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Treatment of Elderly Patients With Non-Small-Cell Lung Cancer

Treatment of Elderly Patients With Non-Small-Cell Lung Cancer

ABSTRACT: One of the main reasons for the increased acceptance of chemotherapy for both early and advanced non-small-cell lung cancer is the clinical availability of several new cytotoxic drugs. These less toxic, yet highly effective, new drugs not only benefit younger patients, but also offer new treatment opportunities for the elderly; advanced age alone should not preclude appropriate cytotoxic therapy. Vinorelbine (Navelbine) was the first new agent tested in randomized trials with elderly patients having advanced non-small-cell lung cancer. Results proved that vinorelbine does indeed have a survival advantage over best supportive care for these patients. Gemcitabine (Gemzar) is probably the most effective cytotoxic agent in the treatment of non-small-cell lung cancer today, showing high antitumor activity as a single agent and in combination. Moreover, it has a favorable toxicity profile. Since it can be effectively used for the palliation of tumor-related symptoms and can thus positively influence performance status, gemcitabine may be of great clinical importance in the treatment of elderly and unfit patients. Docetaxel (Taxotere) has recently become the first agent to be registered for second-line chemotherapy in non-small-cell lung cancer. This decision was based on survival advantages and clinical benefit data stemming from two randomized phase III studies. Nonetheless, chemotherapy for elderly patients continues to be a major unresolved oncologic problem. Clinical research with the new cytotoxic agents should be intensified to further define the most appropriate use for these drugs as single agents or in combination for the treatment of elderly patients. [ONCOLOGY 15(Suppl 6):46-51, 2001]

Introduction

The issue of treating elderly patients with chemotherapy is of great clinical relevance today.[1-3] In the United States and Europe, the leading cause of cancer death in men and women is lung cancer. The large majority of lung cancer patients are more than 55 years old, and the number of patients over the age of 65 has grown considerably in the course of the past decade. When incidence rates are calculated for age specificity, lung cancer rates escalate to more than 500,000 persons for those 70 to 85 years of age.[4,5]

Age itself is not one of the definitive prognostic factors of lung cancer.[6] Because untreated lung cancer patients have an extremely poor prognosis, the question of which treatment patients should receive should not be based on age. Older patients should be offered the same general treatment as younger, healthier patients. This general principle should apply to all treatment modalities: surgery, radiotherapy, and chemotherapy.[7-9] At the same time, daily contact with older patients shows that standard recommendations for the proper dose and application time are often difficult to fulfill and must be modified for the elderly.[3]

Many older patients have additional complex medical problems, including chronic obstructive airway disease, congestive heart failure, and decreased renal function, which must be considered. In addition to the problems of comorbidity, poor performance status, and polypharmacy, specific mental, emotional, and social-economic conditions are often found in the elderly and differ from their younger counterparts. There are, for example, many cases of cognitive and emotional disturbances, family dysfunctions, limited access to clinic and hospital care, confused reactions to complex medical schedules, and less motivation to withstand the ordeal of aggressive treatment—all of which may adversely influence cancer treatment and result in inadequate treatment compliance.

Of all the treatment modalities, the use of chemotherapy in the elderly has remained the most controversial.[10-12] The skepticism often expressed[13] is related to (1) the perception of chemotherapy’s limited benefit in general; (2) older data suggesting that chemotherapy is of benefit mainly to patients younger than 70 years and that the recommended therapy should be platinum-based combination chemotherapy; (3) the potential for increased toxicity in the elderly; (4) the small number of studies dedicated to the elderly and the fact that the elderly were, in the past, frequently excluded from clinical studies; (5) preselection as a major problem in interpreting data from retrospective reviews; and (6) the widespread reluctance to treat elderly patients in the same way that younger patients are treated. With the general improvements in cytotoxic therapy over the past few years, new possibilities are being opened to elderly patients for more individualized treatment, which is easier to adapt to the specific age group and general condition of the patients being treated.[14]

New Generation of Agents

The new generation of chemotherapeutic agents largely responsible for these positive changes belong pharmacologically to the antimetabolites, the topoisomerase I inhibitors, and the antitubulins. These new agents show great single-agent efficacy in both first- and second-line therapy, and are therefore especially attractive for use as single agents in the older population. Furthermore, the toxicity profile of these new drugs differs from that found in traditional chemotherapy and is generally found to be better tolerated. In addition, these drugs can be administered flexibly in various schedules and dosages, thus opening new options for platinum-free combination chemotherapy, for chemoradiotherapy regimens, as well as for the application of cytotoxic drugs on an outpatient basis.

