screening: stage distribution and curability

    Lung Cancer

    (2012)
  • G.R. Simon et al.

    American College of Chest Physicians. Management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition)

    Chest

    (2007)
  • F.A. Shepherd

    Surgery for limited stage small cell lung cancer: time to fish or cut bait

    J. Thorac. Oncol.

    (2010)
  • American Cancer Society
    (2011)
  • A. Amini et al.

    Progress in the management of limited-stage small cell lung cancer

    Cancer

    (2014)
  • R. Govindan et al.

    Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the surveillance, epidemiologic, and endresults database

    J. Clin. Oncol.

    (2006)
  • C.L. Hann et al.

    The change in pattern and pathology of small cell lung cancer

    World Health

    (2009)
  • M. Peifer et al.

    Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer

    Nat. Genet.

    (2012)
  • M. Kazarian et al.

    Small-cell lung cancer-associated autoantibodies: potential applications to cancer diagnosis, early detection, and therapy

    Mol. Cancer

    (2011)
  • M. Zelen

    Keynote address on biostatistics and data retrieval

    Cancer Chemother. Rep.

    (1973)
  • L.H. Sobin et al.

    International Union Against Cancer (UICC) TNM Classification of Malignant Tumors

    (2002)
  • S.H. Ignatius Ou et al.

    The applicability of the proposed IASLC staging revisions to small cell lung cancer (SCLC) with comparison to the current UICC 6th TNM edition

    J. Thorac. Oncol.

    (2009)
  • R. Feld et al.

    Combined modality induction therapy without maintenance chemotherapy for small cell carcinoma of the lung

    J. Clin. Oncol.

    (1984)
  • S. Sundstrøm et al.

    Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in small-cell lung cancer: results from a randomized phase III trial with 5 years’ follow-up

    JCO

    (2002)
  • J.P. Pignon et al.

    A meta-analysis of thoracic radiotherapy for small-cell lung cancer

    N. Engl. J. Med.

    (1992)
  • P. Warde et al.

    Does thoracic irradiation improve survival and local control in limited-stage small-cell carcinoma of the lung? A meta-analysis

    J. Clin. Oncol.

    (1992)
  • M. Takada et al.

    Phase III study of concurrent versus sequential thoracic radiotherapy in combination with cisplatin and etoposide for limited-stage small-cell lung cancer: results of the Japan Clinical Oncology Group Study 9104

    J. Clin. Oncol.

    (2002)
  • N. Murray et al.

    Importance of timing for thoracic irradiation in the combined modality treatment of limited-stage small-cell lung cancer. The National Cancer Institute of Canada Clinical Trials Group

    J. Clin. Oncol.

    (1993)
  • Cited by (29)

    • Polo-like kinase 1 inhibitor BI 6727 induces DNA damage and exerts strong antitumor activity in small cell lung cancer

      2018, Cancer Letters
      Citation 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].

    • Prophylactic Cranial Irradiation for Resectable Small-Cell Lung Cancer

      2018, Clinical Lung Cancer
      Citation 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

    • Nonneuroendocrine Carcinomas (Excluding Sarcomatoid Carcinoma) and Salivary Gland Analogue Tumors of the Lung

      2018, Practical Pulmonary Pathology: A Diagnostic Approach A Volume in the Pattern Recognition Series
    • SCLC–State of the Art and What Does the Future Have in Store?

      2016, Clinical Lung Cancer
      Citation 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.

    View all citing articles on Scopus
    View full text