Lung Cancer: Detection, Prevention, and Therapeutics

Lung Can r: Detection, Prevention, and Therapeutics By Rebecca S. Finley, PharmD

Introduction

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ung cancer is the leading cause of cancer death in American men and now exceeds breast cancer as the leading cause of cancer death in American women. Overall incidence of lung cancer increases with age; the average age of onset is about 60 years. The disease accounts for 22% of all malignancies in men and 11% of all malignancies in women. 1 Although many environmental and industrial exposures - such as asbestos and radon - have been associated with the development of lung cancer, the American Cancer Society estimates that cigarette smoking is responsible for about 83% of all lung cancer cases. Likewise, the increasing rate of lung cancer deaths in women has been attributed to increased cigarette smoking in women during the past four decades. 1 There is a direct relationship between amount of smoking and development of lung cancer. 2 In addition, exposure to other carcinogens probably acts synergistically with cigarette smoke. Individuals with chronic obstructive3 and chronic interstitial diseases 2 are also believed to be predisposed to the development of lung cancer. Smoking cessation is associated with a gradual decrease in the risk of lung cancer, but five or more years are 'necessary before an appreciable diminution of the risk occurs. 4 ,5 Although early detection through large-scale screening efforts has appeared to decrease the mortality rates of some cancers, including breast and melanoma, randomized, controlled detection studies utilizing chest x-rays and sputum cytology have failed to show any significant impact on lung cancer mortality, even in high-risk populations. 6,7,8 Various dietary substances, such as beta Rebecca S. Finley, PharmD, MS, is assistant professor ofclinical phannacy, University ofMaryland Sclwol ofPhannacy, and assistant professor of oncology, University of Maryland Cancer Center, 22 S. Greene St., Baltimore, MD 21201. Received August 1989; accepted August 1989.

carotene, have been reported to have a protective role in decreasing the risk of lung cancer, especially among high-risk individuals. 9 - 12 Epidemiologic studies are underway to further assess the influence of such chemoprevention strategies.

Clinical Presentation

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he initial signs and symptoms associated with lung cancer are related to the location and size of the tumor. Most frequently these include cough, dyspnea, chest pain, increased sputum production, and hemoptysis. However, it is important to remember that many of these patients are long-term smokers and therefore early symptoms are often attributed to smoker's cough or the irritant effects of smoking. Patients may also experience anorexia, weight loss, hoarseness, or difficulty swallowing. Pneumonia is common in patients with lung cancer. Tumors of the lung may also compress the superior vena cava resulting in distension of ann and neck veins; facial, neck and arm edema; and suffusion of the mucous membranes. If the tumor has metastasized beyond the lungs, extrapulmonary signs and symptoms may occur. For example, liver metastases may produce jaundice or significant abnonnalities in liver function tests; bone metastases may produce severe bone pain or pathologic fractures. Some patients may also experience signs or symptoms not attributed to direct invasion by the primary tumor or its metastases. The effects are called paraneoplastic syndromes. In some cases, these effects may be the first signs or symptoms of the illness. Although the mechanisms of most paraneoplastic syndromes are unknown, some tumors, including lung tumors, secrete peptide honnones that produce these remote effects. Generalized or systemic symptoms such as anorexia, weight loss, and fatigue are usually considered to be paraneoplastic effects. Other paraneoplastic syndromes that have been associated with lung tumors include endocrine and metabolic effects

American Pharmacy, Vol. NS29, No. 11 November 19891709

39

such as hyponatremia and hypercalcemia, neurologic effects such as the Eaton-Lambert myasthenic syndrome, or hematologic abnormalities such as anemia or granulocytosis (Table 1). If the tumor is effectively treated, the paraneoplastic syndrome will usually reverse.

Staging and Evaluation

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hest x-rays and computed tomography . (CT) scans are the most valuable tools for diagnosing lung cancer. However, pathological confirmation is necessary by either cytological examination of the sputum or tumor biopsy by fiber-optic bronchoscopy, percutaneous needle biopsy, or open lung biopsy. Although more than 10 different histologic types of lung cancer are currently recognized (Table 2),13 four major types (adeno-

Table 1. Paraneoplastic Syndromes in Lung Cancer

carcinoma, squamous cell or epidermoid, large cell, and small cell) account for more than 90% of all cases. 2 Confirmation of the cell type and the extent (or stage) of disease must be established to determine the most appropriate management strategy and provide insight to the probability of cure and duration of survival. 14 Before initiating therapy it is also important to assess the patient's performance and physiologic (cardiac, pulmonary, renal, and hepatic) status to evaluate if aggressive therapy will be tolerated.

