The New England Journal of Medicine BEditorial Volume 346:126-128 January 10, 2002 Number 2 Lung Cancer — Time to Move on from Chemotherapy In 2001 lung cancer caused more than 1 million deaths worldwide. Despite the well-recognized link between tobacco use and the development of lung cancer, the number of new cases continues to rise, especially among women. In girls and women 15 to 64 years of age, lung cancer is now the leading cause of death from cancer, and this disease remains the most common cause of death from cancer in men. 1 <http://content.nejm.org/cgi/content/full/346/2/#R1> During the past 20 years, numerous efforts have been made to reduce the death rate among patients with lung cancer. Treatment involves surgery, radiation therapy, combination chemotherapy, or a combined approach. Yet after 20 years, the improvement in long-term survival has been slight. Indeed, today a minority of patients survive more than one year after diagnosis, and less than 15 percent survive for five years. In this issue of the Journal, two groups of investigators report on new combination-chemotherapy regimens for treating small-cell lung cancer 2 <http://content.nejm.org/cgi/content/full/346/2/#R2> and advanced, inoperable non–small-cell lung cancer. 3 <http://content.nejm.org/cgi/content/full/346/2/#R3> Small-cell lung cancer accounts for 20 to 25 percent of all new cases of lung cancer. At diagnosis, 40 percent of patients have limited disease, defined as disease confined to the thorax. With chemotherapy plus radiotherapy and the selective use of prophylactic cranial irradiation, the median survival of these patients is 18 to 24 months, and up to 20 percent of them may survive for more than 2 years. Without treatment, the median survival is only 6 to 12 weeks. Patients with extensive disease (the remaining 60 percent of all new cases of small-cell lung cancer) have, at the time of diagnosis, metastases involving one or more sites such as the brain, liver, bone, or bone marrow. With combination chemotherapy, the median survival of these patients is seven to nine months, and few, if any, live more than two years. Twenty years of clinical trials involving such patients have yielded an improvement in survival of only two months. 4 <http://content.nejm.org/cgi/content/full/346/2/#R4> The current standard chemotherapy regimen is etoposide plus cisplatin (or carboplatin). In this issue of the Journal, Noda et al. 2 <http://content.nejm.org/cgi/content/full/346/2/#R2> report results with a new combination of irinotecan (a topoisomerase I inhibitor) and cisplatin for the treatment of extensive small-cell lung cancer. They found a 3-month prolongation of the median survival with this combination (12.8 months, vs. 9.4 months with etoposide plus cisplatin), as well as an impressive 2-year survival rate of 19.5 percent with this regimen (as compared with 5.2 percent with etoposide plus cisplatin). These results appear to indicate an advance in the treatment of extensive small-cell lung cancer, but confirmatory trials are required before the new combination becomes the standard of therapy for this disease. The role of chemotherapy in the treatment of advanced, inoperable non–small-cell lung cancer continues to be a subject of debate. In the late 1990s, many phase 2, single-institution trials of new agents alone or in combination with cisplatin found high response rates (40 to 50 percent) with these agents, and substantial numbers of patients survived for one or two years. The study of more than 1200 patients reported by Schiller et al. in this issue of the Journal 3 <http://content.nejm.org/cgi/content/full/346/2/#R3> and the recent study of more than 400 patients by Kelly et al. 5 <http://content.nejm.org/cgi/content/full/346/2/#R5> compared several combinations of agents. The results continue to raise questions about the role and efficacy of combination chemotherapy in advanced non–small-cell lung cancer. In both studies, the response rates were lower than expected (16.6 to 27 percent), as compared with the results of single-institution trials; the median survival ranged from 7.4 to 8.1 months, and the 1-year rate of survival approached 31 to 39 percent. In the study by Schiller et al., most patients had an excellent performance status (Eastern Cooperative Oncology Group performance status, 0 or 1). In this trial, excess toxic effects, some fatal, were noted among patients with a poor performance status, and after the results in the initial 66 patients with poor performance status were analyzed, further such patients were excluded from the trial. These two studies 3 <http://content.nejm.org/cgi/content/full/346/2/#R3> , 5 <http://content.nejm.org/cgi/content/full/346/2/#R5> confirm that the benefits of combination chemotherapy among the fittest patients with advanced non–small-cell lung cancer are marginal (with perhaps a gain in median survival of two to three months). In addition, in the study by Schiller et al., there was no superior combination regimen, and these authors conclude that chemotherapy is best offered only to patients with a good performance status. Whether these results are an improvement over the results of older trials 6 <http://content.nejm.org/cgi/content/full/346/2/#R6> , 7 <http://content.nejm.org/cgi/content/full/346/2/#R7> is questionable when one