- Email: [email protected]
Chemoprevention of lung cancer
9. CHEMOPREVENTION OF L U N G CANCER Elizabeth Rosvold, MD
CHEMOPREVENTION The chemoprevention of lung cancer is a major challenge for health care providers and researchers, but it also presents a significant opp o r t u n i t y for r e d u c i n g lung cancer m o r b i d i t y and mortality. Chemoprevention strategies can be applied to those at high risk, such as current or former smokers, and to those who have survived earlystage non-small cell lung cancer (NSCLC) but are at risk for second primary tumors. Many agents are being studied for chemopreventive activity. The most widely studied compounds are retinoids. These are a group of natural and synthetic vitamin A analogs that have been shown in animal models to suppress carcinogenesis and to affect the growth and differentiation of normal, premalignant, and malignant epithelial cells in vitro and in vivo. These agents work through a group of nuclear receptors that are part of the steroid and thyroid hormone receptor family. These receptors selectively regulate gene transcription, thereby regulating cell differentiation and proliferation. ~ Specific retinoid compounds studied in clinical trials include isotretinoin (13-cis-retinoic acid), etretinate, and retinol (retinyl palmitate). Their administration is associated with dose-related skin toxicity, which is reversible but often limits their use. In epidemiologic studies, dietary i~-carotene intake has been shown to be inversely correlated with lung cancer risk. 2i~-Carotene is thought to function as an electron-scavenging antioxidant. 3 Vitamin E intake has also been associated with decreased incidence of cancer at several sites. 4 This vitamin also acts as an antioxidant. N-acetylcysteine is an aminothiol cysteine derivative and a precursor of glutathione. Glutathione plays a role in the detoxification of reactive electrophiles and free radicals through conjugation or reduction reactions. N-acetylcysteine has been shown in animal models to have preventive activity against many carcinogenic agents? Aspirin and other nonsteroidal antiinflammatory compounds are 266
Curt Probl Cancer, July/August 1996
also being explored as chemopreventive agents. They are thought to decrease proliferation by reducing prostaglandin levels? Reversal of premalignant changes in the tracheobronchial tree has been attempted to decrease the incidence of lung cancer, and trials of various agents have been performed. The synthetic retinoid etretinate was compared with placebo in a 6-month randomized trial to reverse the atypia seen in s p u t u m samples. Although the drug was well tolerated and compliance was good, no differences between the two groups was observed. 7 Sputum atypia was also used as a marker in a 4-month trial of folate and vitamin B12 versus placebo. An improvement in atypia was seen in the treatment group? Cis-retinoic acid (cRA) was given to reverse sputum atypia in an uncontrolled trial, but no effect was seen? Changes in bronchial epithelium have been monitored by bronchoscopy in at least two trials. An uncontrolled trial of etretinate given for 6 months to otherwise healthy heavy smokers demonstrated improvement in the extent of bronchial metaplasia. 1~A randomized, controlled trial was performed to confirm these findings. Heavy smokers with significant bronchial metaplasia were treated with cRA or placebo for 6 months. Squamous metaplasia decreased in both groups after treatment, but without significant difference between the two. The drug therefore had no effect on metaplasia. Smoking cessation did affect metaplasia; significant declines in the extent of metaplasia were seen in those who stopped smoking, and no changes were seen in those who continued to smoke? 1 A large, placebo-controlled, randomized prevention trial has been completed. In this trial, Finnish men between the ages of 50 and 69 years who were current smokers were treated with fi-carotene, c~-tocopherol, both, or placebo with the development of lung cancer as the study endpoint. The m e n receiving fi-carotene unexpectedly had a higher incidence of lung cancer compared with those not receiving it. No effect on lung cancer incidence was seen with a-tocopherol, and no interaction between l~-carotene and ct-tocopherol was observed. Mortality in the l~-carotene group was 8% higher, thought to reflect deaths from lung cancer and ischemic heart disease. This study raises the possibility that t~-carotene supplementation may be harmful. 