Non-Small-Cell Lung Cancer Squamous-cell and large-cell carcinomas and adenocarcinomas are frequently grouped together and referred to as non-small-cell lung cancer (NSCLC). NSCLC accounts for approximately 75% of all lung cancers and is often confined to the lungs early in the course of the disease. However, all have the propensity to metastasize to the liver, bone, adrenal glands, and central nervous system. Because fewer than 15% of patients have distant metastases at the tiJlle of initial diagnosis, special scans (liver, brain, or bone) or biopsies (e.g., bone marrow or liver) are generally carried out only if symptoms (e.g., pain, swelling, or jaundice) or routine blood tests (e.g., elevated liver function tests) suggest metastatic involvement. 2,15 The staging system used for NSCLC is based on the size of the primary lung tumor, the presence of regional lymph node involvement, and the presence or absence of distant metastases. A more generalized staging sys-

Table 2. World Health Organization Classification of Lung Cancer

40

American Pharmacy, Vol. NS29, No. 11 November 19891710

tern is also used in which stage I refers to tumors confined to the lung, with no lymph node involvement; stage II includes tumors with regional lymph node involvement; stage III includes tumors with mediastinal lymph node involvement or tumors that invade the surrounding tissues or produce a pleural effusion; and stage IV includes all metastatic (advanced) tumors.16 In general, as the stage increases, the overall prognosis worsens. The presence or absence of lymph node involvement is the single most important prognostic factor in patients with early-stage disease. For patients without lymph node involvement the five-year survival rate approaches 50%; however, if there is mediastinal lymph node involvement this rate drops to less than 10%.17 The size of the tumor also carries prognostic significance, with patients with smaller tumors having a longer overall survival.

Small-Cell Lung Cancer Small-cell lung cancer (SCLC) is a very aggressive and usually rapidly growing tumor; about 70% of patients at diagnosis have metastatic involvement to the lymph nodes, alternate lung, liver, adrenal glands, bone, bone marrow, or central nervous system. For this reason, a thorough systemic evaluation (i.e., radionuclide scans of the bone and liver, CT scan of the brain, and biopsies of the bone marrow) are usually completed following initial diagnosis. In addition, any suspicious signs or symptoms detected during the physical examination should be carefully investigated. A twostage system is usually applied to SCLC. Limited disease includes tumors confined to one hemithorax and to the regional lymph nodes. All advanced SCLCs are considered to be extensive.17 As one would expect, the prognosis for those patients with extensive disease is much poorer than for those with limited disease.

Management of Lung Cancer

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urgery, radiation therapy, and chemotherapy each playa role in the management of lung cancer. The most appropriate therapeutic modality is determined by the histologic classification, the state of the disease, and the patient's physical condition and ability to withstand rigorous therapy.

NSCLC Surgery and, to a lesser extent, radiotherapy offer the only chance for curative therapy for patients with NSCLC. Therefore, surgical resection is the treatment of choice for patients with apparent early stage I or II disease. At the time of surgery, re-

