January 13, 2007

Lung Cancer, Oat Cell (Small Cell)

Synonyms and related keywords: small cell lung cancer, SCLC, non–small-cell lung cancers, NSCLCs, small cell carcinoma, SCC, oat cell carcinoma, paraneoplastic syndromes, tumor suppressor genes


Background: Small cell lung cancer (SCLC) is considered distinct from the other lung cancers, called non–small-cell lung cancers (NSCLCs), because of their clinical and biologic characteristics. SCLC 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 (less than 5% of patients) in which it presents at a very early stage as a solitary pulmonary nodule. Even then, adjuvant chemotherapy after surgical resection is recommended, since SCLC always should be considered a systemic disease.

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 SCLC. To what extent these changes are causal events in the development of SCLC 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 SCLC cell lines, xenografts in nude mice, and fresh tumor specimens. This change, however, is not identified in all SCLC tumors. Therefore, myc expression is unlikely to be an initial event in the pathogenesis of SCLC. C-myc, a member of the myc family, is found more commonly in relapsed tumors than in untreated tumors, and its expression in SCLC 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 SCLC. N-myc amplification in SCLC 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 SCLC is not clearly understood at present and requires further study.

Other oncogenes that have been found to be amplified in SCLC 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 SCLCs (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 SCLC. The most common molecular abnormality, however, is deletion of part of chromosome 3 (3p14). Mutations of the p53 tumor suppressor gene are found commonly in both SCLC and NSCLC, but their precise role in pathogenesis is not clear. Tobacco smoking and radon exposure are associated with p53 gene mutations.


Mortality/Morbidity: Approximately 65-70% of patients with SCLC have disseminated disease at presentation. Extensive-stage SCLCs are incurable, and patients with extensive disease have a median survival duration of less than 1 year. Even patients presenting with localized disease (ie, limited stage) have a median survival duration of less than 2 years. The 5-year survival rate for SCLC is less than 20%.

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, 16-25 among Hispanics and Chinese, 31-44 among Vietnamese, whites, and blacks 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. In the United States, 169,500 new lung cancer cases were expected in 2001: approximately 90,700 in males and 78,800 in females. 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 the following: 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%.


History: For patients with SCLC to present without any symptoms is very unusual. Less than 5% of patients have a small, asymptomatic primary tumor at presentation. SCLC typically presents with a relatively short duration of symptoms. The onset of symptoms usually is 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:

Physical: Physical findings in 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: SCLC may cause pericardial effusion and is the malignancy most often causing 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 usually are 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 SCLC 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, eg, 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 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 every 6 hours) 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 usually is 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 GI 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 SCLC, as of NSCLC, is tobacco smoking. Of all histologic types of lung cancer, in fact, SCLC and squamous cell carcinoma have the strongest correlation to tobacco.

  • Uranium miners: All types of lung cancers occur with increased frequency in uranium miners, but SCLC is most common. The incidence is increased further in smokers.
  • Radon: Exposure to radon, which is an inert gas developing from the decay of uranium, also has been reported to cause SCLC.


Lung Cancer, Non-Small Cell
Lymphoma, Mediastinal


Lab Studies:

  • 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 performed routinely 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/mL, hemoglobin >10 g/dL, and platelet count >100 x 103/mL 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 adequately stage the disease. 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 SCLC, 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 SCLC 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 SCLC 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 NSCLC, 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.
  • Bronchoscopy: SCLC usually is 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.


  • 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 currently is 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: SCLC typically are 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 usually are positive.
  • Approximately 5% of SCLCs exhibit features of mixed small cell and large cell components and, less frequently, may exhibit mixed small cell and squamous cell components.
  • The WHO classified SCLCs 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 and large cell carcinoma.

Staging: Almost all solid tumors are staged by utilizing the tumor, node, metastases (TNM) system because it provides important prognostic information and is used to design management plans. However, the TNM system has failed to provide important prognostic information in patients with SCLC and is useful only in a few patients (less than 5%) who may benefit from a very detailed staging according to the TNM system.

The 2-stage system used for SCLC 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 provided in Table 2.

Table 2. Staging of Small Cell Carcinoma of Lung

Stage Description
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 SCLC. Patients with limited-stage disease are offered combined chemoradiotherapy, while those with extensive-stage disease usually are treated with chemotherapy alone.


Medical Care: As discussed earlier, 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 SCLC, except in a small minority of patients who present with very early stage disease confined to lung parenchyma. If the diagnosis of SCLC is established before resection by nonsurgical means, ie, sputum cytology, bronchoscopy, or transthoracic percutaneous needle biopsy, these patients should be offered chemotherapy and radiation as opposed to primary surgical resection.

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

Extensive-stage SCLC remains incurable with current management options, and patients are treated with combination chemotherapy. Several chemotherapy combinations are active in SCLC, but usually a platinum-containing regimen is chosen.

