According to current statistics, lung cancer is the third most common cancer in the United States and continues to be the leading cause of cancer death for both males and females . Non-small-cell-lung cancer represents 70% to 80% of newly diagnosed lung cancers. Most patients have an advanced stage of disease at the time of initial diagnosis.
The treatment of patients with advanced non-small-cell lung cancer has proven to be difficult [2-5]. Until recently, the use of chemotherapy was considered to be of doubtful value . However, recent randomized studies demonstrating improved survival in patients with stage III [6-10] and stage IV non-small-cell lung cancer [11-15] as a result of the use of chemotherapy have given rise to renewed optimism. This article will review the recent experience with the
use of chemotherapy in stage IV non-small-cell lung cancer and will describe the results obtained with vinorelbine (Navelbine), a novel vinca alkaloid, in this disease.
Most patients with advanced non-small-cell lung cancer present with stage IV disease. An additional 20% to 30% may present with unresectable stage III disease. All patients with stage IV disease and some of those with stage IIIB disease (ie, positive pleural effusion or supraclavicular lymph node involvement) are treated with palliative intent. Whereas the majority of patients will require local palliative measures at some point during the course of their disease, treatment is usually based on the use of systemic chemotherapy. Historically, drugs with modest reproducible single-agent activity in non-small-cell lung cancer have included cisplatin (Platinol), mitomycin (Mutamycin), ifosfamide (Ifex) , etoposide (VePesid), and the vinca alkaloids vinblastine and vindesine (Eldisine; available in Europe) [2,16-19].
Activity of these agents is defined by single-agent response rates of 15% or greater in phase II studies. Almost all responses have been partial only and of short duration, usually lasting 3 to 6 months. Other agents, including doxorubicin and carboplatin (Paraplatin), also have been shown to have activity [20-23], although response rates tend to be less than 15%. Carboplatin has not been compared directly with cisplatin as a single agent in randomized studies of non-small-cell lung cancer, but nevertheless is frequently used in clinical practice in place of cisplatin due to its ease of administration and more acceptable toxicity profile .
In order to increase the effectiveness of systemic therapy, combinations of single chemotherapy agents have been investigated. During the 1970s, such combinations included the CAMP regimen (cyclophosphamide, Adriamycin, methotrexate, and procarbazine) developed at the University of Chicago. In a single institution trial, this combination had a 26% response rate in 160 patients .
Cisplatin-Based Regimens--Subsequent clinical trials focused on cis-platin based combination chemo- therapy . Among the regimens tested were the popular combinations of etoposide and Platinol (EP regimen), cisplatin and vinblastine, and the MVP regimen consisting of mitomycin, vinblastine, and Platinol [21,26-28]. Phase II studies suggested the possibility of higher response rates with these regimens than with "first-generation" regimens, such as CAMP.
There also have been direct comparisons of cisplatin-based chemotherapy with non-cisplatin-based combination regimens. Although some of these studies confirmed increased response rates for the cisplatin-containing regimens, there was no consistent pattern of increased survival. Jett  summarized six such trials and found a significant survival benefit for the cisplatin-containing regimen in only two studies [30,31].
In addition, Veronesi et al  found a superior survival for the combination of cisplatin and etoposide compared with CAMP, whereas the other studies showed no difference in survival [28,33,34]. For example, the Eastern Cooperative Oncology Group (ECOG) randomized patients to MVP vs therapy with vindesine plus Platinol (VP), etoposide plus Platinol (EP), or CAMP . The MVP regimen produced the highest numerical response rate at 31%. However, there were no statistically significant differences between the four regimens in median survival (4.5 months for MVP, 6.5 months for both VP and EP, and 6.2 months for CAMP). Thus, in this study, the higher response rate with MVP did not translate into superior survival, and the study failed to identify a "standard chemotherapy regimen" for advanced non-small-cell lung cancer.
In another randomized study, the Eastern Cooperative Oncology Group compared MVP to single-agent platinum-based chemotherapy (carboplatin or iproplatin) followed by MVP at the time of first progression and to two other combination chemotherapy regimens (vinblastine plus cisplatin and MVP alternating with CAMP) . In this five-arm study, MVP again resulted in the highest response rate (20%), but with a trend toward shorter survival. Patients treated initially with carboplatin had a statistically significantly longer survival than patients treated with the other four regimens; this was observed despite a low response rate (9%) for carboplatin. The median survival of patients receiving carboplatin followed by MVP was 32 weeks (vs 23 weeks for MVP alone), demonstrating the continued need to identify more active chemotherapy.