gional lymph nodes must be removed for pathological examination to determine if there is tumor involvement. Chemotherapy and radiation therapy (RT) have also been used with surgery in the management ofNSCLC (i.e., combined modality therapy). When given before surgical resection of the tumor, this is referred to as neoadjuvant therapy; when given following surgery it is called adjuvant therapy. The rationale for either approach is that additional therapy may improve the complete response rate and decrease the chance of recurrence. Randomized studies of neoadjuvant RT have not shown significant benefit, but have reported increased complications in the RT groUp. 2 Although postoperative RT is widely used, there is little or no scientific support for improved survival or cure. 18 ,19 Patients receiving combined modality therapy have generally experienced more complications. Early evaluations of adjuvant chemotherapy did not show improvement; however, it is now recognized that the drug regimens employed were not effective in NSCLC. Preliminary results of a cisplatin-based regimen have reported encouraging results 20 and it is likely that further trials will continue ·to explore this approach. The rationale for the use of neoadjuvant chemotherapy has been that it may increase the incidence of complete resections due to eradication of microscopic spread of the tumor and permit less extensive surgery, thus possibly preserving lung function. 2 The disadvantages of this approach are that the patient will experience increased toxicity (which may delay surgery), and there is the risk that if the tumor does not respond to the chemotherapy it may progress and become inoperable. Cisplatin-based regimens such as those discussed below are the most commonly used in this setting; however, they may be associated with significant complications. Reports of several trials have indicated that tumors previously considered inoperable were rendered resectable by this approach. 2 Patients with lymph node involvement or with tumors that are not resectable because of attachment to a major blood vessel, the trachea, or esophagus may benefit from RT. RT is also considered an alternative modality for patients with stage I or II disease who will not consent to surgery or who are not surgical candidates because of concomitant illness or restrictive pulmonary reserve; however, the overall survival is generally poor under these circumstances. Dissemination of the tumor eventually occurs in most patients and the response rates

American Pharmacy, Vol. NS29, No. 11 November 19891711

41

for chemotherapy in NSCLC have been disappointingly low without clear demonstration of overall survival benefits. One recent review suggested that the median survival time for all treated patients is only five to six months. 2 It does appear that those patients who do respond to chemotherapy are likely to have a longer survival than those who do not respond. Recent studies have yielded more encouraging results and are redefining the role of chemotherapy. 21,22 Several factors have significant prognostic importance in predicting major response to chemotherapy and overall survival. An initial favorable performance status of the patient appears to be the factor that most consistently predicts an improved response and survival. Conversely, elevated serum lactic dehydrogenase (LDH) levels, the presence of extrathoracic disease in two or more organs, or metastatic involvement of the bone all have been reported to have a negative impact on survival. 22 Single-agent chemotherapy has produced response rates of 5% to 15% with no significant effect on overall survival. 23 Although many combination regimens have not demonstrated significant improvements, recent studies have reported higher response rates. Early combination chemotherapy regimens used agents such as cyclophosphamide, methotrexate, lomustine, vincristine, bleomycin, and later doxorubicin (Table 3). These regimens have generally reported response rates under 50% with less than 5% complete responses; although responders usually survived longer than nonresponders, clear-cut advantages have been difficult to substantiate. More recently, regimens containing cisplatin have produced the highest response rates. Among the most intriguing regimens are those that utilize mitomycin C, a vinca alkaloid (vinblastine or vindesine), and cisplatin, or etoposide and cisplatin. These regimens have yielded response rates ranging from about 30% to greater than 70%. Regimens including fluorouracil and cisplatin have also produced encouraging results. 21 Preclinical studies indicated that cisplatin and etoposide were synergistic against some experimental leukemia cell lines, and highly successful results of this combination in testicular cancer led to its logical evaluation in lung cancer and other tumors. Two randomized studies comparing single-agent cisplatin with cisplatin plus etoposide 24 ,25 reported higher response rates for the combinations but no overall survival benefit. In comparing a series of combinations the Eastern Cooperative Oncology Group (ECOG) has reported a higher percentage 42

of one-year survivors in the cisplatin plus etoposide trials versus several other regimens. 2 Interestingly, the highest response rates have been demonstrated when the individual agents have been administered at higher dosages (Le., 100 mg/m 2 vs. 50 mg/m 2 of cisplatin). It is likely that clinical studies will continue to evaluate high-dose, aggressive therapies; however, intensive supportive care measures will be necessary to ensure optimal patient care. In patients receiving chemotherapy, a minimum of two courses of therapy are usually given before evaluating the patient for response. If no response is seen the therapy is usually discontinued. Patients responding to therapy should continue therapy until disease progression has been documented. Optimal chemotherapy regimens for the treatment of NSCLC have not been defined. Therefore, it is important that well-designed clinical trials continue to evaluate such therapies.