Single-Agent Therapy

Among the new drugs with probably the greatest impact on the treatment of elderly patients are the classical antitubulin vinorelbine (Navelbine), the antimetabolite gemcitabine (Gemzar), and the taxane docetaxel (Taxotere).[15-19] This has been demonstrated in a number of nonrandomized studies, in a few randomized trials, and in several retrospective analyses.

Vinorelbine was probably the first new agent tested in nonrandomized and randomized trials in elderly patients with non-small-cell lung cancer.[20-24] One milestone was the study of the elderly done by the Elderly Lung Cancer Vinorelbine Italian Study Group, which has become known as the ELVIS trial.[22] Here, elderly patients over the age of 70 were randomized to either single-agent vinorelbine or best supportive care alone. A statistically significant survival advantage was seen in patients receiving vinorelbine (Figure 1). This trial clearly established the potential benefit of single-agent therapy for the elderly population. Vinorelbine is, therefore, widely considered to be more or less the "standard arm" for upcoming comparative studies, especially for testing the value of new agents in elderly patients with non-small-cell lung cancer.

Another agent that has proven to be active and well tolerated in non-small-cell lung cancer patients is gemcitabine.[25] Gemcitabine is a novel deoxycytidine analog with structural similarities to cytosine arabinoside. Gemcitabine was the first cytotoxic drug registered for use in the palliation of tumor-induced symptoms[26] and was shown to be effective as a single agent in both first- and second-line therapy.

When administered once weekly on days 1, 8, and 15 of a 28-day cycle at a dose of 800-1,250 mg/m2, gemcitabine showed an objective response rate of 20% to 26% in chemotherapeutically nonpretreated patients. The median duration of response ranged from 3.3 to 12.7 months, and the overall median survival time was 8.1 to 9.4 months. Single-agent gemcitabine was shown to be especially effective in reducing tumor-induced dyspnea, pain, and hemoptysis. It was also well tolerated by elderly patients. In the majority of cases, gemcitabine promises a better quality of life; in one-third of the cases, it leads to an improvement in performance status. Gemcitabine has also proven to be superior to best supportive care in advanced non-small-cell lung cancer.

A specific review of single-agent gemcitabine investigations in patients over 65 years old enrolled in four phase II trials has recently been published.[27] In these studies, 250 patients were under the age of 65 and 105 patients were 65 or older. Baseline patient characteristics for gender, performance status, stage of disease, and histology did not differ significantly between the age groups. There were no statistically significant differences for the overall response rates, which showed 16% for the younger and 24% for the older patients, respectively (Table 1).

Of interest is the fact that the group under age 65 had a median survival of 8 months and a 1-year survival rate of 27%, whereas the older population had a median survival of 9.1 months and a 36% 1-year survival rate. Gemcitabine was well tolerated and toxicities were similar for both age groups (Table 2). The number of cycles associated with dose reductions and/or dose omissions and the mean number of treatment cycles administered were also similar. The feasibility and effectiveness of single-agent gemcitabine in patients older than 70 years of age has recently been confirmed by a number of other investigators.[28-31]

Combination Chemotherapy

Because of their mild side-effect profiles, the new drugs are also good candidates for combination chemotherapy. The question of whether the addition of gemcitabine to vinorelbine improves survival and the quality of life among elderly patients has recently been addressed in a randomized study of the Southern Italy Co-Operative Oncology Group and the Inter-Regional Association for the Study of Lung Cancer Italy.[23] A total of 120 patients 70 years of age or older with advanced non-small-cell lung cancer were randomized. In the vinorelbine/gemcitabine group, median survival was 7 months, and the 1-year survival rate was 30% compared with 2.5 months and 13% for single-agent vinorelbine. This difference was statistically significant. The combination therapy was also associated with a clear delay in symptom and quality-of-life deterioration (Table 3).