Cisplatin Dose Intensification--Another subject of interest has been the potential role of cisplatin dose intensification. An early trial of cisplatin-based chemotherapy suggested a positive dose-response relationship when the cisplatin dose was increased from 60 to 120 mg/m²/wk in combination with vindesine , although this was not consistently supported . Gandara et al  reported the experience of the Northern California Oncology Group (NCOG) with high-dose cisplatin (100 mg/m² on days 1 and 8 of a 4-week cycle). The overall response rate to single-agent, high-dose cisplatin was 33%, with a median survival time of 8.4 months.
Based on this background, the Southwestern Oncology Group (SWOG) initiated a three-arm randomized study comparing standard-dose cisplatin (50 mg/m² on days 1 and 8 of a 28-day cycle) with high-dose cisplatin (100 mg/m² on days 1 and 8) and with high-dose cisplatin plus mitomycin (8 mg/m² on day 1 of a 4-week cycle) . Overall response rates for the three regimens were 12%, 14%, and 27%, respectively (P < 0.05). Complete responses were noted only in the high- dose cisplatin arms (3% and 4%, respectively). However, there were no statistically significant differences in median survival times, which were 7, 5, and 7 months for the standard-dose, high-dose, and high-dose combination arms, respectively. In addition, high-dose cisplatin therapy was reported to result in increased ototoxicity, emesis, and myelosuppression.
Since greater dose intensity of cis-platin was indeed achieved, with actual cisplatin doses of 41 and 39 mg/m²/wk attained in the high-dose arms vs 23 mg/m²/wk for the standard-dose arm, this study refutes the suggestion that doses of cisplatin exceeding 100 mg/m² per cycle might lead to significantly improved therapeutic outcome in stage IV non-small-cell lung cancer.
Pretreatment Patient Characteristics
Stanley et al analyzed the pretreatment patient characteristics of more than 5,000 patients with inoperable non-small-cell lung cancer . In this classic analysis, initial performance status, extent of disease, and weight loss in the 6 months preceding diagnosis were most predictive of survival. O'Connell et al  confirmed the significance of performance status in 387 patients with advanced non-small-cell lung cancer. Good performance status was predictive of response to therapy and prolonged survival duration, whereas the presence of bony metastases, an elevated lactic dehydrogenase (LDH) level, male gender, and the presence of two or more extrathoracic involved sites were associated with a poor prognosis.
Finkelstein et al  determined prognostic factors in 893 patients who participated in ECOG studies. Good initial performance status, absence of bony metastases, female gender, and weight loss < 5% of pretreatment body weight were associated with improved survival times. Histologic subtype had no influence on survival.
More recently, Albain et al  used Cox modeling and recursive partitioning and amalgamation to determine the prognostic independence and significance of host- or tumor-related characteristics in 2,531 patients with extensive-stage non-small-cell lung cancer treated on SWOG protocols. In this analysis, good performance status, female gender, and age 70 years or older were significant independent predictors of increased survival for the entire study population. In a model of only those patients with good performance status, pretreatment hemoglobin levels exceeding 11 g/dL, normal serum LDH and calcium, and the presence of no more than one metastatic site were significant favorable prognostic factors. Of interest, the use of cisplatin was also an independent predictor of improved survival.
In addition to these clinical pretreatment patient characteristics, molecular parameters have been investigated as prognostic factors. Slebos et al  determined that the presence of a K- ras mutation has adverse prognostic significance; this was subsequently confirmed in other studies . Similarly, Lee et al  demonstrated a correlation between the absence of blood group antigen A and a shorter survival time.
Additional prognostic information utilizing molecular biology is being generated  and may aide in the determination of prognostic subgroups and, possibly, a differential choice of therapy for tumors expressing specific biologic markers in the near future.
Given the limited activity observed with first- and second-generation combination chemotherapy regimens, randomized studies comparing the effect of chemotherapy vs best supportive care (ie, no chemotherapy) on survival were initiated. The first of these studies was reported by Cormier et al . In this small study, only 40 patients were randomized to either best supportive care or a non-cisplatin-based chemotherapy regimen. Nevertheless, improved survival was demonstrated for chemotherapy-treated patients.