SCLC SCLC tends to spread at a very early stage" therefore surgery is almost never indicated except in a small group of patients (< 1%) who have small isolated lesions. The

Table 3. Combination Chemotherapy Regimens in Lung Cancer

American Pharmacy, Vol. NS29, No. 11 November 19891712

aggressive use of combination chemotherapy regimens has resulted in dramatic responses and demonstrated a fowfold to fivefold increase in median survival. 26 Radiation therapy is often used in combination with chemotherapy or to treat recurrences. Several factors have been shown to influence the extent and duration of response to chemotherapy and therefore the overall prognosis. Patients who are found to have limited disease at initial diagnosis have a significantly longer median survival than patients with extensive disease who are given the same aggressive chemotherapy regimens. In addition, those patients with a better perfonnance status and no weight loss also appear to have an improved prognosis. 26 ,27 Interestingly, in several reports women appear to have a better prognosis, as do patients under the age of60 years. 26,27 Many cytotoxic agents have been shown to be active in the treatment ofSCLC. These agents include etoposide, doxorubicin, cyclophosphamide, vincristine, lomustine, cisplatin, carboplatin, and methotrexate. Combination chemotherapy is clearly superior to single-agent therapy, and the best results are generally observed when three or more active agents are combined (Table 3). The most commonly used regimens have been CAY (C=cyclophosphamide, A=Adriamycin, V = vincristine), CAE (E = etoposide) and CMCc (M = methotrexate, Cc = lomustine). More recently, cisplatin has been included in some regimens. Results of initial trials evaluating cisplatin plus etoposide have been comparable to those achieved with CAY; however, randomized trials will be necessary to confirm these observations. In addition, cisplatin plus etoposide usually produces less hematologic toxicity than CAV28 but increased gastrointestinal toxicity. Clear-cut dose responsiveness has been seen with the use of chemotherapy in SCLC. Aggressive combination regimens using higher doses of active agents generally result in a complete response rate of 40% to 50% in patients with limited disease and 15% to 20% in patients with extensive disease. Overall, the median survival is approximately 14 months among patients with limited disease and eight months in those with extensive disease. Without therapy the average survival is only two to four months. However, it should be noted that these regimens may produce serious toxicities, including granulocytopenia, thrombocytopenia, and severe mucosal damage. Relapse of SCLC is believed to be the result of the growth of clones of tumor cells that were resistant to the initial chemotherapy. Further attempts of chemotherapy

after relapse are usually unsuccessful. In an attempt to eradicate residual resistant cells during the primary therapy, another strategy used in SCLC is to alternate chemotherapy regimens for consecutive cycles of therapy. In theory, using different, noncross-resistant agents should improve eradication of tumor cells resistant to the opposite regimen. Initial trials using this strategy failed to demonstrate significant benefit, and a recent triaP9 has reported a mod" est survival improvement when alternating CAVwith CEo Patients are usually reevaluated after two or three courses of chemotherapy. Those responding should continue the same regimen until there is evidence of disease progression or a complete response has been documented. In patients achieving a complete response the optimal duration to continue therapy is controversial with recommendations ranging from six to 24 months. SCLC is very sensitive to the cytotoxic effects of RT. Combined chemotherapy and RT has been used to treat SCLC that is limited to the thoracic cavity. Although this approach may decrease the incidence or delay the onset of thoracic tumor recurrences, it is not certain that it will improve the overall median survival when compared to chemotherapy alone. Several studies have reported improved survival. It should be noted that combined modality therapy is generally associated with greater toxicity (e.g., bone marrow suppression, mucosal damage) than chemotherapy alone. and these additional risks must be taken into consideration when contemplating combined modality therapy. Central nervous system metastases are present in about 10% of patients at initial diagnosis and occur at some point during the disease process in more than 50% of patients. For this reason it is common practice at some institutions to use prophylactic radiation to the cranium in patients who achieve a complete response to chemotherapy. If intracranial metastases do occur, therapeutic cranial irradiation usually controls the CNS disease. Adrenocorticosteroids (to decrease intracranial pressure) and anticonvulsants (to prevent seizures) are often used until the RT shrinks the tumor mass. Although SCLC is responsive, the low number of long-term survivors (only 8% to 10% of patients survive more than three years) is disappointing. Therefore, it is important that clinical trials continue to explore new regimens in an effort to extend the median survival and improve the overall cure rate.

