eMedicine Specialties > Oncology > Carcinomas of the Lung and Other Intrathoracic Carcinomas

Lung Cancer, Oat Cell (Small Cell)

Irfan Maghfoor, MD, Consulting Oncologist, Department of Oncology, King Faisal Specialist Hospital and Research Center, Saudi Arabia
Michael Perry, MD, MS, MACP, Nellie B Smith Chair of Oncology Emeritus, Professor, Department of Internal Medicine, Division of Hematology and Oncology, University of Missouri/Ellis Fischel Cancer Center

Updated: May 22, 2009

Introduction

Background

Small cell lung cancer (SCLC) is considered distinct from other lung cancers, called non–small-cell lung cancers (NSCLCs), because of their clinical and biologic characteristics. Small cell lung cancer exhibits aggressive behavior, with rapid growth, early spread to distant sites, exquisite sensitivity to chemotherapy and radiation, and frequent association with distinct paraneoplastic syndromes. Surgery usually plays no role in its management, except in rare situations.¹

Pathophysiology

Small cell carcinomas arise in peribronchial locations and infiltrate the bronchial submucosa. Widespread metastases occur early in the course of the disease, with common spread to mediastinal lymph nodes, liver, bones, adrenal glands, and brain. In addition, production of a variety of peptide hormones leads to a wide range of paraneoplastic syndromes. The most common paraneoplastic syndromes are the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and the syndrome of ectopic adrenocorticotropic hormone (ACTH) production. In addition, autoimmune phenomena may lead to various neurological syndromes.

Molecular pathogenesis

Recent studies have identified both activation of oncogenes and inactivation of tumor suppressor genes in small cell lung cancer. To what extent these changes are causal events in the development of small cell lung cancer is not clearly known and remains an area of active research.

Oncogenes

Amplification of the myc family of oncogenes is the most common molecular abnormality identified in small cell lung cancer cell lines, xenografts in nude mice, and fresh tumor specimens. This change, however, is not identified in all small cell lung cancer tumors. Therefore, myc expression is unlikely to be an initial event in the pathogenesis of small cell lung cancer. C-myc, a member of the myc family, is found more commonly in relapsed tumors than in untreated tumors, and its expression in small cell lung cancer may carry a worse prognosis.

Other members of the myc oncogene family include N-myc and L-myc, which have been found to be amplified in small cell lung cancer. N-myc amplification in small cell lung cancer also has been associated with resistance to therapy and poorer prognosis. Overall, the exact role of amplification of the myc family of oncogenes in the pathogenesis of small cell lung cancer is not clearly understood at present and requires further study.

Other oncogenes that have been found to be amplified in small cell lung cancer include c-raf, c-erb -b1, and c-fms, but their association with pathogenesis and prognosis is even less clear.

Tumor suppressor genes

The retinoblastoma (RB) tumor suppressor gene is on chromosome 13 (13q14), and a high percentage of small cell lung cancers (as many as 60%) do not express RB messenger ribonucleic acid (mRNA). This high frequency of inactivation of a tumor suppressor gene suggests that this may be an important step in the molecular pathogenesis of small cell lung cancer. The most common molecular abnormality, however, is deletion of part of chromosome 3 (3p14). Mutations of the p53 tumor suppressor gene are commonly found in both small cell lung cancer and non-small-cell lung cancer, but their precise role in pathogenesis is not clear. Tobacco smoking and radon exposure are associated with p53 gene mutations.

Frequency

United States

Lung cancer is the second most common malignancy in both sexes, second only to prostate cancer in men and breast cancer in women. More women die of lung cancer each year than die of breast cancer. About 215,020 new lung cancer cases (114,690 in men and 100,330 in women) are expected to be diagnosed in the United States in 2008,  and 161,840 people (90,810 men and 71,030 women) are expected to die from lung cancer in 2008,  accounting for approximately one third of all cancer related deaths in the United States in 2008.² The epidemiology of small cell lung cancer (SCLC) has not changed over the last 30 years. The incidence of small cell lung cancer was about 20-25% of all newly diagnosed lung cancers in the past. It currently stands at 13%.

International

Globally, lung cancer is the most frequent malignancy in males, while it is the fifth most common cancer in females. According to World Health Organization (WHO) statistics, slightly more than 1 million cases of lung cancer are diagnosed annually around the world. This is less than expected, and the disparity most likely results from lack of diagnosis and/or underreporting in the developing countries.

Mortality/Morbidity

Approximately 65-70% of patients with small cell lung cancer have disseminated or extensive disease at presentation. Extensive-stage small cell lung cancers are incurable, and patients with extensive disease have a median survival duration of 6 weeks. Patients presenting with localized disease (ie, limited stage) have a median survival duration of about 12 weeks. These survival figures are for untreated patients. The median survival of patients with small cell lung cancer who are treated with multiple agent chemotherapy and multimodality therapy are as follows:

• For limited disease, 20 months with a 2-year survival rate of 45% and a 5-year survival rate of 20%
• For extensive disease, 12 months with a 2-year survival rate in 1973 of 1.5% and 2-year survival rate in 2000 of 4.6%

Race

Separate data for small cell carcinoma are not available. Among men, the age-adjusted incidence of lung cancer (per 100,000) ranges from 14 in Native Americans, 42-53 for Hispanic and Chinese Americans, 71-89 for Vietnamese and whites, to 117 among blacks. Among women, the age-adjusted incidence of lung cancer ranges from 15 among Japanese persons, 16-25 among Hispanic and Chinese persons, 31-44 among Vietnamese, white, and black persons to 51 among Alaskan natives. Among each ethnic group, the incidence is at least twice as high in males as in females. Age-adjusted mortality rates among different ethnic groups follow a similar pattern.

Sex

The incidence of lung cancer is twice as high in males as in females. See Frequency. The incidence of lung cancer started to decline among males in the early 1980s and has continued to do so over past 20 years. By contrast, the incidence in women started to increase in the late 1970s and only recently reached a plateau.

Age

According to information from the American Cancer Society, the probabilities of developing lung cancer among males are as follows: from birth to 39 years, 0.04%; 40-59 years, 1.24%; 60-79 years, 6.29%; and from birth to death, 8.09%. Among females, the probabilities are as follows: from birth to 39 years, 0.03%; 40-59 years, 0.92%; 60-79 years, 4.04%; and birth to death, 5.78%. As with other histopathological cases of lung cancer, most cases of small cell lung cancer occur in individuals aged 35-75 years; incidence peaks in persons aged 55-65 years.