To date, at least eight such studies have been reported [47-54]. Three of these individually demonstrated a statistically significant benefit for chemotherapy-treated patients [47-49], whereas the other five indicated a trend toward improved survival with chemotherapy that did not achieve statistical significance. Thus, in balance, these studies tend to favor chemotherapy over best supportive care. The largest and best known of these studies compared cisplatin and vindesine vs CAP (cyclophosphamide, Adriamycin, and Platinol) vs best supportive care . Of interest, both improved survival and decreased cost  resulting from the use of chemotherapy were demonstrated.
In order to more accurately assess the impact of chemotherapy on survival, four meta-analyses have also been performed, with similar conclusions (Table 1) [12-15]. The most recent of these utilized updated individual patient data . The preliminary report of this analysis also suggested a beneficial effect from the use of chemotherapy for cisplatin-based studies. Rates of 1-year survival were estimated to be 16% vs 26% in favor of patients receiving chemotherapy, with an increase in median survival from 6 to 8 months.
Quality-of-life data have been collected in some trials, but to date, no firm conclusions regarding chemotherapy in non-small-cell lung cancer have been formulated. One might postulate a psychological benefit and increased quality of life afforded by specific anticancer therapy, in addition to the potential benefit of prolonged survival time. In the Canadian randomized study, patients receiving chemotherapy had a lower incidence of disease-related complications . This indirect assessment also suggests a beneficial impact on quality of life by chemotherapy.
In summary, chemotherapy for stage IV non-small-cell lung cancer has been demonstrated to result in a small, but statistically significant, increase in survival time, with objective response rates of approximately 30%. Given this information, it might be suggested that newly diagnosed patients with this disease should be offered chemotherapy, with the goal of prolonging life and decreasing tumor-related symptoms . This approach is not yet universally accepted, however .
A "best" standard chemotherapy regimen for non-small-cell lung cancer has not been established. Therefore, the identification of additional single agents and combinations with higher activity and less toxicity is a high priority. Several promising new drugs are currently undergoing testing in non-small-cell lung cancer [57-59]. These include the taxanes (paclitaxel [Taxol], docetaxol [Taxotere]), camptothecan analogs (irinotecan, topotecan, and 9-amino camptothecan), gemcitabine (Gemzar), and vinorelbine.
1 Boring CC, Squires TS, Tong T, et al: Cancer Statistics, 1994. Cancer Journal for Clinicians 44:7-26, 1994.
2. Ginsberg RJ, Kris MG, Armstrong JG: Non-small cell lung cancer, in DeVita VT, Jr., et al (eds): Cancer: Principles & Practice of Oncology, 4th Ed, p 673. Philadelphia, JB Lippincott, 1993.
3. Ihde DC: Chemotherapy of lung cancer. N Engl J Med 327:1434-1441, 1992.
4. Haraf DJ, Devine S, Ihde DC, et al: The evolving role of systemic therapy in carcinoma of the lung. Semin Oncol 19(4, suppl 11):72-87, 1992.
5. Vokes EE, Bitran JD, Vogelzang NJ: Chemotherapy for non-small cell lung cancer: The continuing challenge. Chest 99(6):1326-1328, 1991.
6. Dillman RO, Seagren SL, Propert K: A randomized trial of induction chemotherapy plus high-dose radiation versus radiation alone in stage III nonsmall cell lung cancer. N Engl J Med 323:940-945, 1990.
7. Le Chevalier T, Arriagada R, Quoix E, et al: Radiotherapy alone versus combined chemotherapy and radiotherapy in nonresectable non-small-cell lung cancer: First analysis of a randomized trial in 353 patients. J Natl Cancer Inst 83:417-423, 1991.
8. Le Chevalier T, Arriagada R, Lacombe-Terrier M-J, et al: Significant effect of adjuvant chemotherapy on survival in locally advanced non-small-cell lung carcinoma. J Natl Cancer Inst 84:58, 1992.
9. Sause W, Scott C, Taylor S, et al: RTOG 8808 ECOG 4588, Preliminary analysis of a phase Ill trial in regionally advanced unresectable non-small cell lung cancer (abstract). Proc Am Soc Clin Oncol 13:325, 1994.
