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© 2000 American Society for Clinical Oncology Phase II Trial of Docetaxel and Vinorelbine in Patients With Advanced Non–Small-Cell Lung CancerFrom the Thoracic Oncology Service, Division of Solid Tumor Oncology, and Departments of Medicine and Radiology, Memorial Sloan-Kettering Cancer Center, Cornell University Medical College, New York, NY. Address reprint requests to Vincent A. Miller, MD, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email millerv{at}mskcc.org
PURPOSE: Docetaxel and vinorelbine are active agents in advanced non–small-cell lung cancer (NSCLC) and demonstrate preclinical synergism perhaps, in part, through their inactivation of the proto-oncogene bcl-2. We show that docetaxel (60 mg/m2) and vinorelbine (45 mg/m2) can be safely combined when given on an every 2-week schedule with filgrastim, with encouraging antitumor activity observed. PATIENTS AND METHODS: Thirty-five chemotherapy naïve patients with advanced NSCLC received vinorelbine as an intravenous push immediately followed by docetaxel as a 1-hour intravenous infusion once every 2 weeks. Prophylactic corticosteroids, ciprofloxacin, and filgrastim were used. RESULTS: We delivered median doses of 450 mg/m2 of vinorelbine and 600 mg/m2 of docetaxel. The major objective response rate was 51% (95% confidence interval [CI], 34% to 68%). With a median follow-up of 14 months, the predicted median survival time was 14 months, and the 1-year survival rate was 60% (95% CI, 44% to 80%). Febrile neutropenia occurred in five patients and five (1.3%) of 384 treatments. No dose-limiting neurotoxicity occurred. Symptomatic onycholysis and excessive lacrimation were observed after several months or more of therapy. CONCLUSION: Docetaxel 60 mg/m2 and vinorelbine 45 mg/m2, both given every 2 weeks, is a highly active combination for the treatment of advanced NSCLC. Filgrastim largely obviates neutropenic fever and allows for the single-agent dose-intensity of both drugs to be delivered. The occurrence of certain late toxicities can limit use in some cases and suggests that the combination could also be beneficial in settings requiring briefer, fixed periods of treatment, such as in induction or postoperative therapy.
DOCETAXEL AND VINORELBINE are active agents in advanced non–small-cell lung cancer (NSCLC) and demonstrate preclinical synergism perhaps, in part, through their inactivation of the proto-oncogene bcl-2.1 Docetaxel is a semisynthetic taxane prepared from a precursor compound derived from the needles of the European yew, Taxus baccata, that exerts antitumor effects partially through promotion of microtubule assembly and inhibition of tubulin depolymerization. Phase II trials of docetaxel in several hundred advanced NSCLC patients have reported major response rates ranging from 19% to 38%, making this agent one of the most active drugs ever tested in NSCLC.2 Vinorelbine is a semisynthetic vinca alkaloid approved in the United States as a single agent or in combination with cisplatin for the treatment of advanced NSCLC.3 An extensive body of preclinical in vivo and in vitro data suggests synergistic or at least additive antitumor effects when docetaxel or paclitaxel and vinorelbine are combined and administered at approximately the same time. Alternate schedules may result in increased toxicity or lessened efficacy.4-8 Our phase I trial demonstrated that vinorelbine 45 mg/m2 and docetaxel 60 mg/m2 could be safely combined on an every 2-week schedule.9 Therefore, this phase II study was undertaken to define the activity and more fully characterize the toxicity of the combination in patients with advanced NSCLC.
Eligibility All patients had unresectable stage IIIB (malignant pleural or pericardial effusion) or IV NSCLC and a Karnofsky performance status  70%. Unirradiated measurable or assessable indicator lesions were required. No radiotherapy to major bone marrow areas was allowed within 4 weeks of treatment initiation. No prior chemotherapy for NSCLC was permitted. Laboratory requirements for eligibility included an absolute neutrophil count 2,000/µL, platelet count 100,000/µL, serum bilirubin  the upper limit of normal (ULN), AST 1.5 times the ULN, alkaline phosphatase five times the ULN, and creatinine 2.0 mg/dL. Patients with symptomatic brain metastases or symptomatic peripheral neuropathy grade 2 (National Cancer Institute common toxicity criteria [NCI CTC]) were excluded. Written informed consent was obtained from all patients, and the protocol was approved by the Institutional Review Board of Memorial Sloan-Kettering Cancer Center.
Treatment Plan
Docetaxel and vinorelbine were administered in the outpatient department. Vinorelbine 45 mg/m2 (Navelbine; Glaxo Wellcome, Research Triangle Park, NC) was prepared according to manufacturer’s instructions, diluted in 125 mL of normal saline, and given over 6 to 10 minutes as an intravenous push. Docetaxel 60 mg/m2 (Taxotere, Rhone-Poulenc Rorer, Collegeville, PA) was packaged, dispensed, and stored, as previously reported.14 Docetaxel was administered as a 1-hour infusion immediately after the completion of vinorelbine. All patients received dexamethasone, 8 mg orally every 12 hours for five doses, starting 24 hours before planned chemotherapy administration. No other prophylactic antiemetics were used. Filgrastim was given as a subcutaneous injection at a dose of 5 µg/kg starting 48 hours after treatment and continued for a minimum of 6 days and then until the absolute neutrophil count was
From March 1997 to October 1998, 35 patients with pathologically confirmed NSCLC were enrolled, all of whom were treated and assessable for response and toxicity. Nearly all patients had stage IV disease (91%), and approximately half were women. Patient characteristics are summarized in Table 1.