Clinical

History

For patients with small cell lung cancer (SCLC) to present without any symptoms is very unusual. Fewer than 5% of patients have a small, asymptomatic primary tumor at presentation. Small cell lung cancer typically presents with a relatively short duration of symptoms. The onset of symptoms is usually within 8-12 weeks prior to presentation. The symptoms can result from local tumor growth, intrathoracic spread, distant spread, and/or paraneoplastic syndromes. Symptoms include the following:

• Constitutional symptoms
  • Fatigue
  • Anorexia
  • Weight loss
• Symptoms due to primary tumor
  • Cough
  • Dyspnea
  • Hemoptysis
• Symptoms due to intrathoracic spread
  • Superior vena cava obstruction
  • Hoarseness (ie, palsy of the recurrent laryngeal nerve)
  • Phrenic nerve palsy
  • Dysphagia (ie, compression of esophagus)
  • Stridor (ie, compression of the trachea mainstem bronchus)
• Symptoms due to distant spread
  • Neurological dysfunction (ie, brain metastasis, spinal cord compression)
  • Bone pain (bone metastasis)
  • Abdominal/right upper quadrant pain (ie, liver metastasis)
• Local tumor growth: Small cell carcinomas usually are centrally located and may cause irritation, obstruction, or both of the major airway. Common symptoms resulting from local tumor growth include cough, dyspnea, and hemoptysis. Patients give a short history of symptoms of recent onset, with rapid worsening. Rapid tumor growth may lead to obstruction of major airways, with distal collapse and consequent postobstructive pneumonitis. Fever may result from infections distal to obstruction or from the tumor itself.
• Intrathoracic spread: Small cell carcinomas grow in size rapidly and metastasize to the mediastinal lymph nodes relatively early in the course of the disease. At presentation, patients may have a very large intrathoracic tumor, and distinguishing primary tumor from lymph node metastasis may be impossible. Pressure on mediastinal structures can cause a variety of symptoms.
  • Superior vena cava obstruction: Malignancy is the most common cause of superior vena cava (SVC) obstruction, and lung cancer accounts for the overwhelming majority of cases (60-90%). Small cell lung cancer causes SVC obstruction more often than non-small-cell lung cancer (NSCLC) does. Patients present with swelling of the face and upper extremities. Headache, dizziness, and other neurological symptoms are late occurrences.
  • Paralysis of the recurrent laryngeal nerve: The recurrent laryngeal nerve may be compressed by a mediastinal mass (ie, primary tumor or lymph node metastasis) as it traverses up on the left to supply the vocal cords. Patients complain of hoarseness of recent onset.
  • Phrenic nerve palsy: Compression of the phrenic nerve causes paralysis of the ipsilateral hemidiaphragm, contributing to respiratory symptoms.
  • Esophageal compression: Compression of the esophagus can lead to dysphagia and odynophagia.
  • Tracheal compression: Compression of the mainstem bronchi and trachea can cause severe shortness of breath and stridor.
• Symptoms from distant spread: These symptoms depend upon the site of spread. Common sites of spread include brain, bones, liver, adrenals, and bone marrow.

Table 1. Paraneoplastic Syndromes*

*For more information, see Paraneoplastic Syndromes.

Physical

Physical findings in small cell lung cancer (SCLC) depend upon the extent of local and distant spread and the organ system involved.

• Respiratory system: Patients usually complain of shortness of breath, and examination may reveal use of accessory muscles of respiration (scalene muscles, intercostal muscles, flaring of alae of nose). In addition, by virtue of central tumor location, patients may develop distal atelectasis and postobstructive pneumonia. With pleural effusion, examination reveals dullness to percussion and decreased or absent breath sounds on the side of the effusion.
• Cardiovascular system: Small cell lung cancer may cause pericardial effusion and is the malignancy that most often causes obstruction of the SVC.
  • Pericardial effusion: Pericardial effusions may be asymptomatic when small or may result in tamponade if they are large or accumulate over a short period. Patients are usually short of breath. Heart sounds may be distant on auscultation. Jugular venous pulsation is elevated; paradoxically, it rises with inspiration.
  • Pulsus paradoxus is a classic sign of pericardial tamponade. The diagnosis is established with cardiac catheterization, which reveals equalization of pressures in cardiac chambers. Tamponade is an emergency and requires immediate decompression of the pericardium. Definitive management may include chemotherapy and/or surgical creation of a pleuropericardial window.
• Central nervous system: Patients with small cell lung cancer may have asymptomatic brain metastasis in 5-10% of cases, which may be picked up on staging workup.
  • Brain metastasis: Patients with symptomatic brain metastases may have raised intracranial pressure secondary to mass lesions, as well as surrounding brain edema, and may complain of headache (usually worse early in the morning), blurring of vision, photophobia, nausea, vomiting, and various localizing symptoms, such as weakness of an extremity. The physical findings again are dependent upon site of the brain lesions.
    • The examination should include funduscopy to look for signs of raised intracranial pressure and a detailed neurologic examination, including evaluation of cerebellar function, coordination, and gait.
    • The diagnosis is established with a CT scan of the brain with contrast (if renal function is adequate). In difficult cases, a magnetic resonance scan of the brain may be appropriate. Since MRI is more sensitive than CT scan with contrast for detection of brain metastasis, it is used as the first-line imaging study in many institutions.
    • Management includes high doses of corticosteroids (eg, dexamethasone 10 mg IV initially, followed by 4-6 mg IV/PO q6h) and immediate radiation therapy.
  • Vertebral and paraspinal metastases: The importance of early recognition of these metastases is due to their close proximity to the spinal cord, potentially leading to permanent loss of neurological function if diagnosis is delayed. The initial symptom is usually back pain, with or without neurological dysfunction.
    • The main objective is to establish diagnosis early, before neurological dysfunction is established. Once present, neurological dysfunction can progress very rapidly (ie, within hours) to cause quadriplegia or paraplegia, depending upon the location. This condition is an oncologic emergency.
    • Even though a CT myelogram can establish the diagnosis, MRI is noninvasive and very sensitive in establishing the diagnosis.
    • Patients in whom spinal cord compression is suspected should receive a dose of intravenous corticosteroids even before being sent to the MRI suite. The typical dose is 10 mg of dexamethasone IV, followed by 4-6 mg IV/PO every 6 hours. The authors prefer the intravenous route because of the reliability of drug delivery.
    • If the etiological cause is known (ie, a prior histologic diagnosis of SCLC), definitive management is radiation therapy, which should be started without any delay. Otherwise, if the patient presents with spinal cord compression and no prior diagnosis of cancer, surgical resection, if technically feasible, provides both immediate decompression and tissue diagnosis of the cancer.
• Gastrointestinal system: The liver is the common site of spread, and physical examination may reveal icterus (secondary to widespread liver metastasis or obstruction of biliary outflow) or hepatomegaly. However, most patients do not have any specific finding related to the gastrointestinal tract on examination.
• Lymphatic system: Lymph node examination should be carried out carefully. Currently, enlarged ipsilateral supraclavicular lymph nodes are included in limited stage, but enlarged axillary lymph nodes upstage the diagnosis to extensive-stage disease.
• Extremities: Examination of the extremities may reveal clubbing, cyanosis, or edema. In the presence of SVC obstruction, the right upper extremity usually is edematous.

