Perspective

The results of a recently published study have demonstrated that in some elderly, poor-performance status patients with multiple comorbidities, single-agent chemotherapy with vinorelbine (Navelbine) or gemcitabine (Gemzar) was equally efficacious as the combination of vinorelbine/gemcitabine in the treatment of advanced non-small cell lung cancer (NSCLC).¹ The combination of vinorelbine/gemcitabine is frequently used in elderly NSCLC patients or in those with poor-performance status because it is less toxic than platinum-based chemotherapeutic regimens. The finding that the efficacy of single-agent chemotherapy is comparable to that of combination chemotherapy in treating elderly, poor-performance status NSCLC patients with multiple comorbidities should result in savings in terms of total healthcare expenditures and toxicity.

Lung cancer continues to be the leading cause of cancer-related death in the United States. It is estimated that approximately 171,900 new cases of lung cancer will be diagnosed and approximately 157,200 deaths from lung cancer will occur in 2003.² The median age of newly diagnosed lung cancer patients is approximately 68 years and as many as 40% of patients may be older than 70 years at diagnosis.³ Many of these patients have significant comorbidities and/or age-related declines in organ function that limit their ability to tolerate standard chemotherapy;^4,5 therefore, these patients pose a significant challenge for oncologists.

Previous studies have suggested that single-agent vinorelbine or gemcitabine may be viable treatment options for these difficult-to-treat patients. In the Elderly Lung Cancer Vinorelbine Italian Study (ELVIS),⁶ single-agent vinorelbine significantly prolonged median survival compared to best supportive care (28 weeks vs 21 weeks; P = .03) and improved aspects of quality-of-life for patients.^6,7 The 1-year survival rate also favored patients receiving single-agent vinorelbine (32% vs 14%).⁷ Despite the age of the patients studied (≥70 years), only mild toxicities were observed. Retrospective subgroup analyses of single-agent gemcitabine trials have demonstrated similar positive findings.^8,9

New Evidence: The Multicenter Italian Lung Cancer in the Elderly Study (MILES)

The Multicenter Italian Lung Cancer in the Elderly Study (MILES) was a large, open-label phase 3 clinical trial designed to examine the use of non-platinum, moderately toxic chemotherapy in elderly, poor-performance NSCLC patients. MILES compared the effectiveness and toxicity of single-agent (vinorelbine, n = 233; or gemcitabine, n = 233) and combination (vinorelbine plus gemcitabine, n = 232) therapy in chemotherapy-naпve elderly patients (≥70 years, median age 74 years, range, 63-86 years) with advanced (Stage IIIB or IV disease with Eastern Cooperative Oncology Group [ECOG] performance status of 0, 1, or 2) NSCLC. Patients were randomized in a 1:1:1 ratio to receive vinorelbine (30 mg/m²), gemcitabine (1200 mg/m²) or vinorelbine (25 mg/m²) plus gemcitabine (1000 mg/m²) twice on Days 1 and 8 during each 6-week cycle for a maximum of 6 cycles. The vinorelbine/gemcitabine combination was evaluated against each single-agent treatment arm (no comparison of single-agent vinorelbine to single-agent gemcitabine). The majority of patients had comorbidities at baseline (89% had at least 1 and 67% had 2 or more). Cardiovascular and respiratory comorbidities were common, present in 60% and 35% of patients, respectively.

Efficacy endpoints were survival (the time from randomization to death or study closure; primary endpoint), progression-free survival (time from randomization to disease progression or death from disease progression or unknown causes), and tumor response (complete = disappearance of all known sites of disease; partial = ≥50% reduction in the sum of the products of the largest perpendicular diameters of measurable lesions, no new lesions, and no progression of any lesion; stable disease = <50% or an increase of less than 25% in the sum of the products of the largest perpendicular diameters of measurable lesions and no new lesions; and progressive disease = an increase of 25% or more in the size of one or more measurable lesions).

Quality-of-life and toxicity were also evaluated as secondary outcome measures. Linear-transformed results of the European Organisation for Research and Treatment of Cancer (EORTC) core questionnaire (QLQ-C30) and lung-cancer-specific module (QLQ-LC13) were used to assess quality-of-life. The EORTC QLQ-C30 questionnaire consists of multi-item functioning scales, and multi- and single-item scales that evaluate general cancer-related symptoms.¹⁰ The EORTC QLQ-LC13 module consists of single items that evaluate specific symptoms of lung cancer.¹¹ Scores reported after the third chemotherapy cycle were compared to those scores reported at baseline.

Single-agent Chemotherapy is as Efficacious as Combination Therapy

MILES demonstrated that single-agent vinorelbine and single-agent gemcitabine regimens were no less effective than the vinorelbine/gemcitabine combination regimen tested (Table 1). All regimens improved survival to a similar extent; median survival was 36 weeks (95% Confidence Interval (CI), 30-45 weeks) in the vinorelbine group, 28 weeks (95% CI, 25-34 weeks) in the gemcitabine group, and 30 weeks (95% CI, 27-36 weeks) in the vinorelbine/gemcitabine group. The probability of being alive at 1 year was 0.38 with single-agent vinorelbine compared with 0.28 and 0.30 with single-agent gemcitabine and vinorelbine/gemcitabine therapy, respectively. Hazard ratios for death were 1.17 (95% CI, 0.95-1.44) for vinorelbine/gemcitabine versus single-agent vinorelbine and 1.06 (95% CI, 0.86-1.29) for vinorelbine/gemcitabine versus vs single-agent gemcitabine. The differences in survival between the vinorelbine/gemcitabine group versus the single-agent groups were not statistically significant (P = .93 vinorelbine/gemcitabine vs single-agent vinorelbine; P = .65 vinorelbine/ gemcitabine vs single-agent gemcitabine). Although the study was not designed to compare the single-agent treatment arms, there was a numerical trend (probability) in favor of the single-agent vinorelbine treatment arm for median and 1-year survival. Moreover, statistical comparisons of treatment effects were not influenced by sex, age, ECOG performance status, tumor stage and histologic type, or major comorbidities.