Another important ongoing clinical trial is the phase III MILES trial (Multi-agent Italian Lung Cancer Elderly Trial), in which the combination of gemcitabine and vinorelbine is being compared to single-agent vinorelbine and single-agent gemcitabine. Patients are eligible if they are 70 years of age or older and if they are diagnosed as having inoperable stage III or IV non-small-cell lung cancer. The primary end point of the MILES study is survival, and more than 600 patients are to be enrolled. Preliminary response data from 98 patients who received single-agent gemcitabine at 1,200 mg/m2 on days 1 and 8 every 3 weeks (49 patients) or gemcitabine at 1,000 mg/m2 combined with vinorelbine at 25 mg/m2 on days 1 and 8 every 3 weeks (49 patients) were recently published.[32] The data showed that nine patients responded to single-agent gemcitabine (9 partial responses) and that another nine responded to gemcitabine/vinorelbine (8 partial responses, 1 complete response) giving an identical response rate of 18.4% (95% confidence interval [CI] = 8.8%-32.0%) for each treatment arm.

Our own experience with combination chemotherapy for elderly patients having advanced non-small-cell lung cancer comes from a randomized, two-arm phase II study, where gemcitabine and docetaxel were given sequentially.[33]

Patients were randomized either to gemcitabine at 1,000 mg/m2 on days 1, 8, and 15, every 4 weeks or to docetaxel at 35 mg/m2 also given on days 1, 8, and 15 every 4 weeks for up to six cycles. In case of tumor progression during or after completion of first-line therapy, treatment crossover was planned (Table 4).

Patients were included only if they had documented non-small-cell lung cancer either in stage IIIB disease with pleural effusion and/or superclavicular lymph node involvement or in stage IV disease. Patients also had no prior chemotherapy, no prior radiotherapy of measurable lesions, a performance status of 0-2, adequate hematology and biochemistry, no clinical evidence of brain metastases, and were 18 years of age or older, and gave informed, written consent. About 25% of the patients enrolled were 70 years of age or older.

The major pretreatment characteristics for the two age groups were well balanced (Table 5). For patients who were assigned initially to receive single-agent gemcitabine and then, in case of progression, were switched to or planned to cross over to docetaxel, the 1-year survival rates were almost identical (30%). The median survival rate was about 8 months between the two age groups (Table 6).

In spite of the great skepticism about using platinum-based chemotherapy for older and unfit patients, the investigation of therapy regimens using new drugs in combination with cisplatin (Platinol) for the elderly continues.[34-37] From a randomized phase III study of gemcitabine plus cisplatin vs cisplatin, subset analyses of 260 patients treated with gemcitabine/cisplatin were carried out by Nguyen for patients over 70 years of age.[38] These results showed that gemcitabine/cisplatin was as well tolerated in the elderly as in younger patients. There were also no statistically significant differences in tumor response, time to progression, and median survival (Table 7).

The feasibility and efficacy of cisplatin-based chemotherapy in elderly patients has lately been confirmed by a retrospective analysis using the Eastern Cooperative Oncology Group (ECOG) 5592 database.[39] Response, toxicity, and survival for fit, elderly non-small-cell lung cancer patients were similar to the rates shown by younger patients. The authors therefore concluded that advanced age alone should not preclude appropriate platinum-based chemotherapy.

Conclusion

Chemotherapy for elderly patients with advanced non-small-cell lung cancer continues to be a major unresolved clinical problem. The availability of new chemotherapeutic agents, however, has increased the chemotherapeutic treatment options for patients with non-small-cell lung cancer in general, but even more so for the elderly.

For advanced disease, as the recently published results of randomized studies indicate, single-agent therapy using new chemo- therapeutic agents or their combinations may offer an appropriate alternative to a platinum-based combination chemotherapy for elderly patients. Physiologically fit elderly patients with early-stage non-small-cell lung cancer who are in good clinical condition should not be excluded from the clinical investigation of platinum-based two- or even three-drug combinations to determine their role within multimodality treatment concepts.