12 Two other ongoing trials will further examine t~-carotene supplementation in chemoprevention. The Harvard Physicians Health Study is examining the effects of t~-carotene alone in reducing the incidence of all cancers. The t~-carotene and retinol efficacy trial (CARET) is a randomized, double-blind trial comparing the administration of i~-carotene and retinyl palmitate with placebo in reducing lung cancer incidence in two populations: heavy smokers and asbestos-exposed individuals. Accrual is nearly complete, and results are expected in early 1998. 3 The prevention of second primary cancers in patients treated for early-stage squamous cell cancers of the head and neck was initially demonstrated by Hong et al. ~3 In those treated with cRA for 1 year C u r t P r o b l Cancer, July/August 1996
267
after definitive treatment of the primary lesion, the incidence of second primaries was 4%, compared with 24% in the placebo group. There was no effect on the rates of recurrence or distant metastasis. The concept of field carcinogenesis in the pathogenesis of head and neck cancers applies to lung cancer as well, and the positive effect of cRA on head and neck cancers has led to the use of retinoids to prevent second primary lung cancers. Pastorino et al. ~4 reported the results of a randomized trial of treatment with retinyl palmitate for 12 m o n t h s versus placebo after resection of stage I NSCLC. Eighteen patients in the treatment group developed a second primary, as did 29 patients in the placebo group. The time to development of a new primary was significantly longer in the treatment group, and there was a trend toward a longer disease-free interval (time to relapse or new primary) with treatment. Two large trials are being performed to further explore prevention of second primary cancers. The Euroscan trial is designed to study more than 2000 patients throughout Europe who have a history of laryngeal cancer, oral cavity cancer, or NSCLC. Patients will receive retinyl palmitote, N-acetylcysteine, both, or placebo for a 2-year period, is A second trial is being performed in the United States and Canada. It randomizes patients with resected stage I NSCLC to receive cRA or placebo for 3 years. Approximately 1300 patients will be accrued. TM QUALITY OF LIFE AND COST EFFECTIVENESS Most patients with NSCLC have disease that cannot be cured by surgical resection. Neither chemotherapy nor radiation therapy has had a substantial impact on the long-term survival of these patients. Because advanced disease is uniformly fatal and response rates to chemotherapeutic regimens are at best 30% to 40%, there is controversy regarding the role of chemotherapy in advanced disease. To address this issue, several studies have randomized patients with advanced NSCLC (stage IIIB or IV) to chemotherapy or to best supportive care (BSC). A metaanalysis of seven such trials has been performed, lz Three of the trials 18-2~ showed a statistically significant improvement in median survival in the treatment group. The seven trials combined revealed decreased mortality at 3 and 6 months with chemotherapy. There continued to be decreased mortality at 9, 12, and 18 months, although the differences did not reach statistical significance. A similar meta-analysis has been published, 2~ and although it excluded one TM of the three positive trials, combined results for the remaining six trials 18,2~ revealed a median survival of 27.4 weeks in the treatment group versus 16.7 weeks in the BSC group. Treatment was associated with a 24% reduction in the probability of death. The improvement in mortality decreased significantly after 6 months. 2~ Two important issues were not specifically addressed by these stud268
Curt Probl Cance~
July/August 1996