Table 3. Commonly Used Chemotherapy Regimens in Small Cell Lung Cancer

Cyclophosphamide 1000 mg/m2 IV day 1
Doxorubicin (Adriamycin) 50 mg/m2 IV day 1
Vincristine 2 mg IV
Cisplatin 25 mg/m2 IV days 1-3
Etoposide 100 mg/m2 IV days 1-3
Cyclophosphamide 1000 mg/m2 IV day 1
Doxorubicin (Adriamycin) 50 mg/m2 IV day 1
Vincristine 1.4 mg/m2 IV day 1 (maximum 2 mg)
Etoposide 100 mg/m2 IV day 1
Paclitaxel 200 mg/m2 IV day 1
Etoposide 50 mg PO per day alternating with
100 mg PO per day from days 1-10
Carboplatin AUC 6 IV day 1
Topotecan 1.5 mg/m2 IV day 1-5
Etoposide 50 mg PO bid days 1-14

  • 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 SCLC. Even though cisplatin currently is the most widely utilized agent in combination chemotherapy programs, response rate data for single-agent cisplatin in previously untreated patients with SCLC 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 SCLC. 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 SCLC, especially in those with poor performance status, but recent studies suggest combination chemotherapy may be better than single-agent oral etoposide in those with good performance status.
    • More recently, the taxanes and topotecan have emerged as active agents in previously untreated patients with SCLC. 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 SCLC, 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) currently is the most widely used regimen in both limited- and extensive-stage SCLC.
    • 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 SCLC 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 SCLC. 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. 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 SCLC: 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. The cycles are repeated every 3 weeks, and currently no data support continuation of chemotherapy beyond 6 cycles. 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.

      Another recent randomized trial by Turrisi and colleagues demonstrated a slight superiority of concurrent hyperfractionated radiotherapy given with 4 cycles of PE in limited-stage SCLC. Five-year survival rates in this trial were 26% versus 16% in favor of hyperfractionated radiotherapy.

    • Prophylactic cranial irradiation: Until recently, the use of prophylactic cranial irradiation (PCI) was controversial. 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 recently reported a meta-analysis of randomized trials of PCI in limited-stage SCLC and showed a 5% overall survival advantage in those receiving PCI. Even though such an analysis has inherent limitations, PCI currently is offered to patients with limited-stage SCLC who have achieved complete remission after having completed the full chemoradiotherapy regimen.
  • Standard management of extensive-stage SCLC: 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 SCLC. 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%. At present, a combination of cisplatin with either etoposide or irinotecan appears appropriate as first-line therapy for extensive-stage SCLC.
    • Radiation therapy is used only to palliate symptoms, if required (eg, for painful bone metastases). Response rates are excellent, but patients invariably relapse.
    • PCI currently is not offered routinely to patients with extensive-stage SCLC who have achieved complete remission after chemoradiotherapy.
  • Management of relapse: Patients with relapsed SCLC 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. Patients who have a progression-free interval of more than 6 months are candidates for additional chemotherapy. Because of the lack of long-term benefit of this therapy, however, patients with relapsed or refractory SCLC should be encouraged to enroll in clinical trials, if their condition permits.

Surgical Care: Most patients with SCLC are treated nonsurgically. The exceptions are the relatively small number of patients (less than 5%) who present with very early stage disease confined to the lung without any lymph node involvement. Such patients usually undergo resection of lung tumors as the initial diagnostic procedure. Even in these patients, surgery alone is not considered curative, and they should be offered adjuvant chemotherapy. Veterans Administration trials have reported superior survival in patients who received adjuvant chemotherapy than in those who did not.

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 SCLC. 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.


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

Drug Category: 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 patients refuse further treatment. Some antineoplastic agents are more emetogenic than others. Prophylaxis with antiemetic agents prior to and following cancer treatment often is essential to ensure administration of the entire chemotherapy regimen.