10. Schaake-Koning C, van den Bogaert W, Dalesio 0, et al: Effects of, concomitant cisplatin and radiotherapy on inoperable non-small cell lung cancer. N Engl J Med 326(8):524-530, 1992.
11. Grilli R, Oxman AD, Julian JM: Chemotherapy for advanced non-small cell lung cancer: How much benefit is enough? J Clin Oncol 11:1866-1872.
12. Souquet PJ, Chauvin F, Boissel JP, et al: Polychemotherapy in advanced nonsmall cell lung cancer: A meta-analysis. Lancet 342:19-21, 1993.
13. Marino P, Pampallona S, Prestoni A, et al: Chemotherapy vs supportive care in advanced non- small cell lung cancer: Results of a meta-analysis of the literature. Chest 106:861-865, 1994.
14. Stewart LA, Pignon JP, Parmar AKB, et al: A meta-analysis using individual patient data from randomised clinical trials of chemotherapy in non-small cell lung cancer: Survival in the supportive care setting (abstract). Proc Am Soc Clin Oncol 13:337, 1994.
15 Vokes EE and Bitran JD: Non-small cell lung cancer: towards the next plateau (editorial). Chest 106:659-661, 1994.
16. Joes RA, Cavalli F, Goldhirsch A, et al: New agents in non-small cell lung cancer. Cancer Treat Rev 11:205-236, 1984.
17. Vokes EE, Vijayakumar S, Bitran JD, et al: The role of systemic therapy in advanced non-small cell lung cancer: A review. Am J Med 89:777-786, 1990.
18. Robert F, Omura GA, Birch R, et al: Randomized phase III comparison of three doxorubicin-based chemotherapy regimens in advanced non- small cell lung cancer: A Southeastern Cancer Study Group trial. J Clin Oncol 2:391-395, 1984.
19. Rosso R, Salvati F, Ardizzoni A, et al: Etoposide vs etoposide plus high dose cisplatin in the management of advanced non-small cell lung cancer: Results of a prospective randomized FONICAP trial. Cancer 65:130-134, 1990.
20. Bunn PA, Jr.: Review of therapeutic trials of carboplatin in lung cancer. Semin Oncol
16(suppl 5):27-33, 1989.
21. Green MR, Kreisman H, Doll DC, et al: Carboplatin in NSCLC: An updated on the Cancer and Leukemia Group B experience. Semin Oncol 19(1, suppl 2):44-49, 1992.
22. Bonomi PD, Finkelstein DM, Ruckdeschel JC, et al: Combination chemotherapy versus single agents followed by combination chemotherapy in stage IV non-small-cell lung cancer: A study of the Eastern Cooperative Oncology Group. J Clin Oncol 7:1602-1613, 1989.
23. Comis RL: Carboplatin in the treatment of non-small cell lung cancer: A review. Oncol 50(suppl 2):37-41, 1993.
24. Shepard KV, Golomb HM, Bitran JD, et al: CAMP chemotherapy for metastatic non-oat cell bronchogenic carcinoma. Cancer 56:2385-2390, 1985.
25. Bonomi P: Brief overview of combination chemotherapy in non-small cell lung cancer. Semin Oncol 13(suppl. 3):89-91, 1986.
26. Kris MG, Gralla RJ, Kalman LA, et al: Randomized trial comparing vindesine plus cisplatin with vinblastine plus cisplatin in patients with non-small cell lung cancer, with an analysis of methods of response assessment. Cancer Treat Rep 69:387-395, 1985.
27. Schulman P, Budman DR, Weiselberg L, at al: Phase II trial of mitomycin, vinblastine, and cisplatin (MVP) in non-small cell bronchogenic carcinoma. Cancer Treat Rep 67:943-945, 1983.
28. 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 4:14-22, 1986.
29. Jett JR: Current treatment of unresectable lung cancer. Mayo Clin Proc 68:603-611, 1993.
30. Luedke DW, Einhorn L, Omura GA, et al: Randomized comparison of two combination regimens versus minimal chemotherapy in non-small cell lung cancer: A Southeastern Cancer Study Group trial. J Clin Oncol 8:886-891, 1990.
31. Miller TP, Chen TT, Coltman CA Jr., et al: Effect of alternating combination chemotherapy on survival of ambulatory patients with metastatic large-cell and adenocarcinoma of the lung: A Southwest Oncology Group study. J Clin Oncol 4:502-508, 1986.