ies. One is quality of life. Data from other trials indicate that chemotherapy may improve disease-related symptoms, including dyspnea, cough, pain, and weight loss. 26"29In one study, 70% of patients had improvement of symptoms, despite an objective response rate of only 2 8 ~ 26 These trials, however, did not include a control (BSC) arm. Whether potentially toxic chemotherapy improves the quality of life compared with BSC may never be fully answered. Measures of improvement in quality of life have become a necessary part of the approval process for new chemotherapeutic agents. 3~ The instruments used to measure such data have been in development since the early 1980s. The Lung Cancer Symptom Scale is an instrument developed at Memorial Sloan-Kettering Cancer Center specifically far the assessment of symptoms of patients with lung cancerJ ~ This instrument has been tested at multiple centers and has been found to be feasible, reliable, valid, and internally consistent. 3~ The European Organization for the Research and Treatment of Cancer uses a general quality of life (QOL) survey with a supplement specific for lung cancer. These surveys measure patient functioning, symptom status, and perception of QOL, and they have been translated into 10 languages. 31'32The Southwest Oncology Group uses categorical scales in the form of multiple-choice questions and visualanalog scales. 32 The Eastern Cooperative Oncology Group trials for lung cancer employ the FACT-L questionnaire, which includes a 28item general questionnaire and a lung cancer-specific module. This questionnaire has demonstrated validity, reliability, and sensitivity to changes over time. 32,33 A second major issue to evaluate in the treatment of NSCLC is cost. A cost-effectiveness analysis of a National Cancer Institute of Canada trial of chemotherapy versus BSC has been reported? 4 One of the chemotherapy regimens used was found to be less costly than BSC. Most costs were accounted for by hospitalization, with increased hospital time for those on BSC. Chemotherapy costs accounted for little of the total cost (17% to 22%). The cost effectiveness of treatment with chemotherapy was comparable to that for coronary artery bypass grafting, home dialysis, renal transplantation, and s treatment for hypertension. 34 A second study from Canada demonstrated that the administration of chemotherapy to approximately 50% of patients with stage IV NSCLC would n o t add significantly to the total cost for the treatment of all cases of NSCLC, and the iffvestigator points out that the cost would be less than one half of the cost of neoadjuvant chemotherapy for earlier-stage cancers. 35 The potential reduction in the cost for staging patients with small cell lung cancer has been calculated? 6 An algorithm for staging was d e v e l o p e d , w i t h the m a j o r source of savings r e l a t e d to the discontinuation of testing after the identification of a site of metastatic disease. A proposed set of sequential staging procedures was Curl" Probl Cancer, July/August 1996
269
p r o j e c t e d to d e c r e a s e c o s t s b y m o r e t h a n o n e third. 36 S u c h an algor i t h m for s t a g i n g m a y b e f e a s i b l e for N S C L C a n d m a y p o t e n t i a l l y s a v e m o n e y , time, a n d effort for p a t i e n t s . REFERENCES
1. Zhang X, Liu Y, Lee M-O, Pfahl M. A specific defect in the retinoic acid response associated with human lung cancer cell lines. Cancer Res 1994;54: 5663-9. 2. Mayne ST, Janerich DT, Greenwald P, et al. Dietary beta-carotene and lung cancer risk in U.S. nonsmokers. J Natl Cancer Inst 1994;86:33-8. 3. Omenn GS, Goodman G, Thornquist M, et al. The beta-carotene and retinal efficacy trial (CARET) for chemoprevention of lung cancer in high risk p o p u l a t i o n s : smokers a n d a s b e s t o s - e x p o s e d workers. Cancer Res 1994;54:$2038-43. 4. Knekt P, Aromaa A, Maatela J, et al. Vitamin E and cancer prevention. Am J Clin Nutr 1991;53:$283-6. 5. van Zandwijk N. N-acetylcysteine for lung cancer prevention. Chest 1995;107:1437-41. 6. Nelson C. Aspirin prevention update: new data ori lung and colon cancers. J Nail Cancer Inst 1995;87:567-9. 7. Arnold AM, Browman GE Levine MN, et al. The effect of the synthetic retinoid etretinate on sputum cytology: results from a randomised trial. Br J Cancer 1992;65:737-43. 8. Heimburger DC, Alexander CB, Birch R, et al. Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12: report of a preliminary randomized double-blind intervention trial. JAMA 1988;259: 1525-30. 9. Saccomanno G, Moran PG, Schmidt RD, et al. Effects of 13-cis retinoids on premalignant and malignant cells of lung origin. Acta Cytol 1980;26:78-85. 10. Misset JL, Santelli G, Homasson JP, et al. Regression of bronchial epidermoid metaplasia in heavy smokers with etretinate treatment. Cancer Detect Prey 1986;9:167-70. 