SYMPOSIUM ON SOLID TUMORS
Small Cell Lung Cancer

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Small cell lung cancer accounts for approximately 15% of bronchogenic carcinomas. It is the cancer most commonly associated with various paraneoplastic syndromes, including the syndrome of inappropriate antidiuretic hormone secretion, paraneoplastic cerebellar degeneration, and Lambert-Eaton myasthenic syndrome. Because of the high propensity of small cell lung cancer to metastasize early, surgery has a limited role as primary therapy. Although the disease is highly sensitive to chemotherapy and radiation, cure is difficult to achieve. The combination of platinum and etoposide is the accepted standard chemotherapeutic regimen. It is also the accepted standard therapy in combination with thoracic radiotherapy (TRT) for limited-stage disease. Adding TRT increases absolute survival by approximately 5% over chemotherapy alone. Thoracic radiotherapy administered concurrently with chemotherapy is more efficacious than sequential therapy. Furthermore, the survival benefit is greater if TRT is given early rather than late in the course of chemotherapy. Regardless of disease stage, no relevant survival benefit results from increased chemotherapy dose intensity or dose density, altered mode of administration (eg, alternating or sequential administration) of various chemotherapeutic agents, or maintenance chemotherapy. Prophylactic cranial radiation prevents central nervous system recurrence and can improve survival. In Japan and some other Asian countries, the combination of irinotecan and cisplatin is the standard chemotherapeutic regimen. Clinical trials using thalidomide, gefitinib, imatinib, temsirolimus, and farnesyltransferase inhibitors have not shown clinical benefit. Other novel agents such as bevacizumab have shown promising early results and are being evaluated in larger trials.

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PATHOLOGY

Histologically, the tumor cells are small, round to ovoid or spindle shaped, with scant cytoplasm. The mitotic count is high; cells grow in clusters that exhibit neither glandular nor squamous organization. Electron microscopy shows dense-core neurosecretory granules 100 nm in diameter. Nearly all SCLC are immunoreactive for keratin, thyroid-transcription factor 1, and epithelial membrane antigen. Neuroendocrine and neural differentiation result in the expression of dopa decarboxylase,

ETIOLOGY AND PATHOGENESIS

The most important known cause of SCLC is cigarette smoking,9 accounting for approximately 95% of cases. Interaction of environmental factors with the genome of the respiratory epithelium results in carcinogenesis in susceptible patients.

Increasing evidence has implicated autocrine growth loops, proto-oncogenes, and tumor-suppressor genes in the pathogenesis of SCLC. Several chromosome and oncogene abnormalities have been identified in fresh SCLC tissues and cell lines, such as deletions on the

HEREDITARY PREDISPOSITION TO LUNG CANCER

The Genetic Epidemiology of Lung Cancer Consortium (GELCC) conducted the first family linkage study searching for susceptibility genes for lung cancer. This study identified linkage of lung, laryngeal, and pharyngeal cancer in families to a region on chromosome 6q23-25.32, 33, 34 Attempts at defining genetic susceptibility are ongoing. Studies have identified people with certain alleles of the CYP1A1 gene to have an increased capacity to metabolize procarcinogens derived from cigarette smoke

CLINICAL DIAGNOSIS AND STAGING

The most common presenting symptoms are dyspnea, persistent cough, and hemoptysis. Postobstructive pneumonia may be the presenting clinical syndrome. Small cell lung cancer is the most common malignant cause of superior vena cava syndrome. Metastatic disease can produce pain, headache, malaise, seizures, fatigue, anorexia, and weight loss. Common sites of metastasis include bone, liver, lymph node, the central nervous system, adrenal glands, subcutaneous tissue, and pleura.37 Pancoast tumor,

NATURAL HISTORY

Historical survival data for people with untreated SCLC came from an early VALCSG trial in which cyclophosphamide treatment was compared with placebo. In this trial, median survival was 12 weeks for patients with LD and 6 weeks for patients with ED. Small cell lung cancer is very responsive to chemotherapy, with major responses in 70% to 90% of cases on initial treatment. However, most patients relapse and die within 2 years. The most important prognostic features are disease stage, performance

Limited-Stage Disease

At diagnosis, approximately 30% of patients with SCLC have LD.48, 49, 50 Combined modality treatment with chemotherapy and concurrent radiotherapy is the current standard of treatment. Addition of radiation to chemotherapy produces modest but significant improvement in survival. Two meta-analyses have shown a 5% improvement in 3-year survival rates for patients receiving a combination of chemotherapy and radiation vs those receiving chemotherapy alone.51, 52

With its propensity for early

CONCLUSION

Small cell lung cancer remains a therapeutic challenge despite high initial responses to chemotherapy and radiotherapy. The 5-year survival is 15% to 25% for patients with LD-SCLC and less than 1% for patients with ED-SCLC. Concurrent chemoradiation therapy in patients with LD-SCLC and PCI are the primary advances made in therapy during the past decade. The fact that several promising molecularly targeted agents have not shown adequate activity in the clinical setting does not spell the doom of

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