32. Veronesi A, Magri MD, Tirelli U, et al: Chemotherapy of advanced non-small call lung cancer with cyclophosphamide, adriamycin, methotrexate, and procarbazine versus cisplatin and etoposide: A randomized study. Am J Clin Oncol 11:566-571, 1988.
33. Einhorn LH, Loehrer PJ, Williams SD, et al: Random prospective study of vindesine versus vindesine plus high-dose cisplatin versus vindesine plus cisplatin plus mitomycin C in advanced non-small cell lung cancer. J Clin Oncol 4:1037-1043, 1986.
34. Krook JE, Fleming TR, Eagan RT, et al: Comparison of combination chemotherapy programs in advanced adenocarcinoma-large cell carcinoma of the lung: A North Central Cancer Treatment Group study. Cancer Treat Rep 68:493-498, 1984.
35. Gralla RG, Casper ES, Kelsen DP, et al: Cisplatin plus vindesine combination chemotherapy for advanced carcinoma of the lung: A randomized trial investigating two dosage schedules. Ann Intern Med 95:414-420, 1981.
36. Klastersky J, Sculier JP, Ravez P, et al: A randomized study comparing a high and a standard dose of cisplatin in combination with etoposide in the treatment of advanced non-small cell lung carcinoma. J Clin Oncol 4:1780-1786, 1986.
37. Gandara DR, Wold H, Perez EA, et al.: Cisplatin dose intensity in non-small cell lung cancer: Phase 11 results of a day 1 and day 8 high-dose regimen. J Natl Cancer Inst 81:790-794, 1989.
38. Gandara DR, Crowley J, Livingston RB, et al: Evaluation of cisplatin intensity in metastatic non-small-cell lung cancer: A phase III study of the Southwest Oncology Group. J Clin Oncol 11:873-878, 1993.
39. Stanley K: Prognostic factors for survival in patients with inoperable lung cancer. J Natl Cancer Inst 65:25-32, 1980.
40. O'Connell JP, Kris MG, Gralla RJ, et al: Frequency and prognostic importance of pretreatment clinical characteristics in patients with advanced non-small-cell lung cancer treated with combination chemotherapy. J Clin Oncol 4:1604-1614, 1986.
41. Finkelstein DM, Ettinger DS, Ruckdeschel JC: Long-term survivors in metastatic non-small-cell lung cancer: An Eastern Cooperative Oncology Group study. J Clin Oncol 4:702-709, 1986.
42. Albain KS, Crowley JJ, LeBlanc M, et al: Survival determinants in extensive-stage NSCLC: The Southwest Oncology Group experience. J Clin Oncol 9:1618-1626, 1991.
43. Slebos RJC, Kibbelaar RE, Dalesio 0, et al: K-Ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med 323:561 565, 1990.
44. Sugio K, Ishida T, Yokoyama H, et al: ras Gene mutations as a prognostic marker in adenocarcinoma of the human lung without lymph node metastasis. Cancer Res 52:2903-2906, 1992.
45. Lee JS, Ro JY, Sahin AA, et al: Expression of blood-group antigen A-A favorable prognostic factor in non-small-cell lung cancer. N Engl J Med 324:1084-1090, 1991.
46. Pezzella F, Turley H, Kuzu I, et al: bcl-2 Protein in non-small-cell lung carcinoma. N Engl J Med 329:690-694, 1993.
47. Cormier Y, Bergeron D, La Forge J, et al: Benefits of polychemotherapy in advanced non-small-cell bronchogenic carcinoma. Cancer 50:845-849, 1982.
48. Rapp E, Pater JL, Willan A, et al: Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer-Report of a Canadian multicenter randomized trial. J Clin Oncol 6:633-641, 1988.
49. Cartei G, Cartei F, Cantone A, et al: Cisplatin-cyclophosphamide-mitomycin combination chemotherapy with supportive care versus supportive care alone for treatment of metastatic non-small-cell lung cancer. J Natl Cancer Inst 85:794-800, 1993.
50. Quoix E, Dietemann A, Charbonneau J, et al: La chimiotherapie comportant du cisplatine est-elle utile dans le cancer bronchique non microcellulaire au stade IV? Resultants dune etude randomisee. Bull Cancer 78:341-346, 1991.
51. Woods RL, Williams CJ, Levi J, et al: A randomised trial of cisplatin and vindesine versus supportive care only in advanced non-small cell lung cancer. Br J Cancer 61:608-611, 1990.