11. Lee JS, Lippman SM, Benner SE, et al. Randomized placebo-controlled trial of isotretinoin in chemoprevention of bronchial squamous metaplasia. J Clin Oncol 1994;12:937-45. 12. Heinonen OP, Albanes D, and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-35. 13. Hang WK, Lippman SM, Itri LM, et al. Prevention of second primary tumors with isotretinoin in squamous cell carcinoma of the head and neck: longterm follow-up. N Engl J Med 1990;323:795-801. 14. Pastorino U, Infante M, Maioli M, et al. Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol 1993;11:1216-22. 15. DeVries N, van Zandwijk N, Pastorino U. The Euroscan study. Br J Cancer 1991;64:985-9. 16. Benner SE, Lippman SM, Hang WK. Chemoprevention of lung cancer. Chest 1995:107:$316-21. 17. Souquet PJ, Chauvin F, Boissel JR et al. Polychemotherapy in advanced non small cell lung cancer: a recta-analysis. Lancet 1993;342:19-21[ 18. Cormier Y, Bergeron D, La Forge J, et al. Benefits of polychemotherapy in advanced nan-small-cell bronchogenic carcinoma. Cancer 1982;50:845-9. 270
Curt Probl Cancer, July/August 1996
19. Quoix E, Dietmann A, Charbonneau J, et al. Disseminated non small cell lung cancer: a randomised trial of chemotherapy versus palliative care. Congress of IASLC Interlaken. Lung Cancer 1988;4:A181. 20. Rapp E, Pater J, Willan A, et al. Chemotherapy can prolong survival in patients with advanced non small cell lung cancer. Report of a Canadian multicenter randomized trial. J Clin Oncol 1988;6:633-41. 21. Grilli R, Oxman AD, Julian JA. Chemotherapy for advanced non-small-cell lung cancer: how much benefit is enough? J Clin Oncol 1993;11:1866-72. 22. Cellerino R, Tummarello D, Guidi F, et al. A randomized trial of alternating chemotherapy versus best supportive care in advanced non-small-cell lung cancer. J Clin Oncol 1991;9:1453-61. 23. Ganz PA, Figlin RA, Haskell CM, et al. Supportive care versus supportive care and combination chemotherapy in metastatic non small cell lung cancer. Does chemotherapy make a difference? Cancer 1989;63:1271-8. 24. Kaasa S, Lund E, ~ThorodE, et al. Symptomatic treatment versus combination chemotherapy in' patients with extensive non small cell lung cancer. Cancer 1991;67:2443-7. 25. Woods RL, Williams CJ, Levt'J, et al. A randomized trial of cisplatin and vindesine versus supportive care only in advanced non-small cell lung cancer. Br J Cancer 1990;61:608-11. 26. Osoba D, Rusthoven JJ, Turnbull KA, et al. Combination chemotherapy with bleomycin, etoposide, and cisplatin in metastatic non-small cell lung cancer. J Clin Oncol 1985;3:1478-85. 27. Hardy JR, Noble T, Smith IE. S y m p t o m relief with moderate dose chemotherapy (mitomycin c, vinblastine and cisplatin) in advanced nonsmall cell lung cancer. Br J Cancer 1989;60:764-6. 28. Kris MG, Gralla RJ, Potanovich LM, et al. Assessment of pretreatment symptoms and improvement after EDAM + mitomycin + vinblastine (EMV) in patients with inoperable non-small cell lung cancer (NSCLC) [abstract 883]. Proc Am Soc Clin Oncol 1990;9:229. 29. Fernandez C, Rossell R, Abda-Estave A, et al. Quality of life during chemotherapy in non-small cell lung cancer. Acta Oncol 1989;28:129-33. 30. Hollen PJ, Gralla RJ, Kris MG, et al. Measurement of quality of life in patients with lung cancer in multicenter trials of new therapies. Psychometric assessment of the Lung Cancer Symptom Scale. Cancer 1994;73:2087-98. 31. Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, et al. The EORTC QLQ-L313: a modular supplement to the EORTC core quality of life questionnaire (QLQC3O) for use in lung cancer clinical trims. Eur J Cancer 1994;30A:635-42. 32. Moinpour CM. Measuring quality of life: an emerging science. Semin Oncol 1994;21:48-63. 33. Celia DF, Tulsky DS, Gray G, et al. The functional assessment of cancer therapy scale: development and validation of the general measure. J Clin Oncol 1993;11:570-9. 34. Jaakkimainen L, Goodwin PJ, Pater J, et al. Counting the costs of chemotherapy in a National Cancer Institute of Canada randomized trial in nonsmall-cell lung cancer. J Clin Oncol 1990;8:1301-9. 35. Evans WK. Management of metastatic non-small-cell lung cancer and a consideration of cost. Chest 1993;103:$68-71. 36. Richardson GE, Venzon DJ, Edison M, et al. Application of an algorithm for staging small-cell lung cancer can save one third of the initial evaluation costs. Arch Intern Med 1993;153:329-37.