considers the effects of stage migration (resulting from the increasingly detailed workup of patients), as well as the fact that in the other large trials, 3 <http://content.nejm.org/cgi/content/full/346/2/#R3> , 5 <http://content.nejm.org/cgi/content/full/346/2/#R5> patients with excellent performance status accounted for the majority of the eligible subjects. It is clear that new approaches are required. These should include prevention, screening and early detection, and novel treatments based on our understanding of the biology and molecular biology of this disease. Tobacco products kill more than 450,000 Americans each year, and another 50,000 die of the effects of secondhand smoke. A tobacco-free environment would greatly improve the health of our society and would reduce the rates of death from coronary artery disease, lung cancer, and chronic lung disease. 8 <http://content.nejm.org/cgi/content/full/346/2/#R8> Will the early detection of lung cancer decrease mortality from the disease? In early studies, screening with radiography of the chest or cytologic examination of sputum samples did not improve survival, and thus screening for lung cancer fell out of favor. However, several new approaches are noteworthy. One is the use of spiral computed tomography (CT) at low doses of radiation. 9 <http://content.nejm.org/cgi/content/full/346/2/#R9> , 10 <http://content.nejm.org/cgi/content/full/346/2/#R10> This procedure can detect nodules highly suggestive of lung cancer in asymptomatic persons who are at high risk. In one study of 1000 such persons, 23 of 27 cancers (85 percent) detected with the use of spiral CT were stage I cancers. 9 <http://content.nejm.org/cgi/content/full/346/2/#R9> Chest radiography alone detected only seven cancers in this group (26 percent). Since most of the cancers that were detected with spiral CT were early-stage tumors curable by surgery, this technique may reduce mortality from lung cancer. However, because there still are no data on mortality from lung cancer after screening with spiral CT, this technique cannot currently be advocated for mass screening. Studies of the molecular biology of lung cancer and lung-cancer cell lines have increased our understanding of the multistep pathway for the pathogenesis of lung cancer. Genetic alterations such as mutant K-ras and TP53 genes are detectable on cytologic examination of sputum and bronchial-lavage samples. 11 <http://content.nejm.org/cgi/content/full/346/2/#R11> , 12 <http://content.nejm.org/cgi/content/full/346/2/#R12> The use of such molecular markers, combined with advances in bronchoscopy (e.g., laser-induced fluorescence endoscopic bronchoscopy), may make possible the detection of preinvasive and invasive lung cancer and the identification of the site of the lesions in persons at high risk. 13 <http://content.nejm.org/cgi/content/full/346/2/#R13> The detection of very early lesions in persons at risk would also identify candidates for studies of chemoprevention. Prospective trials are required to determine whether the use of these invasive approaches in asymptomatic persons will reduce mortality from lung cancer. Another approach is chemoprevention in persons who are at risk. 14 <http://content.nejm.org/cgi/content/full/346/2/#R14> To date, several large, randomized trials of beta carotene, retinol, and isotretinoin for the prevention of lung cancer have not produced positive results. Indeed, in one trial of the combination of beta carotene and retinol (the Carotene and Retinol Efficacy Trial), there was a 28 percent increase in the incidence of lung cancer in the subjects who received the supplements, along with a 17 percent increase in overall mortality in this group. 15 <http://content.nejm.org/cgi/content/full/346/2/#R15> These results are disappointing, but as we learn more about the molecular carcinogenesis of lung cancer, more specific sites for chemoprevention can be identified and targeted. Chemotherapy in advanced lung cancer has reached a plateau; there are few differences among various combinations of drugs. However, there are now several reports of the use of biologic agents with unique mechanisms of action in this disease. Epidermal growth factor receptor is overexpressed in most cases of non–small-cell lung cancer. 16 <http://content.nejm.org/cgi/content/full/346/2/#R16> Of the many strategies that have been developed to target this receptor, the two most extensively evaluated are monoclonal antibodies against the extracellular domain of the receptor (e.g., trastuzumab [Herceptin]) and inhibition of the tyrosine kinase region of the receptor. Two tyrosine kinase inhibitors, ZD1839 and OSI-774, have antitumor activity in advanced non–small-cell lung cancer, even in patients in whom previous chemotherapy has failed. 17 <http://content.nejm.org/cgi/content/full/346/2/#R17> , 18 <http://content.nejm.org/cgi/content/full/346/2/#R18> These and other novel biologic agents entering phase 1 and phase 2 trials offer the best hope for the future therapy of lung cancer. Confirmation of the activity of such agents in advanced disease would open the possibility of using them in early-stage disease, either as adjuvant therapy or in combination therapy. All physicians caring for patients with lung cancer should, in the absence of contraindications, consider inviting their patients to participate in these ongoing, pivotal trials. The current treatment of advanced small-cell and non–small-cell lung cancer with combination chemotherapy is nonspecific, nonselective, and toxic. New combinations of chemotherapy are not likely to make substantial improvements in survival. However, prevention, early detection, and the use of specific biologic targets offer optimism and hope that mortality from this disease may be reduced. Desmond N. Carney, M.D., Ph.D. Mater Misericordiae Hospital Dublin 7, Ireland References 1. