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
INTRODUCTION
- 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*
Organ System Syndrome Mechanism Frequency Endocrine SIADH Antidiuretic hormone 5-10% Ectopic secretion of ACTH Adrenocor-
ticotropic hormone5% Atrial natriuretic factor Neurological Eaton-Lambert reverse myasthenic syndrome 5-6% Subacute cerebellar degeneration Subacute sensory neuropathy Limbic encephalopathy Anti-Hu, Anti-Yo antibodies *For more information, see Paraneoplastic Syndromes.
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.
DIFFERENTIALS
Lung Cancer, Non-Small Cell
Lymphoma, Mediastinal
WORKUP
- 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.
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 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.
- 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.
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. |
- Complete history and physical examination
- Chest x-ray
- CT scans of chest and abdomen
- CT/MRI scan of brain
- Bone scan
- CBC with differential
- Bone marrow aspiration and biopsy if abnormalities in CBC 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 SCLC.
TREATMENT
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
| Regimen | Dose |
|---|---|
| CAV | |
| Cyclophosphamide | 1000 mg/m2 IV day 1 |
| Doxorubicin (Adriamycin) | 50 mg/m2 IV day 1 |
| Vincristine | 2 mg IV |
| PE | |
| Cisplatin | 25 mg/m2 IV days 1-3 |
| Etoposide | 100 mg/m2 IV days 1-3 |
| CAVE | |
| 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 |
| PEC | |
| 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 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.
- 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.
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.
MEDICATION
The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.
| 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 Dose | 5-10 mg PO or 5-20 mg IV/IM tid |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; pheochromocytoma; GI hemorrhage, obstruction, or perforation; history of seizure disorders |
| 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 |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | Caution 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 Dose | 8-20 mg PO/IV 30 min prior to chemotherapy combined with 5-HT3-receptor antagonist |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; active infection |
| 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 |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| 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 |
| 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 Dose | 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 Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | Although 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. |
| Precautions | Administer 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 Dose | 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 Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | None reported |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | To 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 Dose | 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 Dose | Not established |
| Contraindications | Documented hypersensitivity |
| 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 |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | To 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 Dose | 0.25 mg IV once (30 min before chemotherapy); administer over 30 sec; do not repeat dose within 7 d |
| Pediatric Dose | less than 18 years: Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | None reported |
| Pregnancy | B - Usually safe but benefits must outweigh the risks. |
| Precautions | May cause headache, constipation, diarrhea, or dizziness |
| 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 Dose | 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: 100% dose reduction TB >5: Avoid use CrCl 15-50 mL/min: 25% dose reduction |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; IT administration (may cause death) |
| 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 |
| Pregnancy | D - Unsafe in pregnancy |
| 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 |
| 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 Dose | CAV or CAVE regimens: 1000 mg/m2 IV on day 1 of cycle, repeat every 3-4 wk for 4-6 cycles |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; severely depressed bone marrow function |
| 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 |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Regularly 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 Dose | CAV or CAVE regimens: 50 mg/m2 IV on day 1 of cycle, repeat every 3-4 wk for 4-6 cycles |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; severe heart failure; cardiomyopathy; impaired cardiac function; completed cumulative doses of anthracyclines or anthracenes; preexisting myelosuppression |
| 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 |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Irreversible 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 Dose | 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 Dose | Not established |
| Contraindications | Documented hypersensitivity; IT administration (may be fatal) |
| 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 |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Caution in severe cardiopulmonary impairment, hepatic impairment (decrease dose), or preexisting neuromuscular disease |
| Drug Name | Topotecan (Hycamtin) -- Inhibits topoisomerase I, inhibiting DNA replication. |
|---|---|
| Adult Dose | 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 |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; bone marrow suppression; renal dysfunction |
| Interactions | Other antineoplastics may result in prolonged neutropenia and thrombocytopenia, in addition to increased morbidity/mortality |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Adverse 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 Dose | 200 mg/m2 IV on day 1 of cycle, repeat every 3-4 wk for 4-6 cycles |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; peripheral neuropathy; bone marrow suppression; liver failure; severe cardiac disease |
| 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 |
| Pregnancy | D - Unsafe in pregnancy |
| 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 |
| 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 Dose | 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 Dose | Not established |
| Contraindications | Documented hypersensitivity; bone marrow suppression |
| Interactions | Nephrotoxicity and ototoxicity increase with aminoglycosides and other nephrotoxic drugs |
| Pregnancy | D - Unsafe in pregnancy |
| 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 |
| 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 Dose | 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 Dose | Not established |
| Contraindications | Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment |
| 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 |
| Pregnancy | D - Unsafe in pregnancy |
| 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
MISCELLANEOUS
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