Curr Probl Cancer, July/August 1998
271
CHEMOPREVENTION The chemoprevention of lung cancer is a major challenge for health care providers and researchers, but it also presents a significant opp o r t u n i t y for r e d u c i n g lung cancer m o r b i d i t y and mortality. Chemoprevention strategies can be applied to those at high risk, such as current or former smokers, and to those who have survived earlystage non-small cell lung cancer (NSCLC) but are at risk for second primary tumors. Many agents are being studied for chemopreventive activity. The most widely studied compounds are retinoids. These are a group of natural and synthetic vitamin A analogs that have been shown in animal models to suppress carcinogenesis and to affect the growth and differentiation of normal, premalignant, and malignant epithelial cells in vitro and in vivo. These agents work through a group of nuclear receptors that are part of the steroid and thyroid hormone receptor family. These receptors selectively regulate gene transcription, thereby regulating cell differentiation and proliferation. ~ Specific retinoid compounds studied in clinical trials include isotretinoin (13-cis-retinoic acid), etretinate, and retinol (retinyl palmitate). Their administration is associated with dose-related skin toxicity, which is reversible but often limits their use. In epidemiologic studies, dietary i~-carotene intake has been shown to be inversely correlated with lung cancer risk. 2i~-Carotene is thought to function as an electron-scavenging antioxidant. 3 Vitamin E intake has also been associated with decreased incidence of cancer at several sites. 4 This vitamin also acts as an antioxidant. N-acetylcysteine is an aminothiol cysteine derivative and a precursor of glutathione. Glutathione plays a role in the detoxification of reactive electrophiles and free radicals through conjugation or reduction reactions. N-acetylcysteine has been shown in animal models to have preventive activity against many carcinogenic agents? Aspirin and other nonsteroidal antiinflammatory compounds are 266
Curt Probl Cancer, July/August 1996
also being explored as chemopreventive agents. They are thought to decrease proliferation by reducing prostaglandin levels? Reversal of premalignant changes in the tracheobronchial tree has been attempted to decrease the incidence of lung cancer, and trials of various agents have been performed. The synthetic retinoid etretinate was compared with placebo in a 6-month randomized trial to reverse the atypia seen in s p u t u m samples. Although the drug was well tolerated and compliance was good, no differences between the two groups was observed. 7 Sputum atypia was also used as a marker in a 4-month trial of folate and vitamin B12 versus placebo. An improvement in atypia was seen in the treatment group? Cis-retinoic acid (cRA) was given to reverse sputum atypia in an uncontrolled trial, but no effect was seen? Changes in bronchial epithelium have been monitored by bronchoscopy in at least two trials. An uncontrolled trial of etretinate given for 6 months to otherwise healthy heavy smokers demonstrated improvement in the extent of bronchial metaplasia. 1~A randomized, controlled trial was performed to confirm these findings. Heavy smokers with significant bronchial metaplasia were treated with cRA or placebo for 6 months. Squamous metaplasia decreased in both groups after treatment, but without significant difference between the two. The drug therefore had no effect on metaplasia. Smoking cessation did affect metaplasia; significant declines in the extent of metaplasia were seen in those who stopped smoking, and no changes were seen in those who continued to smoke? 1 A large, placebo-controlled, randomized prevention trial has been completed. In this trial, Finnish men between the ages of 50 and 69 years who were current smokers were treated with fi-carotene, c~-tocopherol, both, or placebo with the development of lung cancer as the study endpoint. The m e n receiving fi-carotene unexpectedly had a higher incidence of lung cancer compared with those not receiving it. No effect on lung cancer incidence was seen with a-tocopherol, and no interaction between l~-carotene and ct-tocopherol was observed. Mortality in the l~-carotene group was 8% higher, thought to reflect deaths from lung cancer and ischemic heart disease. This study raises the possibility that t~-carotene supplementation may be harmful. 12 Two other ongoing trials will further examine t~-carotene supplementation in chemoprevention. The Harvard Physicians Health Study is examining the effects of t~-carotene alone in reducing the incidence of all cancers. The t~-carotene and retinol efficacy trial (CARET) is a randomized, double-blind trial comparing the administration of i~-carotene and retinyl palmitate with placebo in reducing lung cancer incidence in two populations: heavy smokers and asbestos-exposed individuals. Accrual is nearly complete, and results are expected in early 1998. 3 The prevention of second primary cancers in patients treated for early-stage squamous cell cancers of the head and neck was initially demonstrated by Hong et al. ~3 In those treated with cRA for 1 year C u r t P r o b l Cancer, July/August 1996