52. Cellerino R, Tummarello D, Guidi F, et al: A randomized trial of alternating chemotherapy versus best supportive care in advanced non-small-cell lung cancer. J Clin Oncol 9:1453-1461, 1991.
53. Kaasa S, Lund E, Thorud E, et al: Symptomatic treatment versus combination chemotherapy for patients with extensive non-small cell lung cancer. Cancer 67:2443-2447, 1991.
54. Ganz PA, Figlin RA, Haskell CM, et al: Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer: Does chemotherapy make a difference. Cancer 63:1271-1278, 1989.
55. Jaakkimainen L, Goodwin PJ, Pater J, et al: Counting the costs of chemotherapy in a National Cancer Institute of Canada randomized trial in non-small-cell lung cancer. J Clin Oncol 8:1301-1309, 1990.
56. Johnson DH: Chemotherapy for metastatic non-small-cell lung cancer-Can that dog hunt? J Natl Cancer Inst 85:766-767, 1993.
57. Shepherd FA: Treatment of advanced non-small cell lung cancer. Semin Oncol 21(suppl 7):7-18, 1994.
58. Lilenbaum RC, Green MR: Novel chemotherapeutic agents in the treatment of non-small-cell lung cancer. J Clin Oncol 11:1391-1402, 1993.
59. Feigal EG, Christian M, Cheson B, et al: New chemotherapeutic agents in non-small-cell lung cancer. Semin Oncol 20:185-201, 1993.
60. Cortes-Funes H, Mathe: Vinorelbine: A key option in cancer chemotherapy. Drugs 44 (suppl 4):1-69, 1992.
61. Yarbro JW, Bornstein RS, Mastrangelo MJ: Navelbine. Semin Oncol 16(suppl 4):1-45, 1989.
62. Binet S, Fellous A, Lataste H, et al: In situ analysis of the action of Navelbine on various types of microtubules using immunofluorescence. Semin Oncol 16(suppl 4):5-8, 1989.
63. Cros S, Wright M, Morimoto M, et al: Experimental antitumor activity of Navelbine. Semin Oncol 16(suppl 4):15-20, 1989.
64. Adams DJ: Synergy of Navelbine-Taxol combination treatment in two human breast cancer cell lines. Proc Am Assoc Cancer Res 35:327, 1994.
65. Mathe G, Ribaud P, Gouvela J, in Pierre Fabre Internal Report on Navelbine. Part IVB, Vol. 2, p 38, 1988.
66. Favre R, Serage J, in Pierre Fabre Internal Report of Navelbine. Part IVB, Vol. 5, p 38, 1988.
67. Cvitkovic E and Izzo J: The current and future place of vinorelbine in cancer therapy. Drugs 44(suppl 4):36-45, 1992.
68. Jehl F, Quoix E, Leveque D, et al: Pharmacokinetic and preliminary metabolic fate of navelbine in humans as determined by high performance liquid chromatography. Cancer Res 51:2073-2076, 1991.
69. Marquet P, Lachatre G, Debord J, et al: Pharmacokinetics of vinorelbine in man. Eur J Clin Pharmacol 42:545-547, 1992.
70. Rowinsky EK, Noe DA, Trump DL, et al: Pharmacokinetic, bioavailability, and feasibility study of oral vinorelbine in patients with solid tumors. J Clin Oncol 12:1754-1763, 1994.
71. Zhou XJ, Bore P, Monjanel S, et al: Pharmacokinetics of navelbine after oral administration in cancer patients. Cancer Chemother Pharmacol 29:66-70, 1991.
72. Lucas S, Rowinsky E, Wargin W, et al: Results of a study of the effect of food on the bio- availability (BA) and pharmacokinetics (PK) of Navelbine (NVB) liquid-filled soft gelatin capsules (abstract). Proc Am Soc Clin Oncol 12:160, 1993.
73. Depierre A, Lemarie E, Dabouis G, et al: A phase II study of navelbine (vinorelbine) in the treatment of non-small cell lung cancer. Am J Clin Oncol 14:115-119, 1991.
74. Yokoyama A, Furuse K, Niitani H, et al: Multi-institutional phase II study of navelbine (vinorelbine) in non-small cell lung cancer (abstract). Proc Am Soc Clin Oncol 11:287, 1992.