Progression-free survival and objective response rates were also similar among groups (Table 1). Median time to progression was 19 weeks (95% CI, 16-21 weeks) in the vinorelbine/gemcitabine group, 18 weeks (95% CI, 13-20 weeks) in the single-agent vinorelbine group, and 17 weeks (95% CI, 13-19 weeks) in the single-agent gemcitabine group (Table 1). Objective response rates (complete and partial responders) were 21% (95% CI, 16%-26%), 18% (95% CI, 13%-23%) and 16% (95% CI, 12%-21%) in the vinorelbine/gemcitabine group, single-agent vinorelbine group, and single-agent gemcitabine group, respectively. Again, differences between vinorelbine/gemcitabine therapy and single-agent therapy were not statistically significant.

Single-agent Chemotherapy is Less Toxic than Combination Therapy

In addition to demonstrating the comparable efficacy of single-agent vinorelbine or gemcitabine and combination vinorelbine plus gemcitabine therapy in elderly, poor-performance status NSCLC patients, MILES also showed that single-agent therapies are considerably less toxic than combination therapy in this patient population (Table 2). The combination therapy was associated with significantly more thrombocytopenia and hepatic toxicity than vinorelbine and significantly more anemia, neutropenia, nausea/vomiting, diarrhea, fatigue, extravasation sequelae, cardiac toxicity, and constipation than gemcitabine. These findings are clinically significant in light of the baseline status of the patients studied. These were elderly patients, many with comorbidities that placed them at increased risk for negative toxicity-related outcomes.

Reducing the incidence of toxicities in this patient population is critical to maintaining quality-of-life, as toxicities have the potential to worsen existing comorbidities and compromise the patient's overall clinical condition. In MILES, baseline and post-third-cycle quality-of-life data were available for 346 patients. All therapies were associated with similar quality-of-life outcomes on functional and symptom scales (EORTC C30 and QLQ-LC13). Moreover, a substudy of MILES found that baseline self-assessed quality-of-life using the EORTC C30 had significant predictive ability of survival of elderly NSCLC patients.¹²

Conclusion

Approximately 40% of patients with NSCLC are elderly. Many have significant comorbidities that preclude treatment with standard aggressive cytotoxic chemotherapy. MILES was designed to assess the comparative efficacy and tolerability of the moderately toxic chemotherapeutic agents vinorelbine and gemcitabine as single agents and in combination in elderly, poor-performance status NSCLC patients. The results of this study demonstrated that single-agent vinorelbine or gemcitabine are as effective as combination chemotherapy (vinorelbine plus gemcitabine) and are associated with reduced toxicity and the maintenance of quality-of-life. Therefore, single-agent chemotherapy with vinorelbine or gemcitabine may be a viable treatment option for elderly, poor-performance NSCLC patients who would have in the past been considered unfit or unable to withstand the rigors of standard NSCLC chemotherapy.

References

1. Gridelli, C, Perrone F, Gallo C, et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung Cancer in the Elderly Study (MILES) Phase III Randomized Trial. J Natl Cancer Inst. 2003;95:362-372.
2. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. Cancer Statistics, 2003. CA Cancer J Clin. 2003;53:5-26.
3. Bunn PA, Lilenbaum R. Chemotherapy for elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst. 2003;95:341-343.
4. Balducci L. Geriatric oncology: challenge for the new century. Eur J Cancer. 2000;36:1741-1754.
5. Balducci L, Hardy CL, Lyman GH. Hemopoietic reserve in the older cancer patient: clinical and economic considerations. Cancer Control. 2000;7:539-547.
6. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. Elderly Lung Cancer Vinorelbine Italian Study Group. J Natl Cancer Inst. 1999;91:66-72.
7. Gridelli C. The ELVIS trial: a phase III study of single-agent vinorelbine as first-line treatment in elderly patients with advanced non-small cell lung cancer. Elderly Lung Cancer Vinorelbine Italian Study. Oncologist. 2001;6(Suppl 1):4-7.
8. Martin C, Ardizzoni A, Rosso R. Gemcitabine: safety profile and efficacy in non-small cell lung cancer unaffected by age. Aging. 1997;9:297-303.
9. Shepherd FA, Abratt RP, Anderson H, Gatzemeier U, Anglin G, Iglesias J. Gemcitabine in the treatment of elderly patients with advanced non-small cell lung cancer. Semin Oncol. 1997;24(2 Suppl 7):S7-50-S7-55.
10. Aaronson NK, Ahmedzai S, Bergman B, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365-376.
11. Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M. The EORTC QLQ-LC13: a modular supplement to the EORTC core quality of life questionnaire (QLQ-C30) for use in lung cancer clinical trials. Eur J Cancer. 1994;30A:635-642.
12. Perrone F, Gridelli C, Cigolari S, et al. Baseline assessment of quality of life (QOL) is a strong prognostic factor for survival of elderly patients with advanced non-small cell lung cancer (NSCLC). A secondary analysis of the MILES study. Proc Am Soc Clin Oncol. 2002;21. Abstract 1346.