Stat Consult: Small Cell Lung Cancer - Cancer Therapy Advisor
General Information
- Small cell lung cancer (SCLC) is a malignant epithelial neuroendocrine tumor consisting of small cells with scant cytoplasm, ill-defined cellular borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli.
- SCLC accounts for about 13%-15% of lung cancer cases; it can be further classified as pure SCLC or combined SCLC (with mixture of small and non-small cell histology)
- It is characterized by rapid doubling time, high growth fraction, and widespread metastases early in disease; patients often present with hematogenous metastases
- SCLC is suspected in patients with a history of cigarette smoking, coughing, hemoptysis, wheezing, dyspnea, and/or chest pain.
Risk Factors for Lung Cancer
- Tobacco smoke
- Almost all cases of SCLC are related to tobacco use
- > 90% of cases occur in elderly current or past heavy smokers
- Risk of SCLC increases with increasing duration and intensity of smoking
- Environmental exposure to tobacco smoke increases risk of lung cancer
- Environmental exposure to pollutants, such as asbestos, combustion-related fine particulate air pollution, and radon exposure
Pathogenesis
- Mutations causing establishment of autocrine growth loops, activation of proto-oncogenes, or loss or inactivation of tumor-suppressors appear to be involved in pathogenesis
- Genes commonly involved include
- Fragile Histidine Triad (FHIT) gene – deletion observed in almost all cases
- Retinoblastoma 1 (RB1) gene – loss observed in almost all cases
- MAD1L1 gene
- Tumor protein 53 (TP53) gene – more common in SCLC than non-small cell lung cancer
- Genes commonly involved include
- Tumor cells exhibit signs of neuroendocrine and neural differentiation, and tumor growth mediated by multiple neuropeptides and polypeptides
Clinical Presentation
- Perform complete history (especially history of cigarette smoking) and physical examination
- Typically with rapid onset of symptoms (typically 8-12 weeks prior to presentation)
- Most present with extrathoracic (hematogenous) metastases; about 33% of patients present with localized disease confined to chest
- Signs and symptoms related to local primary tumor include:
- Dyspnea
- Persistent cough
- Wheezing
- Hemoptysis, particularly if central/cavitary lesion present
- Fever (due to pneumonia)
- Chest pain
- Clubbing of digits
- Signs and symptoms related to invasive primary tumor/regional lymph node metastases include:
- Hoarseness
- Hemidiaphragm elevation, due to phrenic nerve compression
- Dysphagia
- Chest pain (often dull and nonlocalized
- Superior vena cava (SVC) syndrome
- Pericardial effusion/tamponade
- cervical/supraclavicular lymphadenopathy
- Pancoast syndrome
- Horner syndrome
- Signs and symptoms related to extrathoracic (hematogenous) metastases
- Anorexia/cachexia, fatigue
- Brain metastases: headache, focal weakness/numbness, confusion, Slurred speech, gait instability, and lack of coordination
- Leptomeningeal carcinomatosis: headache, confusion, cranial nerve palsy, diplopia, slurred speech, radicular back pain, spinal cord compression
- Adrenal metastases: mid-back/flank pain
- Liver metastases: right upper quadrant pain, jaundice, and Hepatomegaly
- Bone metastases
Making the Diagnosis
- Suspect SCLC in patients with
- Abnormal findings on chest x-ray
- History of cigarette smoking
- Signs and symptoms suggestive of lung malignancy, including coughing, hemoptysis, wheezing, fever, dyspnea, and/or chest pain
- Initial evaluation to establish diagnosis includes:
- Blood tests
- Chest x-ray
- IV contrast-enhanced computed tomography (CT) of chest, abdomen, and pelvis or of chest extending through liver and adrenal glands
- Confirm diagnosis in patients with radiographic/clinical evidence of SCLC with the least invasive biopsy/pathology method possible, options include:
- Sputum cytology
- Thoracentesis
- Bronchoscopy including transbronchial needle aspiration (TBNA)
- Fine needle aspiration (FNA)
- Transthoracic needle aspiration (TTNA)
- Obtain studies for staging, including:
- Brain MRI or IV contrast-enhanced brain CT to detect metastases