75. Berthaud P, Le Chevalier T, Ruffie P, et al: Phase I-II study of vinorelbine (Navelbine) plus cisplatin in advanced non-small cell lung cancer. Eur J Cancer 28A(11): 1863-1865, 1992.
76. Le Chevalier 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 12:360-367, 1994.
77. Depierre A, Chastang C, Quoix E, et al: Vinorelbine versus vinorelbine plus cisplatin in advanced non-small cell lung cancer: A randomized trial. Ann Oncol 5:37-42, 1994.
78. O'Rourke M, Crawford J, Schiller J, et al: Survival advantage for patients with stage IV NSCLC treated with single agent Navelbine in a randomized controlled trial. Proc Am Soc Clin Oncol 12:343, 1993.
79. Perol M, Guerin JC, Kleisbauer JP, et al: Multicenter randomized trial comparing cisplatin mitomycin-vindesine vs cisplatin-mitomycin-Navelbine in advanced non-small cell lung cancer (NSCLC) (abstract ). Lung Cancer 11(suppl 1):114, 1994.
80. Vergnenegre A, Pham E, Perol M, et al: Cost effectiveness analysis of two chemotherapy regimens in a randomized multicenter trial for stage Ill and IV non-small cell lung cancer (abstract). Lung Cancer 11 (suppl 1):14, 1994.
81. Vokes EE, Rosenberg RK, Jahanzeb M, et al: Multicenter phase II study of weekly oral vinorelbine for stage IV non-small cell lung cancer. J Clin Oncol 13:637-644, 1995.
82. Brooks BJ, Gralla RJ, McGaw HJ, et al: Cisplatin + vinorelbine (Navelbine) combination chemotherapy for advanced non-small cell lung cancer testing the efficacy of a regimen designed to reduce toxicity and increase dose-intensity (abstract). Proc Am Soc Clin Oncol 13:348, 1994.
83. Drinkard L, Samuels B, Hoffman P, et al: A phase I-II trial of cisplatin (CDDP), 5-fluorouracil (5FU), leucovorin (PFL), and Navelbine (NVB) in advanced non small cell lung cancer (NSCLC) (abstract). Lung Cancer 11(suppl 1): 122, 1994.
84. de Cremoux H, Monnet 1, Axli N, et al: Fluorouracil (FU/leucovorin (AF)/ vinorelbine (VNB) /cisplatin (P) in non small cell lung cancer (NSCLC): A phase II study (abstract). Proc Am Soc Clin Oncol 11:303 , 1992.
85. Bensmiene MA, Monnet I, Cvitkovic E, et al: Cisplatin (P)/5-f luorouracil (5FU) and escalating doses of vinorelbine (VNB) for advanced non small cell lung cancer (NSCLC) (abstract). Proc Am Soc Clin Oncol 13:359, 1994 .
86. Gridelli C, De Placido S, Pepe R, et al: Phase I study of epirubicin (EDX) plus vinorelbine (VNR) with or without G-CSF in advanced non small cell lung cancer (NSCLC) (abstract). Proc Am Soc Clin Oncol 12:343, 1993.
87. Bakker M, Groen HJM, Dieben-Paauwen J, et al: High-dose epirubicin (E) and vinorelbine (V) in previously untreated advanced non-small cell lung cancer (NSCLC): A feasibility study (abstract). Proc Am Soc Clin Oncol 13:360, 1994.
88. Marantz A, Lewi D, Litovska S: Phase II study of vinorelbine (VN) and ifosfamide (IFX) for non-small cell II lung cancer (NSCLC) (abstract). Proc Am Soc Clin Oncol 13:325, 1994 .
89. Morere JF, Brunet A, Duran A, et al: Ifosfamide (IFX) and vinorelbine (NVB) in advanced non small cell lung cancer (NSCLC) (abstract). Proc Am Soc Clin Oncol 134:344, 1994 .
90. Hoffman P, Drinkard L, Masters G, et al: Ifosfamide plus Navelbine: A phase I-study in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol, 1995 (in press).
91. Crawford J, O'Rourke MA, Hohneker J, and Burman S: A phase I/II trial of dose escalation of navelbine in combination with carboplatin in patients with advanced non-small cell lung cancer (NSCLC) (abstract). Proc Am Soc Clin Oncol 13:351, 1994.