267
after definitive treatment of the primary lesion, the incidence of second primaries was 4%, compared with 24% in the placebo group. There was no effect on the rates of recurrence or distant metastasis. The concept of field carcinogenesis in the pathogenesis of head and neck cancers applies to lung cancer as well, and the positive effect of cRA on head and neck cancers has led to the use of retinoids to prevent second primary lung cancers. Pastorino et al. ~4 reported the results of a randomized trial of treatment with retinyl palmitate for 12 m o n t h s versus placebo after resection of stage I NSCLC. Eighteen patients in the treatment group developed a second primary, as did 29 patients in the placebo group. The time to development of a new primary was significantly longer in the treatment group, and there was a trend toward a longer disease-free interval (time to relapse or new primary) with treatment. Two large trials are being performed to further explore prevention of second primary cancers. The Euroscan trial is designed to study more than 2000 patients throughout Europe who have a history of laryngeal cancer, oral cavity cancer, or NSCLC. Patients will receive retinyl palmitote, N-acetylcysteine, both, or placebo for a 2-year period, is A second trial is being performed in the United States and Canada. It randomizes patients with resected stage I NSCLC to receive cRA or placebo for 3 years. Approximately 1300 patients will be accrued. TM QUALITY OF LIFE AND COST EFFECTIVENESS Most patients with NSCLC have disease that cannot be cured by surgical resection. Neither chemotherapy nor radiation therapy has had a substantial impact on the long-term survival of these patients. Because advanced disease is uniformly fatal and response rates to chemotherapeutic regimens are at best 30% to 40%, there is controversy regarding the role of chemotherapy in advanced disease. To address this issue, several studies have randomized patients with advanced NSCLC (stage IIIB or IV) to chemotherapy or to best supportive care (BSC). A metaanalysis of seven such trials has been performed, lz Three of the trials 18-2~ showed a statistically significant improvement in median survival in the treatment group. The seven trials combined revealed decreased mortality at 3 and 6 months with chemotherapy. There continued to be decreased mortality at 9, 12, and 18 months, although the differences did not reach statistical significance. A similar meta-analysis has been published, 2~ and although it excluded one TM of the three positive trials, combined results for the remaining six trials 18,2~ revealed a median survival of 27.4 weeks in the treatment group versus 16.7 weeks in the BSC group. Treatment was associated with a 24% reduction in the probability of death. The improvement in mortality decreased significantly after 6 months. 2~ Two important issues were not specifically addressed by these stud268
Curt Probl Cance~
July/August 1996
ies. One is quality of life. Data from other trials indicate that chemotherapy may improve disease-related symptoms, including dyspnea, cough, pain, and weight loss. 26"29In one study, 70% of patients had improvement of symptoms, despite an objective response rate of only 2 8 ~ 26 These trials, however, did not include a control (BSC) arm. Whether potentially toxic chemotherapy improves the quality of life compared with BSC may never be fully answered. Measures of improvement in quality of life have become a necessary part of the approval process for new chemotherapeutic agents. 3~ The instruments used to measure such data have been in development since the early 1980s. The Lung Cancer Symptom Scale is an instrument developed at Memorial Sloan-Kettering Cancer Center specifically far the assessment of symptoms of patients with lung cancerJ ~ This instrument has been tested at multiple centers and has been found to be feasible, reliable, valid, and internally consistent. 3~ The European Organization for the Research and Treatment of Cancer uses a general quality of life (QOL) survey with a supplement specific for lung cancer. These surveys measure patient functioning, symptom status, and perception of QOL, and they have been translated into 10 languages. 