- Bone scan
- Initial MRI for suspected single small liver or bone metastatic lesion to avoid delay of treatment due to awaiting pathological confirmation
- PET/CT if suspect limited stage or need clarification of stage
- Additional workup for suspected limited stage disease may include:
- Pulmonary function tests
- Bone MRI or x-ray if PET/CT is inconclusive, followed by bone biopsy if MRI or bone scan is inconclusive
- Head MRI or CT in addition to PET, or abdominal CT plus bone scan in patients with clinical stage I disease considering definitive surgery
- Thoracentesis with cytologic analysis if pleural effusion is present
- Bone marrow aspiration and biopsy in select patients with presentation suggestive of bone marrow involvement
- For never smokers with extensive stage disease, consider molecular profiling to clarify diagnosis and evaluate possible targeted therapies
Differential Diagnosis
Other Cancers
- Non-small cell lung cancer
- Mesothelioma
- Other lung neuroendocrine tumors
- Primary pulmonary lymphoma
- Malignant teratoma
- Pulmonary blastoma – rare malignant tumor
Non-cancer Differential Diagnosis
- Benign neoplasms (such as hamartoma, chondroma, hemangioma)
- Infections
- Healed/nonspecific granulomas
- Granulomatous infections (such as tuberculosis, histoplasmosis, pulmonary aspergilloma, etc.)
- Bacterial infection (nocardiosis, actinomycosis, pneumonia)
- Septic embolus
- Abscess
- Other causes
- Amyloid
- Pulmonary infarction
- Lipoid pneumonia
- Sarcoidosis
- Subpleural lymph node
- Rheumatoid arthritis
- Granulomatosis with polyangiitis
- Focal hemorrhage
- Rib fracture
- Pleural thickening/mass/fluid
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Management
Management of Limited Stage Disease
- If limited stage disease and
- Negative pathologic mediastinal staging, perform lobectomy and mediastinal lymph node dissection or sampling (follow with adjuvant treatment based on findings)
- If lymph nodes negative, offer 4 cycles of adjuvant systemic therapy
- If lymph nodes positive, offer sequential/concurrent systemic therapy with or without mediastinal radiation
- Positive pathologic mediastinal imaging in excess of t1-t2, n0 with:
- Performance status (ps) 0-2, offer concurrent systemic therapy plus thoracic radiation
- Ps 3-4 due to sclc, offer systemic therapy with or without either concurrent or sequential radiation
- Ps 3-4 not due to sclc, offer individualized treatment plan, including use of supportive care
- Medically inoperable disease/decision not to pursue surgical resection, consider either stereotactic ablative radiation therapy (sabr) followed by adjuvant systemic therapy or concurrent systemic therapy plus radiation
- A complete or partial response to initial therapy, offer adjuvant prophylactic cranial irradiation
- Negative pathologic mediastinal staging, perform lobectomy and mediastinal lymph node dissection or sampling (follow with adjuvant treatment based on findings)
Management of Extensive Stage Disease
- For patients with extensive stage disease:
- If no localized symptomatic sites/brain metastases, offer supportive care and base additional treatment on performance status (PS):
- PS 0-2 or 3-4 due to SCLC, offer systemic therapy
- PS 3-4 not due to SCLC, offer an individualized treatment plan
- If localized symptomatic sites with superior vena cava syndrome, lobar obstruction, or bone metastases, treatment options include:
- Systemic therapy with or without radiation to symptomatic sites
- Orthopedic stabilization and palliative external beam radiation (if high risk of fracture)
- If spinal cord compression, consider radiation to symptomatic sites before systemic therapy (unless immediate systemic therapy is indicated)
- If brain metastases, consider:
- If patient asymptomatic, systemic therapy before whole brain radiation
- If patient symptomatic, whole brain radiation before systemic therapy (unless immediate systemic therapy is indicated)
- For patients with a complete or partial response to initial therapy, options include adjuvant prophylactic cranial irradiation or MRI surveillance of brain.
