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Single-Agent Chemotherapy for the Treatment of Elderly Patients With Advanced Non–Small-Cell Lung Cancer: What Is the Best Drug?

Division of Medical Oncology, S.G. Moscati Hospital, Avellino, Italy

To the Editor:

Recently, Kudoh et al reported that docetaxel (60 mg/m² day 1 every 3 weeks) provided significantly longer progression-free survival (5.5 months v 3.1 months; P < .001), a significantly higher overall response rate (22.7% v 9.9%; P = .019), a more favorable 1-year survival rate (58.6% v 36.7%), and significantly better disease-related symptom improvement than vinorelbine (25 mg/m² days 1 and 8, every 3 weeks) in elderly patients with advanced non–small-cell lung cancer (NSCLC).¹ These data are derived from a randomized phase III trial that enrolled 182 patients and failed to detect a significant difference in median survival time, the primary objective of the study, despite a longer median survival in favor of patients treated with docetaxel compared with patients treated with vinorelbine (14.3 months v 9.9 months, respectively).

The Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) and the Multicenter Italian Lung Cancer in the Elderly Study (MILES)^2,3 reported that single-agent chemotherapy with a third-generation drug is a reasonable choice for the treatment of elderly patients with advanced NSCLC. The guidelines of the American Society of Clinical Oncology⁴ and an International Consensus Conference recommended this approach.⁵

The article by Kudoh et al is the first prospective, randomized phase III trial in which single-agent treatment results are superior, in several outcomes, to another one in the treatment of elderly patients with advanced NSCLC, but several points must be clarified.

The authors analyzed some of these points, such as the sample size too small to detect a significant difference in survival (primary aim), high median survival time reported in both arms when compared with results from the literature, high incidence of neutropenia in the vinorelbine arm, and a higher rate of docetaxel patients treated with gefitinib as second-line treatment (docetaxel 37.5% and vinorelbine 20.0% of patients, respectively). This last issue is important and can justify the better survival trend reported for docetaxel arm considering the high rate of clinical predictive factors of response to gefitinib present in the patient population (clearly all Asian patients, adenocarcinoma histology 64% and 56%, never-smoker 79.8% and 74.7%, female 22.5% and 25.3% for docetaxel and vinorelbine arm, respectively).

However, other limitations should be considered. The vinorelbine dose, 25 mg/m² days 1 and 8 every 3 weeks, is lower than that reported in other phase III trials (30 mg/m² days 1 and 8, every 3 weeks).^2,3 The authors explain that weekly vinorelbine at 25 mg/m² is the recommended dose in Japan. The reported reference to support this dose is based on a phase II study in which vinorelbine was administered at the dose of 25 mg/m²/week, which also corresponded to the planned dose-intensity.⁶ In the West Japan Thoracic Oncology Group 9904 trial, based on the administered vinorelbine schedule, the planned dose-intensity was 16.67 mg/m²/week. This lower dose-intensity could justify the lower activity of vinorelbine in this trial (9.9% response rate) as compared with that reported in the previously mentioned studies (19.7% and 18% in the ELVIS and MILES studies, respectively).^2,3

The accrual time was very long with a median of 4.55 patients/month enrolled in 32 participating institutions. The median accrual time for the other phase III randomized trials on advanced NSCLC in elderly patients was 11.5 patients/month in the ELVIS study² and 19.94 patients/month in the MILES study.³ A slow accrual could mean a selection of elderly to enroll biasing the external validity of study results.

Quality of life was assessed using a self-administered questionnaire including a visual face scale for global quality of life (primary quality of life analysis) and eight disease-related symptom items derived from two different sources (secondary quality of life analysis).¹ The authors did not explain the use of a sort of puzzle, which was not validated, to assess disease-related symptoms. Moreover, docetaxel scored significantly better than vinorelbine only for anorexia and fatigue (secondary quality of life analysis). Considering that docetaxel was administered with corticosteroid support, not specified in the article, this could play an important role in the reported differences.

Finally, a deep assessment of elderly cancer patients is a key step in the treatment process. Reliable information regarding patient comorbid health problems is important in order to plan an appropriate treatment.⁷ No data are available in the article about comorbid illnesses, except for their presence or absence. More information about the number, type, and grade of comorbid conditions could be useful for the results evaluation. Moreover, no information was available about the administration of geriatric scales, important in trials of elderly patients.

In conclusion, with the evidence currently available from larger randomized trials, single-agent chemotherapy with a third-generation agent can be considered a recommended option for elderly patients with advanced NSCLC.^4,5 However, which single agent? Considering that third-generation agents (vinorelbine, gemcitabine, taxanes) have similar activity and efficacy, other factors should be considered by the clinician when choosing the drug to be administered. This choice should take into account the expected toxicity profile of the agent, pharmacokinetics, patient organ function, and comorbidities. A new generation of clinical trials specifically designed for the elderly population are needed and should include the development and validation of new measures and tools to define biologic versus chronological age. Several treatment options should be evaluated, such as nonplatinum-based combination chemotherapy, platinum-based regimens, and targeted therapies.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Cesare Gridelli, Eli Lilly & Co, Roche, AstraZeneca, Dompè Biotec Stock: N/A Honoraria: Cesare Gridelli, Eli Lilly & Co, Roche, AstraZeneca, Dompè Biotec; Antonio Rossi, GlaxoSmithKline, Roche Research Funds: N/A Testimony: N/A Other: N/A

REFERENCES

1. Kudoh S, Takeda K, Nakagawa K, et al: Phase III study of docetaxel compared with vinorelbine in elderly patients with advanced non-small-cell lung cancer: Results of the West Japan Thoracic Oncology Group trial (WJTOG 9904). J Clin Oncol 24:3657-3663, 2006[Abstract/Free Full Text]

2. 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 91:66-72, 1999[Abstract/Free Full Text]

3. 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 95:362-372, 2003[Abstract/Free Full Text]

4. Pfister DG, Johnson DH, Azzoli CG, et al: American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: Update 2003. J Clin Oncol 22:330-353, 2004[Free Full Text]

5. Gridelli C, Aapro M, Ardizzoni A, et al: Treatment of advanced non-small-cell lung cancer in the elderly: Results of an international expert panel. J Clin Oncol 23:3125-3137, 2005[Abstract/Free Full Text]

6. Furuse K, Kubota K, Kawahara M, et al: A phase II study of vinorelbine, a new derivative of vinca alkaloid, for previously untreated advanced non-small cell lung cancer: Japan Vinorelbine Lung Cancer Study Group. Lung Cancer 11:385-391, 1994[CrossRef][Medline]

7. Yancik R, Ganz P, Varricchio CG, et al: Perspective on comorbidities and cancer in older patients: Approaches to expand the knowledge base. J Clin Oncol 19:1147-1151, 2001[Abstract/Free Full Text]

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