31'32The Southwest Oncology Group uses categorical scales in the form of multiple-choice questions and visualanalog scales. 32 The Eastern Cooperative Oncology Group trials for lung cancer employ the FACT-L questionnaire, which includes a 28item general questionnaire and a lung cancer-specific module. This questionnaire has demonstrated validity, reliability, and sensitivity to changes over time. 32,33 A second major issue to evaluate in the treatment of NSCLC is cost. A cost-effectiveness analysis of a National Cancer Institute of Canada trial of chemotherapy versus BSC has been reported? 4 One of the chemotherapy regimens used was found to be less costly than BSC. Most costs were accounted for by hospitalization, with increased hospital time for those on BSC. Chemotherapy costs accounted for little of the total cost (17% to 22%). The cost effectiveness of treatment with chemotherapy was comparable to that for coronary artery bypass grafting, home dialysis, renal transplantation, and s treatment for hypertension. 34 A second study from Canada demonstrated that the administration of chemotherapy to approximately 50% of patients with stage IV NSCLC would n o t add significantly to the total cost for the treatment of all cases of NSCLC, and the iffvestigator points out that the cost would be less than one half of the cost of neoadjuvant chemotherapy for earlier-stage cancers. 35 The potential reduction in the cost for staging patients with small cell lung cancer has been calculated? 6 An algorithm for staging was d e v e l o p e d , w i t h the m a j o r source of savings r e l a t e d to the discontinuation of testing after the identification of a site of metastatic disease. A proposed set of sequential staging procedures was Curl" Probl Cancer, July/August 1996
269
p r o j e c t e d to d e c r e a s e c o s t s b y m o r e t h a n o n e third. 36 S u c h an algor i t h m for s t a g i n g m a y b e f e a s i b l e for N S C L C a n d m a y p o t e n t i a l l y s a v e m o n e y , time, a n d effort for p a t i e n t s . REFERENCES
1. Zhang X, Liu Y, Lee M-O, Pfahl M. A specific defect in the retinoic acid response associated with human lung cancer cell lines. Cancer Res 1994;54: 5663-9. 2. Mayne ST, Janerich DT, Greenwald P, et al. Dietary beta-carotene and lung cancer risk in U.S. nonsmokers. J Natl Cancer Inst 1994;86:33-8. 3. Omenn GS, Goodman G, Thornquist M, et al. The beta-carotene and retinal efficacy trial (CARET) for chemoprevention of lung cancer in high risk p o p u l a t i o n s : smokers a n d a s b e s t o s - e x p o s e d workers. Cancer Res 1994;54:$2038-43. 4. Knekt P, Aromaa A, Maatela J, et al. Vitamin E and cancer prevention. Am J Clin Nutr 1991;53:$283-6. 5. van Zandwijk N. N-acetylcysteine for lung cancer prevention. Chest 1995;107:1437-41. 6. Nelson C. Aspirin prevention update: new data ori lung and colon cancers. J Nail Cancer Inst 1995;87:567-9. 7. Arnold AM, Browman GE Levine MN, et al. The effect of the synthetic retinoid etretinate on sputum cytology: results from a randomised trial. Br J Cancer 1992;65:737-43. 8. Heimburger DC, Alexander CB, Birch R, et al. Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12: report of a preliminary randomized double-blind intervention trial. JAMA 1988;259: 1525-30. 9. Saccomanno G, Moran PG, Schmidt RD, et al. Effects of 13-cis retinoids on premalignant and malignant cells of lung origin. Acta Cytol 1980;26:78-85. 10. Misset JL, Santelli G, Homasson JP, et al. Regression of bronchial epidermoid metaplasia in heavy smokers with etretinate treatment. Cancer Detect Prey 1986;9:167-70. 11. Lee JS, Lippman SM, Benner SE, et al. Randomized placebo-controlled trial of isotretinoin in chemoprevention of bronchial squamous metaplasia. J Clin Oncol 1994;12:937-45. 12. Heinonen OP, Albanes D, and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study Group. The effect of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-35. 13. Hang WK, Lippman SM, Itri LM, et al. Prevention of second primary tumors with isotretinoin in squamous cell carcinoma of the head and neck: longterm follow-up. N Engl J Med 1990;323:795-801. 14. Pastorino U, Infante M, Maioli M, et al. Adjuvant treatment of stage I lung cancer with high-dose vitamin A. J Clin Oncol 1993;11:1216-22. 15. DeVries N, van Zandwijk N, Pastorino U. The Euroscan study. Br J Cancer 1991;64:985-9. 16. Benner SE, Lippman SM, Hang WK. Chemoprevention of lung cancer. Chest 1995:107:$316-21. 17. Souquet PJ, Chauvin F, Boissel JR et al. Polychemotherapy in advanced non small cell lung cancer: a recta-analysis. Lancet 1993;342:19-21[ 18. Cormier Y, Bergeron D, La Forge J, et al. Benefits of polychemotherapy in advanced nan-small-cell bronchogenic carcinoma. Cancer 1982;50:845-9. 270
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