Causes

The predominant cause of small cell lung cancer, as of non-small-cell lung cancer, is tobacco smoking. Of all histologic types of lung cancer, in fact, small cell lung cancer and squamous cell carcinoma have the strongest correlation to tobacco. Some 98% of patients with small cell lung cancer have a smoking history. Patients with diagnosed small cell lung cancer should be encouraged or required to stop smoking; this may contribute to improved survival.

• Uranium mining: All types of lung cancers occur with increased frequency in uranium miners, but small cell lung cancer is most common. The incidence is increased further in persons who smoke tobacco.
• Radon exposure: Exposure to radon, which is an inert gas developing from the decay of uranium, also has been reported to cause small cell lung cancer.

Differential Diagnoses

Lung Cancer, Non-Small Cell
Lymphoma, Mediastinal

Workup

Laboratory Studies

A full staging workup for small cell lung cancer (SCLC) is described in Staging.

Investigations are performed to identify limited-stage disease (ie, potentially curable and requiring the addition of radiotherapy to its management), as well as to assess organ function before starting therapy.

• CBC count: In 5-10% of patients, the disease may have spread to bone marrow at presentation. Bone marrow examination is not routinely performed unless abnormalities are identified in the CBC count or peripheral smear examination, raising the possibility of bone marrow spread. These may include variable degrees of cytopenias; the presence of immature white and red blood cells (a leukoerythroblastic blood picture) raises the possibility of myelophthisic anemia. Additionally, the absolute neutrophil count should be >1000 x 10³/µL, hemoglobin >10 g/dL, and platelet count >100 x 10³/µL before instituting initial full-dose combination chemotherapy.
• Serum chemistries: Elevated serum calcium and alkaline phosphatase raise the suspicion of bone metastasis, and bone scan should be ordered even in the absence of symptoms. Serum electrolytes should be obtained to look for paraneoplastic syndromes, as already discussed. The presence of hyponatremia is considered an adverse prognostic indicator. Elevated serum lactate dehydrogenase (LDH) indicates increased tumor mass and cell turnover and is an adverse prognostic indicator. Abnormal liver function findings raise the possibility of hepatic metastasis and may provide a clue to the cause (eg, biliary outflow obstruction versus parenchymal liver metastasis).

Imaging Studies

• CT scans: The patient in whom lung cancer is suspected or diagnosed should undergo imaging of the thorax and all common sites of metastasis to stage the disease adequately. In the United States, CT scans of the chest and upper abdomen to include the liver and adrenal glands are standard. Even though some controversy exists regarding routine pretreatment CT/MRI scanning of the brain in asymptomatic patients, most authors consider it prudent to obtain a baseline scan of the brain in all patients.
• Magnetic resonance imaging: MRI scans are not part of the routine staging workup of small cell lung cancer, even though they have been shown to detect abnormal bone marrow signal in patients with bone marrow metastasis. MRI scans have an increased ability to detect disease in proximity to neurovascular structures. MRI examination is considered standard in the workup of patients in whom spinal cord compression is suspected.
• Radionuclide imaging: Bone metastases from small cell lung cancer are predominantly osteoblastic, and a bone scan is superior to plain radiographs in detecting osteoblastic lesions. Bone scans should be obtained in all patients with small cell lung cancer at diagnosis or during follow-up if new bone symptoms develop or if serum calcium or alkaline phosphatase level is elevated.
• Positron emission tomography: Positron emission tomography (PET) scanning still is under evaluation for lung cancers and, to date, has had its greatest application in non-small-cell lung cancer, in which it is used to more accurately stage patients prior to anticipated surgery.

Other Tests

• Sputum cytology is a noninvasive test, and, if positive, usually allows more invasive diagnostic tests to be averted. The highest yield of this test is with large, central tumors. However, because small cell lung cancer cells involve the submucosal layer of the bronchi with little or no exophytic endobronchial extension sputum cytology may be uncommonly positive. This may be true as well of bronchial washings.
• Bronchoscopy: Small cell lung cancer is usually centrally located and can be approached easily with a bronchoscope. The advantage of endoscopy is direct visualization of the tumor, allowing direct biopsy as well as cytologic examination of bronchial washings.
• Transthoracic percutaneous fine-needle aspiration: For accessible tumors, this test is less invasive than bronchoscopy and is carried out under CT scan guidance.

Procedures

• Thoracentesis: The presence of malignant pleural effusion upstages the disease to extensive stage. For adequate staging, pleural effusions should be aspirated and examined for malignant cells if no other sites of distant spread are identified. If a large symptomatic pleural effusion is present, therapeutic thoracentesis provides symptomatic relief. In patients with resistant, relapsed, or nonresponding disease, thoracentesis can be combined with pleurodesis to prevent recurrence. The preferred agent is currently sterilized talc, which can be instilled either as a slurry or as a powder during pleuroscopy. A large randomized study conducted by Cancer and Leukemia Group B will likely answer the question of whether slurry or poudrage is superior.
• Bone marrow aspiration and biopsy: Bone marrow examination is necessary in patients in whom myelophthisic anemia (leukoerythroblastic peripheral blood) is suspected.

Histologic Findings

Small cell lung cancer is typically centrally located, arising in peribronchial locations. They are thought to arise from Kulchitsky cells.

• The tumor is composed of sheets of small, round cells with dark nuclei, scant cytoplasm, fine granular nuclear chromatin, and indistinct nucleoli.
• Crush artifact leading to nuclear molding is a common finding, but it is not considered diagnostic.
• Very high rates of cell division are observed, and necrosis, sometimes extensive, may be seen. Because of the central location, the cells exfoliate in sputum and bronchial washings.
• Neurosecretory granules can be identified on electron microscopy, and the neuroendocrine nature of the neoplasm is suggested by its frequent association with paraneoplastic syndromes caused by peptide hormones.
• Immunohistochemical stains for chromogranin, neuron-specific enolase, and synaptophysin are usually positive.
• Approximately 5% of small cell lung cancers exhibit features of mixed small cell and large cell components and, less frequently, may exhibit mixed small cell and squamous cell components.
• The World Health Organization (WHO) classified small cell lung cancers into 3 subcategories: oat cell carcinoma, intermediate cell type, and combined oat cell carcinoma. This subclassification has been difficult to reproduce, however, even by expert lung cancer pathologists, and in 1988, the International Association for the Study of Lung Cancer recommended dropping the intermediate cell type from the classification and adding the category of mixed small cell carcinoma and large cell carcinoma.