References

1. Brown JS, Eraut D, Trask C, et al: Age and the treatment of lung cancer. Thorax 51:564-568, 1996.

2. Cohen HJ: Cancer and aging: Overview. ASCO educational book 223-226, 1998.

3. Aapro MS: Using cytotoxic chemotherapy agents in the elderly. ASCO educational book 341-345, 1999.

4. Lee-Chiong TLYr, Matthay RA: Lung cancer in the elderly patient. Clin Chest Med 14:453-478, 1993.

5. Yancik R, Reis LA: Cancer in older persons—Magnitude of the problem. How do we apply what we know? Cancer 74(suppl 1):1995-2002, 1994.

6. Osterlind K, Sorensen JB: Prognostic factors, in Aisner J, Arriagada R, Green MR, et al (eds): Comprehensive Textbook of Thoracic Oncology, pp 319-335. Baltimore, Williams & Wilkins, 1996.

7. Giovanazzi-Bannon S, Rademaker A, Lai G, et al: Treatment tolerance of elderly cancer patients entered onto phase II clinical trials: An Illinois Cancer Center study. J Clin Oncol 12:2447-2452, 1994.

8. Monfardini S, Sorio R, Boes GH, et al: Entry and evaluation of elderly patients in European Organization for Research and Treatment of Cancer (EORTC) new-drug-development studies. Cancer 95:333-338, 1995.

9. Hickish TF, Smith IE, O’Brien MER, et al: Clinical benefit from palliative chemotherapy in non-small-cell lung cancer extends the elderly and those with poor prognostic factors. Br J Cancer 78:28-33, 1998.

10. Festen J: Lung cancer therapy in the elderly. Eur J Cancer 27:1544-1545, 1991.

11. Finkelstein DM, Ettinger DS, Ruckdeschel JC: Long-term survivors in metastatic non-small-cell lung cancer: An Eastern Co-operative Oncology Group Study. J Clin Oncol 4:702-709, 1986.

12. Yellen SB, Cella DR, Leslie WT: Age and clinical decision-making in oncology patients. J Natl Cancer Inst 86:1766-1770, 1994.

13. Hutchins LF, Unger JM, Crowley JJ, et al: Under-representation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 341:2061-2067, 1999.

14. Manegold C: The new generation of chemotherapy agents in the treatment of the eldery. Lung Cancer 29(suppl 2):17-18, 2000.

15. Shepherd FA, Dancey J, Ramlau R, et al: Prospective randomised trial of docetaxel vs best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 18:2095-2103, 2000.

16. Fossella FV, DeVore R, Kerr RN, et al: Randomised phase III trial of docetaxel vs. vinorelbine or iphosphamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. J Clin Oncol 18:2354-2362, 2000.

17. McKay C, Hainsworth J, Burris H, et al: Weekly docetaxel in the treatment of elderly patients with advanced non-small-cell lung cancer (NSCLC): A Minnie Pearl Cancer Research Network phase II trial (abstract 1964). Proc Am Soc Clin Oncol 19:502a, 2000.

18. Yoshimura N, Kudoh S, Negoro S, et al: A phase II study of docetaxel in elderly patients with advanced non-small-cell lung cancer (NSCLC) (abstract 2093). Proc Am Soc Clin Oncol 19:532a, 2000.

19. Hainsworth JD, Burris HA, Morrissey LH, et al: Weekly docetaxel as first-line therapy for elderly patients with advanced non-small-cell lung cancer (NSCLC) (abstract 203). Lung Cancer 29(suppl 1):63, 2000.

20. Veronesi A, Crivellari D, Magri MD, et al: Vinorelbine treatment of advanced non-small-cell lung cancer with special emphasis on elderly patients. Eur J Cancer 32a:1809-1811, 1996.

21. Crawford J, O’Rourke M, Schiller JH, et al: Randomised trial of vinorelbine compared with fluorouracil plus leucovorin in patients with stage IV non-small-cell lung cancer. J Clin Oncol 14:2774-2784, 1996.

22. Gridelli C: The elderly lung cancer, Vinorelbine Italian Study Group: Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 19:66-72, 1999.

23. Frasci NG, Lorusso V, Panza N, et al: Gemcitabine plus vinorelbine vs. vinorelbine alone in elderly patients with advanced non-small-cell lung cancer. J Clin Oncol 18:2529-2536, 2000.