- For those with residual thoracic disease and low-bulk metastatic disease, may also offer sequential thoracic radiation after systemic therapy
- If no localized symptomatic sites/brain metastases, offer supportive care and base additional treatment on performance status (PS):
Management of Relapsed or Progressive Disease
- Offer palliative management to all patients regardless of performance status (PS), including localized radiation to symptomatic sites
- For patients with PS 0-2, offer systemic therapy with response assessment by chest/abdomen/pelvic CT with contrast after every 2-3 cycles
- If response, continue therapy until disease progression/unacceptable toxicity
- If no response or unacceptable toxicity and PS remains 0-2, options include systemic therapy and palliative symptom management
Paraneoplastic Syndromes
- Paraneoplastic syndromes are common in SCLC; may occur months to years before malignancy is detected
- Variety of paraneoplastic syndromes associated with lung cancer and affect many systems, including:
- Endocrine (such as SIADH, Cushing syndrome, hypercalcemia, carcinoid syndrome)
- Neurologic (subacute cerebellar degeneration, encephalomyelitis, and sensory neuropathy)
- Skeletal (hypertrophic osteoarthropathy and clubbing)
- Renal (glomerulonephritis, nephrotic syndrome, metabolic syndrome)
- Collagen-vascular (dermatomyositis, systemic lupus erythematosus, vasculitis, polymyositis)
- Cutaneous (erythema multiforme, red man syndrome, acanthosis nigricans, Sweet syndrome, pruritus and urticaria)
- Hematologic (anemia, leukemoid reaction, Trousseau syndrome, leukocytosis and eosinophilia, thrombocytopenic purpura, disseminated intravascular coagulation and thromboembolism)
Prognosis
- Median survival without treatment reported to be 2-4 months
- Factors associated with improved prognosis include:
- Improved performance status (karnofsky performance status > 80 or ecog 0-1)
- Female sex
- Younger age (age < 70 years, < 65 years, and < 60 years each independently validated)
- Brain metastases develop in up to 50% of patients with extensive stage disease
Prevention
Smoking Cessation
- American Cancer Society (ACS) recommends avoiding tobacco use, environmental tobacco smoke and avoiding radon exposure to reduce risk
- All clinicians should provide smoking cessation interventions
- 5-A strategy for advising patients recommended by United States Preventive Services Task Force (USPSTF)
- Ask about tobacco use
- Advise to quit through clear personalized messages
- Assess willingness to quit
- Assist to quit
- Arrange follow-up and support
- 5-A strategy for advising patients recommended by United States Preventive Services Task Force (USPSTF)
- Combination of counseling and medication is more effective than either alone and both should be offered
- First-line medication options include nicotine replacement therapy, varenicline, or bupropion
- Other smoking cessation techniques may be useful include cognitive behavioral therapy, acupuncture, mind-body interventions, and hypnotherapy
Screening
- Goal is to benefit individuals by increasing life expectancy and quality of life, but with low false-positive results to prevent additional, unnecessary testing
- Low-dose computed tomography (ldct) screening detects lung cancer in about 1%-2% of patients who smoke or have other risk factors
- Screening of lung cancer using ldct recommended or suggested in patients with
- Age 55-74 years, ≥ 30 pack-year history of smoking, and smoking cessation < 15 years
- Age ≥ 50 years, ≥ 20 pack-year history of smoking, and presence of additional risk factors that increase risk of lung cancer to ≥ 1.3%
- Routine lung cancer screening with ldct not recommended or suggested in patients who are asymptomatic and do not meet above criteria
- Ldct screening has high sensitivity and moderate specificity for lung cancer, but may be associated with high rate of false-positives, leading to unnecessary, invasive follow-up procedures
Sources
- van Meerbeeck JP, Fennell DA, De Ruysscher DK. Small-cell lung cancer. Lancet. 2011;378(9804):1741-2755. doi:10.1016/S0140-6736(11)60165-7
- Ost DE, Yeung SC, Tanoue LT, Gould MK. Clinical and organizational factors in the initial evaluation of patients with lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e121S-141S. doi:10.1378/chest.12-2352
- Rivera MP, Mehta AC, Wahidi MM. Establishing the diagnosis of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5 Suppl):e142S-165S. doi:10.1378/chest.12-2353
- Loo BW, Akerley W, Bassetti M, et al. Small cell lung cancer. Version 2.2020. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines). Access to PDF. https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1462
This article originally appeared on Clinical Advisor
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