Staging

The 2-stage system used for small cell lung cancer initially was proposed by the Veterans Administration Lung Group. Patients with disease confined to one hemithorax, with or without mediastinal, contralateral hilar, or ipsilateral supraclavicular or scalene lymph nodes are considered to have limited-stage disease, while those with disease involvement at any other location are considered to have extensive-stage disease. (The involvement of supraclavicular nodes and the presence of cytologically positive pleural effusion subsequently have been placed in different stage groupings in slightly revised staging classifications.) The key variable in this purposely vague staging definition is the ability to encompass the entire disease within one radiation therapy port. A slight modification of this system is used currently and is as follows:

• Limited stage: Disease confined to one hemithorax; includes involvement of mediastinal, contralateral hilar, and/or supraclavicular and scalene lymph nodes. Malignant pleural effusion is excluded.
• Extensive stage: Disease has spread beyond the definition of limited stage, or malignant pleural effusion is present.

The purpose of the staging workup is to determine the prognosis and management of small cell lung cancer. Patients with limited-stage disease are offered combined chemoradiotherapy, while those with extensive-stage disease are usually treated with chemotherapy alone.

• Staging workup of small cell lung cancer is as follows:
  • Complete history and physical examination
  • Chest radiograph
  • CT scans of chest and abdomen
  • CT scan/MRI of brain
  • Bone scan
  • CBC count with differential
  • Bone marrow aspiration and biopsy if abnormalities in CBC count or peripheral smear
  • Serum electrolytes, including calcium
  • Liver function tests
  • Renal function tests
  • Serum LDH
  • Serum alkaline phosphatase
• History and physical examination: A thorough history and physical examination usually provide clues to the organ systems involved and are used to guide further workup.
• Chest roentgenogram: Good posteroanterior and lateral radiographs are useful in identifying the primary tumor as well as concurrent parenchymal abnormalities. Mediastinal widening may be noticed as well.
• CT scans of chest and abdomen: Evaluation via CT scan of thorax (lungs and mediastinum) and commonly involved abdominal viscera (ie, liver, adrenals) is the minimum requirement in standard staging workup of small cell lung cancer.
• Bone scan: Bone is a common site of metastasis for small cell lung cancer, and a radionuclide bone scan should be obtained to identify bone metastases. Since some benign etiologies can also cause abnormalities on bone scan, obtaining plain radiographs of abnormal areas for radiographic correlation is important.
• CT scan/MRI of brain: Brain metastasis may be present in as many as 10% of patients at diagnosis and may be occult in 5% of patients. Even though obtaining imaging scans of brain in all patients at diagnosis is controversial, the policy of most authors is to obtain a scan of the brain at diagnosis for adequate staging.
• Bone marrow examination: Even though some authorities recommend a bone marrow examination in patients in whom no other site of spread is identified (ie, in cases in which detection of bone marrow involvement would change the staging from limited to extensive disease), the majority of authors recommend bone marrow examination only in patients in whom bone marrow involvement is suspected owing to abnormal findings on CBC count or peripheral smear.
• Blood workup
  • CBC count with differential, serum electrolytes, renal function studies, and liver function tests are all are part of the routine staging workup, and in some cases they may identify the site of metastasis, for instance elevated serum calcium level with bone metastasis. These tests are also important to assess organ function prior to starting therapy.
  • Serum LDH and sodium levels also provide prognostic information. Increased uric acid levels may indicate the possibility of rapid tumor lysis syndrome with therapy.

Treatment

Medical Care

Small cell lung cancer (SCLC) differs from other lung cancer types because of its rapid growth and propensity for early dissemination. Surgery plays little, if any, role in the management of small cell lung cancer, except in a small minority of patients who present with very early stage disease confined to lung parenchyma. 

Patients with limited stage disease with apparent clinical stage T1/T2, N0 should undergo mediastinoscopy. Should the mediastinoscopy prove to be negative, they might have a surgical resection to involve lobectomy, wedge resection, or pneumonectomy together with mediastinal lymph node removal.¹ If mediastinal lymph node involvement is not found, then consideration should be given to a 4-6 cycle course of adjuvant chemotherapy with combinations of agents known to be effective in limited or extensive disease, that is etoposide and either cisplatin or carboplatin. This would be a reasonable recommendation despite the relative lack of evidence-based data to support it because of the aggressive nature of small cell lung cancer and its known tendency to metastasize early and often.

Management of limited-stage small cell lung cancer involves combination chemotherapy, usually with a platinum-containing regimen, and thoracic radiation therapy. If the patient achieves a complete remission, he or she would be offered prophylactic cranial irradiation.

