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The Oncologist, Vol. 6, Suppl 1, 1-3, February 2001
© 2001 AlphaMed Press

SUPPLEMENT

New Directions in the Treatment of Non-Small Cell Lung Cancer: An Overview

Martin J. Edelman

University of Maryland, Greenebaum Cancer Center, Baltimore, Maryland, USA

Correspondence: Martin J. Edelman, M.D., University of Maryland, Greenebaum Cancer Center, 22 South Greene Street, Room N9E09, Baltimore, Maryland 21201-1595, USA. Telephone: 410-328-2703; Fax: 410-328-1975; e-mail: medelman{at}umm.edu


   ABSTRACT
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Despite unequivocal evidence of activity and tolerability, the potential contribution of vinorelbine to the management of non-small cell lung cancer (NSCLC) has been relatively unappreciated. A phase III trial of vinorelbine as a single agent in the elderly demonstrated clear benefits in terms of survival and quality of life compared with supportive care. Two other phase III trials demonstrated that vinorelbine plus platinum was superior when compared either with one of the older platinum combinations, platinum as a single agent or vinorelbine alone. New vinorelbine-based regimens appear to be active but with less toxicity than older combinations in stage IV disease. Chemotherapy plays an essential role in the management of locally advanced (i.e., stage III) disease with the weight of evidence supporting improved curability of this stage when drugs are employed either preoperatively or as part of a chemoradiotherapy regimen. It has been reported that induction therapy using carboplatin/vinorelbine or carboplatin/paclitaxel followed by accelerated conformal radiation therapy has promising results without causing undue toxicity.

Clearly, vinorelbine is an active agent which is well tolerated and suitable for use in the management of NSCLC. It is likely to play a greater role in the future.

The decade of the 1990s saw the introduction of several new agents with promising activity in advanced non-small cell lung cancer (NSCLC). Despite unequivocal evidence of activity and tolerability, the potential contribution of one of those drugs, vinorelbine, to the management of NSCLC has been relatively unappreciated.

Phase II trials in the elderly NSCLC patient suggested vinorelbine had promising activity with a manageable safety profile [1, 2]. The Italian phase III (ELVIS) study, reviewed in Tokyo by Cesare Gridelli [3], was conducted in elderly patients with advanced NSCLC and demonstrated that vinorelbine was superior to best supportive care in terms of survival as well as quality of life [4].

Two other phase III trials, the seminal European trial led by Thierry Le Chevalier and reviewed by him in Tokyo [5], as well as a U.S. trial conducted by the Southwest Oncology Group (SWOG), demonstrated that vinorelbine plus platinum was superior when compared either with one of the older platinum combinations, platinum as a single agent or vinorelbine alone [6, 7]. Follow-up of the European Organization for the Research and Treatment of Cancer (EORTC) study has now been extended to six years, with interesting data on long-term survivors and factors predictive of good prognosis.

Confirming and extending their initial results, the SWOG compared vinorelbine/cisplatin to carboplatin/paclitaxel and demonstrated equivalency in response rate and survival. The two regimens differed in their toxicity profiles, with carboplatin/paclitaxel surprisingly more neurotoxic and cisplatin/vinorelbine more emetogenic (largely due to the employment of high-dose cisplatin) [8]. An economic analysis found cisplatin/vinorelbine less expensive [9]. These trials are summarized in Table 1Go.


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  		Table 1. Summary of key randomized trials of vinorelbine in advanced NSCLC. For indirect comparison, ECOG 1594 results are also shown [2, 4, 6, 8, 11].
 
In addition to an update and review of prior trials and regimens, the Tokyo meeting focused on the future role of vinorelbine. Two areas were discussed: further development of vinorelbine in combination chemotherapy of stage IV disease and the potential role in the multimodality management of stage III disease.

Given the emetogenecity of cisplatin, it is logical to substitute carboplatin and evaluate carboplatin/vinorelbine in stage IV patients. Gregory Masters discussed the potential benefit of substituting carboplatin for cisplatin in combination with vinorelbine [10]. In a phase I/II study in which the two drugs were given on days 1 and 8 every three weeks, little significant hematologic and nonhematologic toxicity was observed [11]. Recent studies have demonstrated that platinums are no longer essential for the treatment of advanced disease, with nonplatinum regimens achieving similar results in terms of response and survival. Rogerio Lilenbaum reported on a phase II trial of vinorelbine/gemcitabine [12, 13]. The response rate of 25%, median eight-month survival and 38% rate of one-year survival are comparable to those seen with the platinum-based combinations employed in Eastern Cooperative Oncology Group 1594 (Table 1Go), and were achieved with little nonhematologic toxicity [12, 14].

Chemotherapy plays an essential role in the management of locally advanced (i.e., stage III) disease with the weight of evidence supporting improved curability of this stage when drugs are employed either preoperatively or as part of a chemoradiotherapy regimen. Mark Socinski reported that induction therapy using carboplatin/vinorelbine or carboplatin/paclitaxel can be followed by accelerated conformal radiation therapy without causing undue toxicity [15]. The rate of response to induction chemotherapy is promising and preliminary analysis suggests the one-year survival rate will be 65%.