24. Buccheri G, Ferrigno D: Vinorelbine in elderly patients with inoperable non-small-cell lung cancer: A phase II study (abstract 111). Lung Cancer 29(suppl 1):35, 2000.

25. Manegold C, Zatloukal P, Krejcy K, et al: Gemcitabine in non-small-cell lung cancer. Invest New Drugs 18:29-42, 2000.

26. Moore M, Andersen J, Burris H, et al: A randomised trial of gemcitabine vs. 5-FU as first-line therapy in advanced pancreatic cancer (abstract 473). Proc Am Soc Clin Oncol 14:199, 1995.

27. Shepherd FA, Abratt RP, Anderson H, et al: Gemcitabine in the treatment of elderly patients with advanced non-small-cell lung cancer. Semin Oncol 24(suppl 7):50-55, 1997.

28. Martoni A, De Fabio F, Guaraldi M, et al: Gemcitabine as single agent in the treatment of elderly patients with stage IIIB-IV non-small-cell lung cancer (NSCLC): Preliminary results of an Italian multi-center phase II study (abstract 1991). Proc Am Soc Clin Oncol 18:517a, 1999.

29. Yokoyama A, Furuse K, Kurita Y, et al: Gemcitabine as a single agent in the treatment of elderly (> 70 years) patients with stage III/IV non-small-cell lung cancer (NSCLC) as compared to those < 70 years old (abstract 2056). Proc Am Soc Clin Oncol 19:523a, 2000.

30. Burkes RL, Wilson J, Shepherd FA, et al: Single agent gemcitabine for elderly patients with non-small-cell lung cancer: A phase II study (abstract 100). Lung Cancer 29(suppl 1):32, 2000.

31. Ricci S, Antonuzzo A, Galli L, et al: Gemcitabine monotherapy in elderly patients with advanced non-small-cell lung cancer: A multi-center phase II study. Lung Cancer 27:75-80, 2000.

32. Gridelli C, Gigolari S, Bilancia D, et al: Phase II study of gemcitabine and gemcitabine plus vinorelbine in advanced NSCLC elderly patients within the phase III MILES (Multi-agent Italian Lung Cancer in the Elderly Study) randomised trial (abstract 2092). Proc Am Soc Clin Oncol 19:532a, 2000.

33. Manegold C, Pilz L, Koschel G, et al: Gemcitabine followed by second-line docetaxel is feasible in advanced NSCLC: Results from a randomised phase II study (abstract 2166a). Proc Am Soc Clin Oncol 19:549a, 2000.

34. Lippe P, Silva RR, Monterubbianesi MC, et al: Advanced non-small-cell lung cancer (ANSCLC) in the elderly: Symptom-relief after weekly gemcitabine and cisplatin (abstract 1984). Proc Am Soc Clin Oncol 18:514a, 1999.

35. Martins SJ, Pereira JR, Ikari FK, et al: Chemotherapy with cisplatin and vinorelbine for elderly non-small-cell lung cancer (NSCLC) patients (abstract 1804). Proc Am Soc Clin Oncol 18:468a, 1999.

36. Ohe Y, Niho S, Kakinuma R, et al: Lower recommended dose but not diminished efficacy obtained in elderly patients age 75 years or older in phase I study of cisplatin and docetaxel administered by three consecutive weekly infusions for advanced non-small-cell lung cancer (abstract 199). Lung Cancer 29(suppl 1):61, 2000.

37. Edelman, Gandara DR, Lau D, et al: Sequential chemotherapy with carboplatin and gemcitabine followed by paclitaxel in poor performance starters and elderly patients with non-small-cell lung cancer (abstract 49). Lung Cancer 29(suppl 1):16, 2000.

38. Nguyen B, Sandler A, Denham C: The safety and efficacy of gemcitabine plus cisplatin in the elderly chemo-naive NSCLC patients (age > 70 years) as compared to those with age < 70 years (abstract 1818). Proc Am Soc Clin Oncol 18:471a, 1999.

39. Langer C, Manola Y, Bernardo P, et al: Advanced age alone does not compromise outcome in fit non-small-cell lung cancer (NSCLC) patients receiving platinum-based therapy: Implications of ECOG 5592 (abstract 1912). Proc Am Soc Clin Oncol 19:489a, 2000.

 
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