Table 2. Commonly Used Chemotherapy Regimens in Small Cell Lung Cancer

• Single-agent chemotherapy: Several chemotherapeutic agents have been identified in the last 3 decades that yield response rates in excess of 30% in previously untreated patients who have small cell lung cancer. Even though cisplatin is currently the most widely used agent in combination chemotherapy programs, response rate data for single-agent cisplatin in previously untreated patients with small cell lung cancer are lacking. In previously treated patients, however, cisplatin has shown a response rate of 17%.
  • Currently cisplatin, etoposide, vincristine, doxorubicin, and cyclophosphamide are the agents most commonly employed to treat previously untreated patients with small cell lung cancer. Scheduling of etoposide has been demonstrated to be important in achieving a higher response rate, and currently etoposide is given over 3 days.
  • Protracted oral administration of etoposide has been an acceptable initial therapy in elderly patients with extensive-stage small cell lung cancer, especially in those with poor performance status, but more recent studies suggest combination chemotherapy may be better than single-agent oral etoposide in those with good performance status.
  • The taxanes and topotecan have emerged as active agents in previously untreated patients with small cell lung cancer. The response rates range from approximately 40% with topotecan to 50% with paclitaxel.
• Combination chemotherapy: Even though a few studies have suggested that the response rates and survival may be comparable between single-agent etoposide and more standard combination chemotherapy regimens in previously untreated patients with small cell lung cancer, combination chemotherapy is accepted widely as being associated with superior response rates and survival. A number of randomized trials have tried to answer the questions of superiority of combination over single-agent chemotherapy, the number of drugs in combination, and dose intensity, and nonrandomized trials of combination chemotherapy have shown superior response rates and survival compared to single-agent chemotherapy.
  • The combination of cisplatin and etoposide (PE) is currently the most widely used regimen in both limited- and extensive-stage small cell lung cancer.
  • The combination of cyclophosphamide, doxorubicin (Adriamycin), and vincristine (CAV) has been compared to PE in at least 2 randomized trials of previously untreated extensive-stage small cell lung cancer showing similar survival outcomes.
  • The combination of cisplatin and etoposide is associated with less myelosuppression, while CAV has the convenience of administration in a single day (PE requires a 3-day program).
• Dose intensity and density: Several trials have tested the use of higher doses of standard chemotherapeutic regimens in previously untreated small cell lung cancer. Despite early enthusiasm brought on by higher initial response rates, most of these trials have failed to improve survival.
  • A trial reported by Arriagada et al comparing standard and higher doses of cyclophosphamide and cisplatin in the first cycle of chemotherapy only yielded a superior survival rate in patients receiving higher dose chemotherapy.⁴ Higher dose regimens, however, may cause life-threatening myelosuppression and, in the absence of survival advantage, should not be used outside a clinical trial.
  • Another approach to increase the intensity of chemotherapy is to shorten the interval between cycles (increased dose density). Again, even though phase II trials suggested the superiority of such an approach, randomized trials failed to show an advantage of intensive weekly chemotherapy over standard regimens. One of the problems has been myelosuppression with weekly programs such that the planned dose intensity has not been reached. Growth factor support may overcome this, but until randomized trials are reported showing clear superiority of such an approach, it remains investigational.
• High-dose chemotherapy with bone marrow or stem cell transplantation: The available data do not support the use of such an approach because it has not yielded better survival rates than standard management and is associated with greater immediate and delayed toxicity.
• Standard management of limited-stage small cell lung cancer: Staging should be adequate. Any pleural effusion should be tested cytologically for malignant cells, and isolated liver or adrenal lesions should be sampled by fine-needle aspiration before a diagnosis of limited stage is made. Some authorities suggest a bone marrow examination in the absence of any other evidence of spread.
  • Standard management involves combination chemotherapy with a cisplatin-containing regimen and concurrent thoracic radiotherapy. The chemotherapy cycles are repeated every 3 weeks, and currently no data support continuation of chemotherapy beyond 6 cycles. In North America, the chemotherapy regimen used is etoposide and cisplatin. (Should the patient relapse after 6 months of completion of induction therapy, an attempt may be made to repeat the induction regimen. Relapses prior to the 6 month point would require salvage therapy.)
    • Patients are started on thoracic radiotherapy, which should be begun as early as possible according to some authorities. Others advocate giving the radiation therapy concomitantly with the fourth cycle of chemotherapy.
    • A randomized trial reported by Takada and colleagues that compared cisplatin and etoposide with concurrent versus sequential thoracic radiotherapy reported superior 2- and 5-year survival rates (2-y survival 35.1% versus 54.4%, and 5-y survival 18.3% versus 23.7% in favor of concurrent chemotherapy and radiation) with concurrent approach. Hematologic toxicity was greater in concurrent arm.⁵
    • Another randomized trial by Turrisi and colleagues demonstrated a slight superiority of concurrent hyperfractionated radiotherapy given with 4 cycles of PE in limited-stage small cell lung cancer. Five-year survival rates in this trial were 26% versus 16% in favor of hyperfractionated radiotherapy.⁶
  • Prophylactic cranial irradiation: The use of prophylactic cranial irradiation (PCI) was initially considered controversial.⁷ Several randomized trials showed a decrease in CNS relapse rate with PCI but no survival advantage. Additionally, patients receiving PCI had a higher incidence of neuropsychiatric dysfunction than those who did not receive PCI. Arriagada et al reported a meta-analysis of randomized trials of PCI in limited-stage small cell lung cancer and showed a 5% overall survival advantage in those receiving PCI.⁴ Even though such an analysis has inherent limitations, PCI is currently offered to patients with limited-stage small cell lung cancer who have achieved complete remission after having completed the full chemoradiotherapy regimen. Such therapy decreases the incidence of later intracranial metastases and prolongs survival. It should be regarded as standard therapy.
• Standard management of extensive-stage small cell lung cancer: Patients with extensive-stage disease are treated with combination chemotherapy alone. Even though a combination of cisplatin and etoposide remains most widely used, a recently reported randomized trial compared the combination of cisplatin with either etoposide or irinotecan in extensive-stage small cell lung cancer. The combination of cisplatin and irinotecan was found superior to that of cisplatin and etoposide, with a median survival of 12.8 months with the cisplatin/irinotecan combination versus 9.4 months with cisplatin and etoposide. The 2-year survival rate was also superior at 19.5% versus 5.2%.^8,9  
  
  However, a confirmatory study in the United States failed to show superiority of either regimen. Possible reasons for these results may be different dose and schedule of chemotherapeutic agents as well as genetic changes within different study populations. Although etoposide/cisplatin and irinotecan/cisplatin had comparable overall response rates and survival outcomes, the combination irinotecan/cisplatin had more gastrointestinal toxicity.¹⁰
  
  Etoposide/cisplatin remains the standard of care in North America for extensive small cell lung cancer. A recent clinical trial in Germany reported that topotecan/cisplatin had a similar overall response rate to etoposide/cisplatin in extensive small cell lung cancer but a better time to progression and objective response rate than did etoposide/cisplatin.¹¹ A trial comparing the two regimens in North America has not yet been performed.    
  • Radiation therapy is used only to palliate symptoms, if required (eg, for painful bone metastases). Response rates are excellent, but patients invariably relapse.
  • Brain metastases at the time of initial diagnosis in extensive small cell lung cancer is present in about 18% of patients. This incidence increases to about 80% at 2 years. A recent study by the European Organization for Research and Treatment of Cancer (EORTC) randomized patients responding to systemic chemotherapy between prophylactic cranial radiation (PCI) versus no PCI. One-year survival for PCI group was 27.1% compared to 13.3% for those without PCI. Prophylactic cranial radiation not only reduced the incidence of brain metastases but also improved disease-free and overall survival rates. Thus, PCI should be offered to all responding patients with extensive stage small cell lung cancer and should be considered standard of therapy for this stage of the disease in these patients. 
  • Management of relapse: Patients with relapsed small cell lung cancer have an extremely poor prognosis. Those whose disease does not respond to or progresses on initial treatment (ie, those with refractory disease) or those whose disease relapses within 6 months of completion of therapy have little chance of responding to additional chemotherapy. In general, PE given after CAV failure produces better response rates than CAV given after PE. Topotecan received US Food and Drug Administration (FDA) approval for use in chemotherapy-sensitive disease after failure of front-line chemotherapy. Because of the lack of long-term benefit of this therapy, however, patients with relapsed or refractory small cell lung cancer should be encouraged to enroll in clinical trials, if their condition permits.

Surgical Care

See Medical Care.

Consultations

Patients in whom lung cancer is suspected may require consultation with a pulmonologist to establish a diagnosis. Once a diagnosis is established, medical and radiation oncologists should be consulted to complete the staging workup and devise a management plan.

Diet

Weight loss is an important factor indicating poor prognosis in patients with small cell lung cancer. A dietary consultation should be obtained for patients with persistent weight loss.

Activity

Performance status is another important prognostic factor. Patients who are ambulating less than 50% of waking hours have a worse prognosis. Activity should be encouraged.

Medication

The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.