Drug Name
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.
Adult Dose5-10 mg PO or 5-20 mg IV/IM tid
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; pheochromocytoma; GI hemorrhage, obstruction, or perforation; history of seizure disorders
InteractionsOpioid 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
Pregnancy B - Usually safe but benefits must outweigh the risks.
PrecautionsCaution in breastfeeding women, depression, hypertension, Parkinson disease, and conditions aggravated by anticholinergic or antidopaminergic effects; may cause tardive dyskinesia
Drug Name
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).
Adult Dose8-20 mg PO/IV 30 min prior to chemotherapy combined with 5-HT3-receptor antagonist
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; active infection
InteractionsInduces 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
Pregnancy C - Safety for use during pregnancy has not been established.
PrecautionsIncreases 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
Drug Name
Ondansetron (Zofran) -- Selective 5-HT3-receptor antagonist. Unclear whether effect is centrally and/or peripherally mediated. Used to prevent chemotherapy-induced nausea and vomiting.
Adult Dose8 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 DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsAlthough potential for cytochrome P-450 inducers (eg, barbiturates, rifampin, carbamazepine, phenytoin) to change half-life and clearance, dosage adjustment usually not required
Pregnancy B - Usually safe but benefits must outweigh the risks.
PrecautionsAdminister for prevention of nausea and vomiting, not for rescue of nausea and vomiting; headache occurs commonly (up to 40%)
Drug Name
Granisetron (Kytril) -- Selective 5-HT3-receptor antagonist. Unclear whether effect is centrally and/or peripherally mediated. Used to prevent chemotherapy-induced nausea and vomiting.
Adult Dose1-2 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 DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsNone reported
Pregnancy B - Usually safe but benefits must outweigh the risks.
PrecautionsTo be administered for prevention of nausea and vomiting, not for rescue of nausea and vomiting; caution in liver disease
Drug Name
Dolasetron (Anzemet) -- Binds to 5-HT3 receptors located on vagal neurons in GI tract, blocking signal to VC, thus preventing nausea and vomiting.
Adult Dose100 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 DoseNot established
ContraindicationsDocumented hypersensitivity
InteractionsAlthough 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
Pregnancy B - Usually safe but benefits must outweigh the risks.
PrecautionsTo be administered for prevention of nausea and vomiting, not for rescue of nausea and vomiting; may prolong QT interval, mildly elevates LFTs
Drug Name
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.
Adult Dose0.25 mg IV once (30 min before chemotherapy); administer over 30 sec; do not repeat dose within 7 d
Pediatric Doseless than 18 years: Not established
ContraindicationsDocumented hypersensitivity
InteractionsNone reported
Pregnancy B - Usually safe but benefits must outweigh the risks.
PrecautionsMay cause headache, constipation, diarrhea, or dizziness
Drug Category: Antineoplastic agents -- Used in curative therapy of limited-stage SCLC 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.
Drug Name
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.
Adult DosePE 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: 100% dose reduction
TB >5: Avoid use
CrCl 15-50 mL/min: 25% dose reduction
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; IT administration (may cause death)
InteractionsMay 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
Pregnancy D - Unsafe in pregnancy
PrecautionsBleeding, severe myelosuppression, nausea, vomiting, hypotension, allergic reaction, and alopecia may occur; reduce dose in hepatic (eg, increased TB) or renal (eg, decreased CrCl) impairment
Drug Name
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.
Adult DoseCAV or CAVE regimens: 1000 mg/m2 IV on day 1 of cycle, repeat every 3-4 wk for 4-6 cycles
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; severely depressed bone marrow function
InteractionsFatal 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
Pregnancy D - Unsafe in pregnancy
PrecautionsRegularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis
Drug Name
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.
Adult DoseCAV or CAVE regimens: 50 mg/m2 IV on day 1 of cycle, repeat every 3-4 wk for 4-6 cycles
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; severe heart failure; cardiomyopathy; impaired cardiac function; completed cumulative doses of anthracyclines or anthracenes; preexisting myelosuppression
InteractionsMay decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels; cyclosporine may induce coma or seizures; mercaptopurine increases toxicity; cyclophosphamide increases cardiac toxicity
Pregnancy D - Unsafe in pregnancy
PrecautionsIrreversible cardiac toxicity and myelosuppression may occur; extravasation may result in severe local tissue necrosis; reduce dose with impaired hepatic function
Drug Name
Vincristine (Oncovin) -- Inhibits tubulin polymerization during mitosis. G2 phase specific.
Adult DoseCAV 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 DoseNot established
ContraindicationsDocumented hypersensitivity; IT administration (may be fatal)
InteractionsMitomycin-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
Pregnancy D - Unsafe in pregnancy
PrecautionsCaution in severe cardiopulmonary impairment, hepatic impairment (decrease dose), or preexisting neuromuscular disease
Drug Name
Topotecan (Hycamtin) -- Inhibits topoisomerase I, inhibiting DNA replication.
Adult DoseSingle-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
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; bone marrow suppression; renal dysfunction
InteractionsOther antineoplastics may result in prolonged neutropenia and thrombocytopenia, in addition to increased morbidity/mortality
Pregnancy D - Unsafe in pregnancy
PrecautionsAdverse effects include myelosuppression and neutropenic fever, dermatitis, nausea, and vomiting; monitor bone marrow function; decrease dose in renal failure
Drug Name
Paclitaxel (Taxol) -- Mechanisms of action are tubulin polymerization and microtubule stabilization.
Adult Dose200 mg/m2 IV on day 1 of cycle, repeat every 3-4 wk for 4-6 cycles
Pediatric DoseNot established
ContraindicationsDocumented hypersensitivity; peripheral neuropathy; bone marrow suppression; liver failure; severe cardiac disease
InteractionsCisplatin 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
Pregnancy D - Unsafe in pregnancy
PrecautionsPremedicate 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
Drug Name
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.
Adult DoseDose 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 DoseNot established
ContraindicationsDocumented hypersensitivity; bone marrow suppression
InteractionsNephrotoxicity and ototoxicity increase with aminoglycosides and other nephrotoxic drugs
Pregnancy D - Unsafe in pregnancy
PrecautionsMonitor 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
Drug Name
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.
Adult DosePE (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 DoseNot established
ContraindicationsDocumented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment
InteractionsIncreases 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
Pregnancy D - Unsafe in pregnancy
PrecautionsAdminister 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


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