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Table 4. Complications Associated with Lung Cancer and Its Treatment (Part 1) Complication

Usual Therapy

Symptoms/Manifestations Disease-Related

Compression of the superior vena cava

Distension of neck and arm veins; facial, neck, arm edema; suffusion of mucous membranes

RT or chemotherapy (SCLC only)

Cardiac tamponade

Decreased cardiac output, tachycardia

Pericardiocentesis or RT

Pulmonary insufficiency

Dyspnea, hypoventilation

Antitumor therapy, ventilation if necessary, optimization of cardiac output, diuresis if needed

Malignant pleural effusion

Hypoventilation, dyspnea

Thoracentesis, chest tube drainage, 'sclerotherapy using tetracycline, bleomycin, or other irritant

Hemorrhage

Hemoptysis

RT

Obstruction of bronchi

Hypoventilation

RT

Brain metastases

Headache, visual disturbances, dizziness, seizures, motor deficits

RT

Bone metastases

Pain, pathologic fractures

Spinal cord compression

Back pain, paraplegia, loss of bladder and anal sphincter control

If

RT

.tXnalgesics,

Pain

~*chemGt "94.

Surgery-Related Hemorrhage

Hemoptysis, hypotension, exsangUination

Pulmonary insufficiency

Deterioration of blood gases, dyspnea

Pneumothorax

Acute respiratory failure

Empyema

Fever, dyspnea

Pneumonitis/fibrosis

Decreased pulmonary compliance$,,/

Cardiac disease Esophagitis

Pain and difficulty swallowing, vomiting, fever if infected Chemotherapy-Related

44

Granulocytopenia

Fever, infection

Thrombocytopenia

Bleeding

Nausea and vomiting

Dehydration, electrolyte ·imbalanc:~'1t

Mucositis/stomatitis

Ulcerations of mouth, lip, tongue

Topical anesthetics such as viscous xylocaine, systemic analgesics and parenteral nutrition if~ere; systemic antimicrobi~:~ if infecte ulture f®' 'tIerpes simplex)

Pulmonary toxicity

Infiltrates on chest x-ray, dyspnea, c0ugh, rales, fever, pleuritic chest pain

Corticosteroids may help, discontinGe probable causative agent(s)

Neurologic toxicities

Peripheral or ~entral ne!yous systerq effects dependent on agent '

, Disfontinue$~! attenua~~~o~ge
Renal dysfunction

Increasing serum creatinrne and blood urea nitrogen, decreased urinary output

Hydration, vyrthhold causative agent(s) until recovery

Rlatelet tran$fusions, b

"*

~ tier:netics1

agent(s) until recovery

0h,

.

American Pharmacy, Vol. NS29, No. 11 November 19891714

Complications

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ung cancer may produce significant morbidity resulting from obstruction or invasion of major organ systems by the primary tumor or its metastases. Indeed, if effective therapy is not promptly initiated, this disease universally results in the death of the patient. Furthermore, many patients with lung cancer have significant preexisting pulmonary and cardiovascular disease resulting from long-term exposure to cigarette smoke. Therapies used to manage lung cancer are also aggressive and commonly produce significant complications. It is not surprising that the management of this disease consumes tremendous health care resources each year. Table 4 outlines some of these complications and the usual approach to their management.

Summary

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ung cancer remains the leading cause of cancer death in the U.S. adult population, and the American Cancer Society estimates that cigarette smoking is responsible for about 83% of all lung cancer cases. It is unlikely that significant reductions in the incidence and mortality associated with lung cancer will be realized without effective antismoking campaigns. Surgery, radiation therapy, and chemotherapy all play a role in the management of lung cancer. At the current time, NSCLC is generally curable only if it is diagnosed while the tumor is small and localized and can be surgically removed. Radiation therapy may also be effective in localized cases. Combination chemotherapy regimens have not consistently produced quality responses in patients with advanced tumors; however, newer regimens utilizing high doses of cisplatin, mitomycin and vinca alkaloids, or cisplatin and etoposide have produced encouraging results. In contrast to NSCLC, SCLC is responsive to combination chemotherapy regimens. Although many different agents are effective in this disease, most small-cell tumors eventually become refractory to chemotherapy and most patients do not survive longer than two years. Although progress has been made in the understanding and management of lung cancer, effective therapies that consistently produce major and durable responses are still lacking. Clinical trials must continue to evaluate therapeutic modalities for all types of lung cancer.