Everett Vokes updated the randomized phase II trial conducted by the Cancer and Leukemia Group B in stage III patients receiving multimodality treatment. The arm utilizing cisplatin/vinorelbine was less toxic than the comparator agents (particularly with respect to esophagitis) while being at least as active [16, 17].

Not discussed at the meeting, but of great interest, is the potential role of vinorelbine in adjuvant therapy. Depending upon stage, between 25%-70% of patients with stage I-IIb who undergo potentially curative resection will ultimately relapse. Despite hints from meta-analysis that adjuvant platinum-based therapy may be beneficial [18], currently available data do not support adjuvant treatment [19]. The NCI-Canada study (JBR-10) of cisplatin/vinorelbine versus no therapy is currently accruing patients and will be the first study to test a "modern" chemotherapy regimen in this setting.

Clearly, vinorelbine is an active agent which is well tolerated and suitable for use in the management of NSCLC. It is likely to play a greater role in the future.


   REFERENCES
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 Abstract
 References
 

  1. 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 1996;32A:1809-1811.[CrossRef]
  2. Gridelli C, Perrone F, Gallo C et al. Vinorelbine is well tolerated and active in the treatment of elderly patients with advanced non-small cell lung cancer. A two-stage phase II study. Eur J Cancer 1997;33:392-397.
  3. 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. The Oncologist 2001;6(suppl 1):4-7.[Abstract/Free Full Text]
  4. 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 1999;85:365-376.[Abstract/Free Full Text]
  5. Le Chevalier T, Brisgand D, Soria JC et al. Long term analysis of survival in the European randomized trial comparing vinorelbine/cisplatin to vindesine/cisplatin and vinorelbine alone in advanced non-small cell lung cancer. The Oncologist 2001;6(suppl 1):8-11.[Abstract/Free Full Text]
  6. Wozniak AJ, Crowley JJ, Balcezark SP et al. Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small cell lung cancer (NSCLC): A Southwest Oncology Group study. J Clin Oncol 1998;16:2459-2465.[Abstract]
  7. LeChevalier T, Brisgand D, Douillard J-Y et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in advanced non-small cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol 1994;12:360-367.[Abstract]
  8. Kelly K, Crowley J, Bunn PA et al. A randomised phase III trial of paclitaxel plus carboplatin versus vinorelbine plus cisplatin in untreated advanced non-small cell lung cancer (NSCLC): a Southwest Oncology Group (SWOG) trial. Proc Am Soc Clin Oncol 1999;18:461a.
  9. Ramsey SD, Moinpour CM, Lovato L et al. An economic analysis of Southwest Oncology Group Trial S9509: cisplatin/vinorelbine versus carboplatin/paclitaxel for advanced non-small cell lung cancer. Proc Am Soc Clin Oncol 2000;19:489a.
  10. Masters G. Carboplatin and vinorelbine in advanced non-small cell lung cancer: a phase I/II study. The Oncologist 2001;6(suppl 1):12-15.[Free Full Text]
  11. Masters GA, Neale M, Shervin D et al. A phase I/II study of vinoreline (NAV) and carboplatin (CARB) for advanced non-small cell lung cancer (NSCLC). Lung Cancer 2000;29(suppl 2):77a.
  12. Lilenbaum R, Cano R, Schwartz M et al. Gemcitabine and vinorelbine in advanced nonsmall cell lung carcinoma: a phase II study. Cancer 2000;88:557-562.[CrossRef][Medline]
  13. Lilenbaum R. Options in advanced non-small cell lung cancer: a review and report on a phase II study of vinorelbine plus gemcitabine. The Oncologist 2001;6(suppl 1):16-19.[Abstract/Free Full Text]
  14. Schiller JH, Harrington D, Sandler A et al. A randomised phase III trial of four chemotherapeutic regimens in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 2000;19:1a.
  15. Socinski M. Carboplatin/paclitaxel or carboplatin/vinorelbine followed by accelerated hyperfractionated conformal radiation therapy: a preliminary report of a phase I dose escalation trial from the Carolina Conformal Therapy Consortium. The Oncologist 2001:6(suppl 1):20-24.[Abstract/Free Full Text]
  16. Vokes EE, Leopold KA, Herndon II JE et al. A randomized phase II study of gemcitabine or paclitael or vinorelbine with cisplatin as induction chemotherapy (Ind CT) and concomitant chemoradiotherapy (XRT) for unresectable stage III non-small cell lung cancer (NSCLC) (CALGB Study 9431). Proc Am Soc Clin Oncol 1999;18:459a.
  17. Vokes EE. Induction chemotherapy followed by concomitant chemoradiotherapy for non-small cell lung cancer. The Oncologist 2001;6(suppl 1):25-27.[Abstract/Free Full Text]
  18. Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized trials. BMJ 1995;311:899-909.[Abstract/Free Full Text]
  19. Keller SM, Adak S, Wagner H et al. A randomised trial of postoperative adjuvant therapy in patients with completely resected stage II or IIIa non-small cell lung cancer. N Engl J Med 2000;343:1217-1222.[Abstract/Free Full Text]
accepted for publication November 28, 2000.





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