Antiemetic agents

Vomiting induced by antineoplastic agents is stimulated through the chemoreceptor trigger zone (CTZ), which then stimulates the vomiting center (VC) in the brain. Increased activity of central neurotransmitters, dopamine in CTZ or acetylcholine in VC, appears to be a major mediator in inducing vomiting. Following administration of antineoplastic agents, serotonin (5-HT) is released from enterochromaffin cells in the GI tract. With serotonin release and subsequent binding to 5-HT3 receptors, vagal neurons are stimulated and transmit signals to the VC, resulting in nausea and vomiting.

Antineoplastic agents may cause nausea and vomiting so intolerable that some patients refuse further treatment. Some antineoplastic agents are more emetogenic than others. Prophylaxis with antiemetic agents prior to and following cancer treatment is often essential to ensure administration of the entire chemotherapy regimen.

Metoclopramide (Clopra, Reglan, Maxolon, Octamide PFS)

Dopamine antagonist that stimulates acetylcholine release in myenteric plexus. Acts centrally on chemoreceptor triggers in floor of fourth ventricle, which provides important antiemetic activity.

Dosing

Adult

5-10 mg PO or 5-20 mg IV/IM tid

Pediatric

Not established

Interactions

Opioid analgesics may increase toxicity in CNS; may cause additive effects with other drugs that cause extrapyramidal reactions; MAOIs, tricyclic antidepressants, or sympathomimetics may cause hypertension; may increase serum levels of cyclosporine, sirolimus, or tacrolimus; may decrease digoxin serum levels

Contraindications

Documented hypersensitivity; pheochromocytoma; GI hemorrhage, obstruction, or perforation; history of seizure disorders

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in breastfeeding women, depression, hypertension, Parkinson disease, and conditions aggravated by anticholinergic or antidopaminergic effects; may cause tardive dyskinesia

Dexamethasone (Decadron)

Synthetic adrenocortical steroid with multiple indications. Widely used in combination with serotonin receptor antagonists in prevention of nausea and vomiting caused by highly emetogenic agents (eg, cisplatin).

Dosing

Adult

8-20 mg PO/IV 30 min prior to chemotherapy combined with 5-HT3-receptor antagonist

Pediatric

Not established

Interactions

Induces CYP-450 3A4, and coadministration of other CYP-450 3A4 enzyme inducers (ie, barbiturates, phenytoin, rifampin) decreases effects; decreases effects of salicylates and vaccines used for immunization; may antagonize effects of neuromuscular blockers

Contraindications

Documented hypersensitivity; active infection

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Increases risk of multiple complications, including severe infections; monitor adrenal function when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications; if mother exposed to substantial doses of corticosteroids during pregnancy, monitor infant for hypoadrenalism

Ondansetron (Zofran)

Selective 5-HT3-receptor antagonist. Unclear whether effect is centrally and/or peripherally mediated. Used to prevent chemotherapy-induced nausea and vomiting.

Dosing

Adult

8 mg PO 30 min before chemotherapy; repeat once following 8 h, then bid/tid for 1-2 d after completion of chemotherapy; dosage in elderly population is same
32 mg IV infused over 15 min 30 min before chemotherapy; alternatively, 0.15 mg/kg IV 30 min before chemotherapy, repeat q4h for 2 doses
Not to exceed 8 mg/d in severe liver disease

Pediatric

Not established

Interactions

Although potential for cytochrome P-450 inducers (eg, barbiturates, rifampin, carbamazepine, phenytoin) to change half-life and clearance, dosage adjustment usually not required

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Administer for prevention of nausea and vomiting, not for rescue of nausea and vomiting; headache occurs commonly (up to 40%)

Granisetron (Kytril)

Selective 5-HT3-receptor antagonist. Unclear whether effect is centrally and/or peripherally mediated. Used to prevent chemotherapy-induced nausea and vomiting.

Dosing

Adult

1-2 mg PO as single dose within 1 h before chemotherapy; no dose adjustment for elderly persons
10 mcg/kg IV 30 min before chemotherapy, usual dose 700-1000 mcg IV

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

To be administered for prevention of nausea and vomiting, not for rescue of nausea and vomiting; caution in liver disease

Dolasetron (Anzemet)

Binds to 5-HT3 receptors located on vagal neurons in GI tract, blocking signal to VC, thus preventing nausea and vomiting.

Dosing

Adult

100 mg/dose PO as single dose within 1 h before chemotherapy; no dose adjustment for elderly persons
1.8 mg/kg IV 30 min before chemotherapy; not to exceed 100 mg/dose; alternatively 100 mg IV 30 min before chemotherapy

Pediatric

Not established

Interactions

Although potential for CYP-450 inducers (eg, barbiturates, rifampin, carbamazepine, phenytoin) to decrease half-life and increase clearance, dosage adjustment usually not required; CYP-450 3A4 inhibitors (eg, itraconazole, erythromycin, ritonavir) may decrease clearance; coadministration with drugs prolonging QT interval (eg, sotalol, amiodarone) may exacerbate cardiotoxicity

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

To be administered for prevention of nausea and vomiting, not for rescue of nausea and vomiting; may prolong QT interval, mildly elevates LFTs

Palonosetron (Aloxi)

Selective 5-HT3 receptor antagonist with long half-life (40 h). Indicated for prevention and treatment of chemotherapy-induced nausea and vomiting. Blocks 5-HT3 receptors peripherally and centrally in chemoreceptor trigger zone.

Dosing

Adult

0.25 mg IV once (30 min before chemotherapy); administer over 30 sec; do not repeat dose within 7 d

Pediatric

<18 years: Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

May cause headache, constipation, diarrhea, or dizziness

Antineoplastic agents

Used in curative therapy of limited-stage small cell lung cancer or to prolong survival in extensive-stage disease. Cancer chemotherapy is based on an understanding of tumor cell growth and how drugs affect this growth. After cells divide, they enter a period of growth (ie, cell-cycle phase G1), followed by DNA synthesis (ie, phase S). The next phase is a premitotic phase (ie, G2); then, finally, mitotic cell division (ie, phase M) occurs.

The cell division rate varies for different tumors. Most common cancers grow very slowly compared with the growth rate of normal tissues, and the rate may decrease further in large tumors. This difference allows normal cells to recover more quickly from chemotherapy than malignant ones, which is the rationale behind current cyclic dosage schedules. Dosage cycles are determined by cancer stage and tolerance of adverse effects.

Antineoplastic agents interfere with cell reproduction. Some agents are cell-cycle specific, while others (eg, alkylating agents, anthracycline, cisplatin) are not. Cellular apoptosis (ie, programmed cell death) also is a potential mechanism of action of many antineoplastic agents.

Etoposide (Toposar, VePesid)

Inhibits topoisomerase II and causes DNA strand breakage, causing cell proliferation to arrest in late S or early G2 portion of cell cycle.