References 1. E. Silverberg and J.A. Lubera, Cancer Statis-

tics, CA, 39, 3 (1989). 2. J.D. Minna et al., Cancer of the Lung, in Cancer: Principles and Practices ofOncology, 3rd ed., V. DeVita et al., eds., Lippincott, Philadelphia, 1989, pp. 591-705. 3. J.M. Samet et al., Personal and Family History of Respiratory Disease and Lung Cancer Risk, Am Rev Respir Dis, 134, 466 (1986). 4. E.L. Wynder, Etiology of Lung Cancer: Reflections on 2 Decades of Research, Cancer, 30, 1332 (1972). 5. L.A. Damber and L.G. Larson, Smoking and Lung Cancer with Special Regard to Type of Smoking and Type of Cancer: A Case-Control Study in North Sweden, BrJ Cancer, 53,673 (1986). 6. R.S. Fontana et al., Lung Cancer Screening: The Mayo Program, J Occup Med, 28, 746 (1986). 7. Lung Cancer Mortality Appears Unaffected by Roentgenographic and Sputum Screening in Asymptomatic Persons: Report from the Nlli, JAMA, 241, 1582 (1979). 8. H.B. Neel III et al., Sputum Cytologic Diagnosis of Upper Respiratory Tract Cancer, Ann Otol Rhinol Laryngol, 87, 468 (1978). 9. G.A. Colditz et al., Diet and Lung Cancer: A Review of the Epidemiologic Evidence in Humans, Arch Intern Med, 147, 157 (1987). 10. G.G. Bond et al., Dietary Vitamin A and Lung Cancer: Results of a Case-Control Study Among Chemical Workers, Nutr Cancer, 9, 109 (1987). 11. R.L. Prentice et al., Rationale and Design of Cancer Chemoprevention Studies in Seattle, Natl Cancer Inst Monofr, 69, 249 (1985). 12. M.S. Menkes et al., Serum Beta-Carotene, Vitamins A and E, Selenium and the Risk of LungCancer,N EnglJ Med, 315,1250 (1986). 13. L.H. Sobin, The World Health Organization's Histological Classification of Lung Thrnors: A Comparison of the First and Second Editions, Cancer Detect Prev, 5, 391 (1982). 14. S.C. Aisner and M.J. Matthews, The Pathology of Lung Cancer, in Lung Cancer, J.A. Aisner, ed., Churchill Livingstone, New York, 1985, pp.1-23. 15. J.W Ramsdell et al., Multiorgan Scans for Staging Lung Cancer: Correlation with Clinical Evaluation, J Thome Cardiovasc Surg, 73, 653 (1977). 16. American Joint Committee on Cancer, Manual for Staging ofCancer, 3rd ed., O.H. Beahrs et al., eds., Lippincott, Philadelphia, 1988, pp. 115--18. 17. D.L. Paulson and J.S. Reisch, Long-Term Survival After Resection for Bronchogenic Carcinoma, Ann Surg, 184, 324 (1976). 18. P.V. Van Houtte et al., Postoperative Radiation Therapy in Lung Cancer: A Controlled Trial After Resection of Curative Design, Int J Radiat Oncol Biol Phys, 6, 983 (1980). 19. Lung Cancer Study Group, Effects of Postoperative Mediastinal Radiation on Completely Rejected Stage IT and Stage ill Epidermoid Cancer of the Lung, N Engl J Med, 315, 1377 (1986). 20. E.C. Holmes and M. Gail, Lung Cancer Study

American Pharmacy, Vol. NS29, No. 11 November 19891715

45

21. 22.

23. 24.

25.