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001;51:15-36. [Erratum, CA Cancer J Clin 2001;51:144.] [Medline] <http://content.nejm.org/cgi/external_ref?access_num=11577478&link_type=MED> 2. Noda K, Nishiwaki Y, Kawahara M, et al. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med 2002;346:85-91. [Abstract/Full Text] <http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=346 /2/85> 3. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002;346:92-98. [Abstract/Full Text] <http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=346 /2/92> 4. Chute JP, Chen T, Feigal E, Simon R, Johnson BE. Twenty years of phase III trials for patients with extensive-stage small-cell lung cancer: perceptible progress. J Clin Oncol 1999;17:1794-1801. [Abstract/Full Text] <http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=jco&resid=17/6 /1794> 5. Kelly K, Crowley J, Bunn PA Jr, et al. Randomized phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in the treatment of patients with advanced non-small-cell lung cancer: a Southwest Oncology Group trial. J Clin Oncol 2001;19:3210-3218. [Abstract/Full Text] <http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=jco&resid=19/1 3/3210> 6. Ruckdeschel JC, Finkelstein DM, Ettinger DS, et al. A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer. J Clin Oncol 1986;4:14-22. [Abstract] <http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=jco&resid=4/1/ 14> 7. Paesmans M, Sculier JP, Libert P, et al. Prognostic factors for survival in advanced non-small-cell lung cancer: univariate and multivariate analyses including recursive partitioning and amalgamation algorithms in 1,052 patients. J Clin Oncol 1995;13:1221-1230. [Abstract] <http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=jco&resid=13/5 /1221> 8. Bal DG, Kizer KW, Felten PG, Mozar HN, Niemeyer D. Reducing tobacco consumption in California: development of a statewide anti-tobacco use campaign. JAMA 1990;264:1570-1574. [Medline] <http://content.nejm.org/cgi/external_ref?access_num=2395199&link_type=MED> 9. Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354:99-105. [Medline] <http://content.nejm.org/cgi/external_ref?access_num=10408484&link_type=MED> 10. Parkin DM, Moss SM. Lung cancer screening: improving survival but no reduction in deaths -- the role of over diagnosis. Cancer 2000;89:2369-2376. [Medline] <http://content.nejm.org/cgi/external_ref?access_num=11147614&link_type=MED> 11. Kersting M, Friedl C, Kraus A, Behn M, Pankow W, Schuermann M. Differential frequencies of p16(INK4a) promoter hypermethylation, p53 mutation, and K-ras mutation in exfoliative material mark the development of lung cancer in symptomatic chronic smokers. J Clin Oncol 2000;18:3221-3229. [Abstract/Full Text] <http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=jco&resid=18/1 8/3221> 12. Sozzi G, Musso K, Ratcliffe C, Goldstraw P, Pierotti MA, Pastorino U. Detection of microsatellite alterations in plasma DNA of non-small cell lung cancer patients: a prospect for early diagnosis. Clin Cancer Res 1999;5:2689-2692. [Abstract/Full Text] <http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=clincanres&res id=5/10/2689> 13. Hirsch FR, Prindiville SA, Miller YE, et al. Fluorescence versus white-light bronchoscopy for detection of preneoplastic lesions: a randomized study. J Natl Cancer Inst 2001;93:1385-1391. [Abstract/Full Text] <http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=jnci&resid=93/ 18/1385> 14. Lippman SM, Spitz MR. Lung cancer chemoprevention: an integrated approach. J Clin Oncol 2001;19:Suppl:74S-82S. [Medline] <http://content.nejm.org/cgi/external_ref?access_num=11560978&link_type=MED> 15. The Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group. The effects of vitamin E and beta carotene on the incidence of lung cancer and other cancers in male smokers. N Engl J Med 1994;330:1029-1035. [Abstract/Full Text] <http://content.nejm.org/cgi/ijlink?linkType=ABST&journalCode=nejm&resid=330 /15/1029> 16. Baselga J. Targeting the epidermal growth factor receptor: a clinical reality. J Clin Oncol 2001;19:Suppl:41S-44S. [Medline] <http://content.nejm.org/cgi/external_ref?access_num=11560970&link_type=MED> 17. Yuen A, Halsey J, Fisher G, et al. Phase I/II trial of ISIS 3521 an antisense inhibitor of PKC-alpha, with carboplatin and paclitaxel in non-small cell lung cancer. Proc Am Soc Clin Oncol 2001;20. abstract. 18. Perez-Solar R, Chachoua A, Huberman M, et al. A phase II trial of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor OS1-774 following platinum based chemotherapy in patients with advanced, EGFR expressing non-small cell lung cancer. Proc Am Soc Clin Oncol 2001;20. abstract. Edward E. Rylander, M.D. Diplomat American Board of Family Practice. Diplomat American Board of Palliative Medicine.