Dosing

Adult

PE regimen: 100 mg/m² IV days 1-3 of cycle, repeat every 3-4 wk for 4-6 cycles
CAVE regimen: 100 mg/m² IV day 1 of cycle, repeat every 3-4 wk for 4-6 cycles
PEC regimen: alternate 50 mg/d and 100 mg/d PO on days 1-10 of cycle, repeat every 3-4 wk for 4-6 cycles
Single-agent regimen: 50 mg PO bid for days 1-14 of cycles, repeat cycle every 3-4 wk for 4-6 cycles
Adjust dose in hepatic or renal dysfunction
Total bilirubin (TB) 1.5-3 mg/dL: 50% dose reduction
TB 3.1-4.9 mg/dL: 75% dose reduction
TB >5: Avoid use
CrCl 15-50 mL/min: 25% dose reduction

Pediatric

Not established

Interactions

May prolong effects of warfarin and increase clearance of methotrexate; cyclosporine has additive effects in cytotoxicity of tumor cells; high dose of cyclosporine (serum concentration >2000 ng/mL) decreases clearance, leading to increased risk of neutropenia; zidovudine increases serum concentration, resulting in increased toxicity

Contraindications

Documented hypersensitivity; IT administration (may cause death)

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Bleeding, severe myelosuppression, nausea, vomiting, hypotension, allergic reaction, and alopecia may occur; reduce dose in hepatic (eg, increased TB) or renal (eg, decreased CrCl) impairment

Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Dosing

Adult

CAV or CAVE regimens: 1000 mg/m² IV on day 1 of cycle, repeat every 3-4 wk for 4-6 cycles

Pediatric

Not established

Interactions

Fatal cardiotoxicity reported with coadministration of pentostatin
Allopurinol may increase risk of bleeding or infection and exacerbate myelosuppressive effects; may potentiate anthracycline-induced cardiotoxicity; may reduce digoxin (tab) serum levels and antimicrobial effects of quinolones; chloramphenicol may increase half-life while decreasing metabolite concentrations; may increase effect of anticoagulants; CYP-450 enzyme inducers (eg, phenobarbital, phenytoin, rifampin, carbamazepine) may increase rate of cyclophosphamide metabolism; thiazide diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular blockade by inhibiting cholinesterase activity; ondansetron may decrease serum levels and half-life

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Doxorubicin (Adriamycin, Rubex)

Inhibits topoisomerase II and produces free radicals, which may cause destruction of DNA. The combination of these 2 events can in turn inhibit growth of neoplastic cells.

Dosing

Adult

CAV or CAVE regimens: 50 mg/m² IV on day 1 of cycle, repeat every 3-4 wk for 4-6 cycles

Pediatric

Not established

Interactions

May decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity; cyclophosphamide increases cardiac toxicity

Contraindications

Documented hypersensitivity; severe heart failure; cardiomyopathy; impaired cardiac function; completed cumulative doses of anthracyclines or anthracenes; preexisting myelosuppression

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Irreversible cardiac toxicity and myelosuppression may occur; extravasation may result in severe local tissue necrosis; reduce dose with impaired hepatic function

Vincristine (Oncovin)

Inhibits tubulin polymerization during mitosis. G2 phase specific.

Dosing

Adult

CAV or CAVE regimens: 1.4 mg/m² IV push; not to exceed 2 mg/dose on day 1 of cycle, repeat every 3-4 wk for 4-6 cycles

Pediatric

Not established

Interactions

Mitomycin-C may cause acute pulmonary reaction; asparaginase, colony-stimulating factors (eg, sargramostim, filgrastim), or nifedipine increases toxicity; CYP-450 3A4 inducers (ie, carbamazepine, phenytoin, phenobarbital, rifampin) may increase clearance; CYP-450 3A4 inhibitors (ie, itraconazole, quinupristin/dalfopristin, sertraline, ritonavir) may decrease clearance

Contraindications

Documented hypersensitivity; IT administration (may be fatal)

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in severe cardiopulmonary impairment, hepatic impairment (decrease dose), or preexisting neuromuscular disease

Topotecan (Hycamtin)

Inhibits topoisomerase I, inhibiting DNA replication.

Dosing

Adult

IV: Single-agent regimen: 1.5 mg/m²/d IV over 30 min days 1-5 of cycle, repeat every 3-4 wk for 4-6 cycles
PO: 2.3 mg/m²/d PO qd for days 1-5 of cycle; repeat q21d
Modify dose with bone marrow toxicity or grade III/IV diarrhea

Pediatric

Not established

Interactions

Other antineoplastics may result in prolonged neutropenia and thrombocytopenia, in addition to increased morbidity/mortality

Contraindications

Documented hypersensitivity; bone marrow suppression; renal dysfunction

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Adverse effects include myelosuppression and neutropenic fever, dermatitis, nausea, and vomiting; monitor bone marrow function; decrease dose in renal failure

Paclitaxel (Taxol)

Mechanisms of action are tubulin polymerization and microtubule stabilization.

Dosing

Adult

200 mg/m² IV on day 1 of cycle, repeat every 3-4 wk for 4-6 cycles

Pediatric

Not established

Interactions

Cisplatin may further increase myelosuppression; CYP-450 3A4 inducers (ie, carbamazepine, phenytoin, phenobarbital, rifampin) may increase clearance; CYP-450 3A4 inhibitors (ie, itraconazole, quinupristin/dalfopristin, sertraline, ritonavir) may decrease clearance

Contraindications

Documented hypersensitivity; peripheral neuropathy; bone marrow suppression; liver failure; severe cardiac disease

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Premedicate with corticosteroids, H1 and H2 blockers to decrease risk of hypersensitivity reactions; myelosuppression, alopecia, arthralgia/myalgias, and cardiac arrhythmias may occur; is vesicant, use extravasation precautions; decrease dose in hepatic impairment

Carboplatin (Paraplatin)

Analog of cisplatin (ie, platinum-salt alkylating agent). Has similar efficacy as cisplatin but with lower toxicity profile. Mechanism of action for cisplatin and carboplatin is production of cross-links within and between strands of DNA.

Dosing

Adult

Dose based on following formula:
Total dose (mg) = (target AUC) X (GFR+25); where AUC expressed in mg/mL/min and GFR expressed in mL/min
Total dose (mg) = 6 mg/mL/min X (GFR + 25) IV on day 1 of cycle, repeat every 3-4 wk for 4-6 cycles

Pediatric

Not established

Interactions

Nephrotoxicity and ototoxicity increase with aminoglycosides and other nephrotoxic drugs

Contraindications

Documented hypersensitivity; bone marrow suppression

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor bone marrow function; do not use needles containing aluminum (forms precipitant); caution in renal impairment (adjust dose); elderly or those previously treated with cisplatin at risk of peripheral neuropathy; high doses associated with vision loss

Cisplatin (Platinol)

Alkylating agent causing intrastrand and interstrand cross-linking of DNA, leading to strand breakage. Has broad range of antitumor activity. Use in testicular, ovarian, and transitional cell carcinomas. Forms backbone of currently available approved combination chemotherapy regimens for NSCLC and SCLC.