Group, Surgical Adjuvant Therapy for Stage IT and Stage ill Adenocarcinoma and LargeCell Undifferentiated Carcinoma, J Clin Oncol, 4, 710 (1986). R.J. Gralla and M.G. Kris, Chemotherapy in Non-Small Cell Lung Cancer: Results of Hecent Trials, Sem Oncol, 15 (suppI4), 2 (1988). J.P. O'Connell etal., Frequency and Prognostic Importance of Pretreatment Clinical Characteristics in Patients with Advanced Non-Small Cell Lung Cancer Treated with Combination Chemotherapy,.J Clin Oncol, 4, 1604 (1986). R.B. Livingston, Combination Chemotherapy of Bronchogenic Carcinoma, Cancer Treat Rev, 4,154(1977). L. Crino et al., A Randomized Trial of Three Cisplatin (CDDP)..Containing Chemotherapy Regimens in Advanced Non-Small Cell Lung Cancer (NSCLC): A Study of the Umbrian Lung Cancer Study Group, Abstract, Proc Am Soc Clin Oncol, 6, 182 (1987). R. Rosso et al., Etoposide (E) vs E Plus Cispla-

26.

27.

28.

29.

tin (P) in the Treatment of Advanced Non Small Cell Lung Cancer (NSCLC), A FONICAP Randomized Trial, Abstract, Proc Am Soc Clin Oncol, 6, 186 (1987). H.H. Hansen et al., Management of SmallCell Carcinoma of the Lung, in Lung Cancer, J.A. Aisner, ed., Churchill Livingstone, New York, 1985, pp. 269-85. K. Osterlind et at, Long-Term Disease-Free Survival in Small-Cell Carcinoma of the Lung: A Study of Clinical Detenninants, J Clin Oncol, 4, .1307 (1986). L.H. Einh(}m et al., Cisplatin Plus Etoposide Consolidation Following Cyclophosphamide, Doxorubicin, and Vincristine in Limited Small Cell Lung Cancer; J Clin Oncol, 6, 451 (1988). WK. Evans et al. ,.Superiority of Alternating Non-Cross Resistant Chemotherapy in Extensive Small Cell Lung Cancer, Ann Intern Med, 1m, 451 (1987). ®

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Statement of Ownership, Management, and Circulation (Required by 39 U.S.C. 3685) 1. A. Title of publication: American Pharmacy B. Publication number: 283660 2. Date of filing: October 1, 1989 3. Frequency of issue: Monthly A. Number of issues published annually: 12 B. Annual subscription price: $45/$65 4. Complete mailing address of known office of publication: 2215 Constitution Ave., NW, Washington, DC 20037 5. Complete mailing address of the headquarters or general business offices of the publishers: Same 6. Full names and complete mailing addresses of publisher, editor, and managing editor: Publisher - John A. Gans, PharmD, Executive Vice-President, American Pharmaceutical Association, 2215 Constitution Ave., NW, Washington, DC 20037; Editor - Marlene Bloom, American Pharmacy, 2215 Con-:stitution Ave., NW, Washington, DC 20037. . 7. Owner: American Pharmaceutical Association, 2215 Constitution Ave., NW, Washington, DC 20037. 8. Known bondholders, mortgagees, and other security holders owning or holding 1 percent or more of total amount of bonds, mortgages, or other securities: None 9. For completion by nonprofit organizations authorized to mail at special rates (Section 423.12 DMM only): The purpose, function, and nonprofit status of this organization and the exempt status for federal income tax purposes has not changed during the preceding 12 months.

American Pharmacy, Vol. NS29, No. 11 November 19891717

10. Extent and nature of circulation:

A. Total no. copies (Net press run) B. Paid and/or requested circulation: 1. Sales through dealers and carriers, street vendors and counter sales 2. Mail subscription (Paid and!or requested) C. Total paid and/or requested circulation (SumoflOBl andlOB2) D. Free distribution by mail, carrier or other means-samples, complimentary and other free copies E. Total distribution (Sum orC andD) F . Copies not distributed: 1. Office use, left over, unaccounted, spoiled after printing 2. Return from news agents G. Total (Sum ofE, Fl and2-should equal net press run shown inA)

Average no. copies each issue during preceding 12 months

Actual no. copies ofsingle issue published nearest to filing date

36,037

36,524

0

0

34,733

34,550

34,733

34,550

901 35,634

923 35,473

403 0

1,051 0

36,037

36,524

11. I certify that the statements made by me above are correct and complete: Marlene Bloom, Editor

47