Management of Small-Cell Lung Cancer: Incremental Changes but Hope for the Future

CHRISTINE L. HANN, MD, PhD
Assistant Professor of Oncology


CHARLES M. RUDIN, MD, PhD
Associate Professor of Oncology
Co-director, Upper Aerodigestive Cancer Program
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Baltimore, Maryland

Financial Disclosure:
The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Acknowledgement:
The authors work on SCLC is supported by the Burroughs Wellcome Fund (CMR) and Flight Attendant Research Institute (CLH and CMR).

ABSTRACT: Over 25,000 people are diagnosed with small-cell lung cancer (SCLC) in the United States annually. SCLC is a highly aggressive tumor with a propensity for early metastases and a high case-fatality rate. Systemic treatment with etoposide plus a platinum agent is recommended for all stages of this disease and has been a standard first-line therapy for SCLC since the 1980s. Three recently presented randomized clinical trials failed to show superiority of newer regimens over etoposide and cisplatin. Patients with limited-stage (LS) disease benefit from the addition of radiotherapy to systemic chemotherapy, a combination that affords high complete response rates and potential cures. Incremental improvements in radiotherapy delivery over the past decade include the use of accelerated hyperfractionated thoracic radiotherapy for LS disease. Prophylactic cranial irradiation, previously recommended for patients with LS disease, has recently been shown to benefit those with extensive-stage (ES) disease as well. Surgery, largely abandoned in the 1970s, is being reevaluated as primary local therapy in patients with very early-stage SCLC. Topotecan remains the only US Food and Drug Administration–approved therapy for recurrent disease. Amrubicin has demonstrated single-agent activity in multiple phase II trials in both chemotherapy-sensitive and -refractory relapse. The past 2 decades have been marked by an improved understanding of SCLC biology, and these discoveries are reflected in the number and diversity of novel therapies entering early-phase testing in this disease.

Small-cell lung cancer (SCLC) accounts for approximately 15% of the 215,000 new lung cancer diagnoses in the United States annually. With a case-fatality rate greater than 90%, SCLC will be the cause of over 25,000 deaths in 2008 alone. SCLC is seen almost exclusively in current or former smokers and is characterized by a rapid tumor doubling time, high growth fraction, and early development of metastases. At the time of diagnosis, SCLC is usually disseminated and, if left untreated, rapidly fatal with an average survival of less than 4 months. Essentially all patients are treated with chemotherapy, either alone or in combination with local therapy such as radiation therapy. EP (etoposide and cisplatin [Platinol]), a chemotherapy regimen established in the 1980s, remains a primary standard of care for first-line therapy today. Here we describe the clinical presentation, diagnosis, and staging of SCLC and discuss standard disease management in the context of recently presented trials.

Clinical Presentation

SCLC typically arises in the central airways and can quickly metastasize to the lymph nodes and beyond. As such, many patients present with symptoms related to central airway disease, including cough, dyspnea, and chest discomfort.[1] SCLC displays the propensity for early metastases to sites including the liver, bones, adrenal glands, and brain. Reflecting the systemic nature of this disease, up to 50% of patients will present with weight loss, fatigue, and anorexia.

SCLC patients may also present with an endocrinologic or neurologic paraneoplastic syndrome. Hyponatremia, due to ectopic production of antidiuretic hormone or atrial natriuretic peptide, is observed in up to 15% of patients with SCLC, while Cushing's syndrome is seen in 2% to 5% of SCLC patients.[2] Clinically disabling paraneoplastic neurologic syndromes, thought to be mediated by antibodies directed against "onconeural" antigens, are observed in 1% to 3% of SCLC patients. Anti-Hu antibodies are seen in multifocal encephalomyelitis/sensory neuronopathy and limbic encephalitis.[3] Lambert-Eaton myasthenic syndrome (LEMS) is associated with anti–voltage-gated calcium channel (VGCC) antibodies. Fifty percent of LEMS patients will eventually be diagnosed with SCLC; accordingly, a smoker diagnosed with LEMS should be closely followed and screened for SCLC.[4] In a minority of patients who present with neurologic paraneoplastic syndromes, symptoms may remit with treatment of the underlying cancer.

Diagnosis

The diagnosis of SCLC is primarily made by light microscopy. With standard hematoxylin-and-eosin stain, the tumors appear as small blue cells with scant cytoplasm and a high mitotic index. Nuclear molding is considered characteristic, and the nuclei themselves have fine granular chromatin and absent nucleoli.[5] Keratin and epithelial membrane antigen are seen almost uniformly. At least one marker of neuroendocrine differentiation is observed in 75% of SCLC cases, including dopa decarboxylase, calcitonin, synaptophysin, chromogranin A, CD56 (nuclear cell adhesion molecule, or NCAM), and gastrin-releasing peptide.[6,7]

Staging

Introduced by the Veterans' Administration Lung Study Group (VALSG) in the 1950s, the two-stage classification system is typically used clinically to stage SCLC.[8] The VALSG system defines patients as having either limited-stage (LS) or extensive-stage (ES) SCLC. Patients with LS SCLC have disease confined to the ipsilateral hemithorax that can be safely included in a tolerable radiation portal, and ES disease includes all remaining patients. Approximately 30% of all new SCLC diagnoses are classified as LS. Patients with LS disease have a median survival of 18 to 23 months, and up to 20% of patients can achieve long-term remission with concurrent chemoradiotherapy. The median survival of patients with ES disease is 8 to 10 months despite aggressive chemotherapy.

In 1987 the International Association for the Study of Lung Cancer (IASLC) published a consensus report revising the VALSG classification in accordance with TNM staging for malignant tumors. By TNM criteria, limited-stage disease includes stages I–III, whereas ES disease is comprised of stage IV tumors only.[9] By convention, LS and ES descriptors are still predominantly used. Staging evaluation for SCLC patients should include a routine history and physical exam, hematology and chemistry panels, and computed tomography (CT) scan of the chest to evaluate the extent of intrathoracic disease, including pleural effusion. Concurrent chemotherapy can offer cures in up to 20% of LS patients but at the cost of significant toxicity. Thus, accurate assessment of extrathoracic disease is imperative. Common sites of metastases include bone, liver, adrenal glands, and brain, and therefore, CT scan of the abdomen, magnetic resonance imaging (MRI) of the brain, and bone scan are recommended. A bone marrow biopsy may be performed as clinically indicated; however, it is rare that patients have bone marrow involvement as a sole site of metastasis.[10] Patients, who present with a pleural effusion in the absence of extrathoracic disease should have further studies of their pleural fluid—such as chemistry studies consistent with an exudate or, better yet, cytopathologic confirmation—to verify tumor involvement.

As SCLC is a highly metabolic tumor that avidly takes up fluorodeoxyglucose, positron-emission tomography (PET) scanning is an attractive modality for staging. In small prospective studies, PET scans have correctly upstaged patients to ES disease.[11,12] However, larger prospective studies are still needed, and reimbursement in the United States for this particular indication remains an issue.