Dosing

Adult

PE (cisplatin-etoposide) regimen: 25 mg/m² IV days 1-3 of cycle, repeat every 3-4 wk for 4-6 cycles (or 100 mg/m² IV day 1)

Pediatric

Not established

Interactions

Increases toxicity of bleomycin and ethacrynic acid; other nephrotoxic drugs (eg, aminoglycosides, amphotericin B, cyclosporine) increase nephrotoxicity; bleomycin, cytarabine, methotrexate, and ifosfamide may accumulate owing to decreased renal excretion; may worsen cytotoxicity of etoposide; mesna and sodium thiosulfate directly inactivate cisplatin; dipyridamole increases cytotoxicity by enhancing cellular uptake; paclitaxel-related peripheral neuropathy may be increased in patients previously treated with cisplatin

Contraindications

Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Administer adequate hydration before and for 24 h after cisplatin dosing to reduce risk of nephrotoxicity; myelosuppression, ototoxicity, nausea, and vomiting may occur; peripheral blood cell counts and serum electrolyte levels should be monitored; requires close monitoring of pretreatment creatinine level and CrCl and posttreatment magnesium levels; neurologic examination should be performed regularly; major dose-limiting toxic effect is peripheral neuropathy; can cause acute or chronic renal failure in up to one third of patients treated but this can usually be prevented by vigorous hydration and saline diuresis; renal tubular wasting of potassium and magnesium is common (monitor closely); cellulitis and fibrosis have rarely occurred after extravasation; avoid aluminum needles

Follow-up

Further Outpatient Care

• Patients with small cell lung cancer (SCLC) require close monitoring for adverse effects and response to therapy. Blood work, including CBC with differential, is needed prior to each cycle of chemotherapy to ensure marrow recovery before the next dose of chemotherapy is administered. Renal function should be monitored because of nephrotoxicity from cisplatin.
• CT scans should be obtained after 2 cycles of therapy to assess response before chemotherapy is continued.
• Serum LDH, if elevated before start of therapy, is a good marker for response and should be monitored.

Deterrence/Prevention

Smoking cessation: Since tobacco smoking is the predominant cause of lung cancer, the only means of decreasing the incidence is decreasing the prevalence of smoking. The evidence is clear that the incidence of lung cancer is decreasing in men in the United States, and this decrease has coincided with a decrease in smoking among males. Concerted efforts are required from government, public health agencies, and health care providers to increase public awareness of the hazards of smoking, devise tougher laws to restrict teen smoking, and restrict smoking in public places.

Complications

• Tumor lysis syndrome: Tumor lysis can occur rapidly in patients with small cell lung cancer on institution of chemotherapy, especially in extensive-stage disease. The laboratory features of tumor lysis syndrome (TLS) are hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia. Patients should be well hydrated and, preferably, premedicated with allopurinol. The management of established tumor lysis syndrome is urinary alkalinization, correction of electrolyte abnormalities, and dialysis, if necessary.
• Spinal cord compression: A thorough neurologic examination and radiologic evaluation of the spine is indicated with any suspicion of spinal cord compression. The goal is to prevent development of neurological deficit.
• Hyponatremia results from inappropriate secretion of ADH, which results in the inability of the kidneys to excrete free water. SIADH is reported in 5-10% of patients with small cell lung cancer. Serum sodium is usually less than 130 mEq/L. Other causes of hyponatremia (ie, volume depletion, abnormal renal function) must be excluded. Fluid restriction and pharmacologic therapy in the form of demeclocycline (a tetracycline antibiotic that decreases the sensitivity of renal tubules to the action of ADH) are usual forms of management.

Patient Education

For excellent patient education resources, visit eMedicine's Cancer and Tumors Center. Also, see eMedicine's patient education articles Lung Cancer and Bronchoscopy.

Miscellaneous

Medicolegal Pitfalls

• Delay in diagnosis and treatment: Because of rapid tumor growth and early dissemination, any delay in instituting therapy may result in upstaging of the tumor from limited to extensive stage, thus converting a potentially curable illness to incurable disease.
• Effects of therapy: Small cell lung cancers may respond very quickly to chemotherapy, which carries a risk of rapid tumor lysis, especially in extensive-stage disease, with associated life-threatening electrolyte abnormalities and risk of renal shutdown. Therefore, treating physicians must remember this potential adverse effect, and patients should be hydrated adequately and, preferably, premedicated with allopurinol.
• Spinal cord compression: New onset of back pain in patients known to have malignant disease should raise the suspicion of cord compression. A thorough neurologic examination and radiologic evaluation of the spine is indicated with any suspicion of spinal cord compression. The goal is to prevent development of neurological deficit. Once present, a neurological deficit can progress within hours to cause complete paraplegia. Any delay in instituting appropriate therapy may result in permanent neurological deficit.
• Electrolyte abnormalities: Small cell lung cancer is associated with a number of electrolyte abnormalities because of frequent production of peptide hormones. The most common abnormality is hyponatremia, and, if severe, it may cause neurological symptoms and signs, including seizures, coma, and death. Prompt recognition of abnormality and severity is important. Management has been discussed already.

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Keywords

small cell lung cancer, SCLC, non–small-cell lung cancers, NSCLCs, lung cancer treatment, lung cancer diagnosis, lung cancer symptoms, small cell carcinoma, SCC, oat cell carcinoma, paraneoplastic syndromes, tumor suppressor genes

Contributor Information and Disclosures

Author

Irfan Maghfoor, MD, Consulting Oncologist, Department of Oncology, King Faisal Specialist Hospital and Research Center, Saudi Arabia
Irfan Maghfoor, MD is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Michael Perry, MD, MS, MACP, Nellie B Smith Chair of Oncology Emeritus, Professor, Department of Internal Medicine, Division of Hematology and Oncology, University of Missouri/Ellis Fischel Cancer Center
Michael Perry, MD, MS, MACP is a member of the following medical societies: Alpha Omega Alpha, American Association for Cancer Research, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, International Association for the Study of Lung Cancer, and Missouri State Medical Association
Disclosure: Bionumerik Consulting fee Consulting; Proactya Consulting fee Consulting; GSK Consulting fee Consulting; NovoNordisk Consulting fee Consulting; Amgen Honoraria Speaking and teaching; GSK Consulting fee Speaking and teaching

Medical Editor

Antoni Ribas, MD, Department of Medicine, Division of Hematology-Oncology, Assistant Professor of Medicine, University of California at Los Angeles Medical Center
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Wendy Hu, MD, Consulting Staff, Department of Hematology/Oncology and Bone Marrow Transplantation, Huntington Memorial Medical Center
Wendy Hu, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Physicians, American Society for Blood and Marrow Transplantation, American Society of Hematology, and Physicians for Social Responsibility
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

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