Response and Survival Eighteen confirmed major responses (16 partial responses and two improved) were documented (major response rate, 51%; 95% confidence interval [CI], 34% to 68%). Thirteen patients had stable disease and four had progressive disease as the best response to therapy. The median time from therapy initiation to documentation of major response status was 2 months (range, 1 to 5 months). The median duration of response was 6 months (range, 4 to 16+ months). The median time to progression was 7 months. The predicted median survival time is 14 months (95% CI, 12 months to not yet reached), and the predicted 1-year survival rate is 60% (95% CI, 44% to 80%). The Kaplan-Meier survival curve is displayed in Fig 1.
Toxicity Toxicity data are reported in Table 2 as the worst toxicity grade experienced per patient at any time in the trial (NCI CTC version 2.0). One patient died of Hemophilus influenza pneumonia and sepsis in the absence of neutropenia. Nonneutropenic infection occurred in 14 other patients and most commonly was bronchitis or mucopurulent rhinitis (grade 2), which was successfully managed in an outpatient setting. Six patients had grade 3 infections including pneumonia (n = 3), paronychia (n = 1), Mediport catheter (n = 1), and emphysematous cholecystitis (n = 1). Febrile neutropenia occurred in five patients and five (1.3%) of 384 treatments. Eighteen patients required some dose reduction or discontinuation of one agent. The most common reasons for dose reduction or discontinuation included onycholysis (four patients, 25% reduction in docetaxel dose only), neutropenic fever (four patients, 25% reduction in both docetaxel and vinorelbine doses), and conjunctivitis/excessive lacrimation (three patients, docetaxel discontinued after six, 11, and 17 cycles). Two patients were felt to have dyspneic reactions attributed to vinorelbine, and, in those individuals, the drug was discontinued after four and 10 cycles, respectively; docetaxel was continued uneventfully. Clinically relevant fluid retention, sensory neuropathy, nausea and vomiting, and thrombocytopenia were rare.
The overall calculated dose-intensity (delivered/planned dose x 100) was 89% for docetaxel and 85% for vinorelbine. The median delivered docetaxel dose was 600 mg/m2 (range, 120 to 1560 mg/m2). The median delivered vinorelbine dose was 450 mg/m2 (range, 90 to 1170 mg/m2). The median number of treatments was 10 (range, two to 26 treatments). The median delivered dose-intensity was 27 mg/m2/wk for docetaxel and 19 mg/m2/wk for vinorelbine.
This study sought to determine the antitumor activity of docetaxel and vinorelbine when administered every 2 weeks with prophylactic filgrastim, dexamethasone, and ciprofloxacin to patients with advanced NSCLC. Our schedule was based on our phase I trial and preclinical studies of the combination, which suggested that simultaneous administration was optimal vis-a-vis toxicity/efficacy and that separation by 24 hours or more might lead to an increase in toxicity. We found the combination to be highly active, with an encouraging response rate and predicted 1-year survival. Clinically meaningful hematologic toxicity was unusual, with febrile neutropenia occurring in only 1.3% of the cycles when prophylactic filgrastim and ciprofloxacin were used. With a high response rate and few neutropenic complications, we were able to deliver a high dose-intensity of both agents for prolonged periods. With protracted treatment duration, excessive lacrimation and onycholysis, often painful, became problematic. Although onycholysis is a known adverse effect of chronic docetaxel therapy, lacrimation has only occasionally been described. The pathogenesis of these adverse effects is unclear and their management is challenging. Meticulous nail care seems paramount to prevention of paronychia, but painful onycholysis may take several months to resolve after discontinuation of therapy. Lacrimation was frequently bothersome (grade 2) but rarely interfered with function (grade 3). There was no clear benefit to the use of artifical tears or topical steroids. We also observed four patients who developed dyspnea at rest and pulmonary infiltrates, which developed after a number of treatments and without any infectious etiology identified at bronchoscopy. These patients responded rapidly to corticosteroids, and treatment with both docetaxel and vinorelbine continued uneventfully. Similar toxicities have been described with gemcitabine and paclitaxel.15,16 Other phase II trials of docetaxel and vinorelbine in NSCLC have generally used an every 3-week schedule of drug administration. Monnier et al17 administered docetaxel 75 mg/m2 (25 mg/m2/wk) every 21 days with vinorelbine 20 mg/m2 (13 mg/m2/wk) on days 1 and 5. Grade 4 neutropenia was reported in 77% of patients and febrile neutropenia in 42% of patients. Six (23%) of 26 patients attained a partial response. A trial of Kourousis et al18 administered vinorelbine 25 mg/m2 (day 1) followed by docetaxel 100 mg/m2 (day 2) every 21 days with prophylactic filgrastim. In this study, the median delivered dose-intensity was 29 mg/m2/wk for docetaxel and 7 mg/m2/wk for vinorelbine. In this trial, a 37% response rate (95% CI, 22% to 51%) was observed in 46 patients. However, four deaths occurred as result of sepsis (n = 2) or nonneutropenic pulmonary infections (n = 2), despite the fact that 70% of patients had a World Health Organization performance status of 0 and filgrastim was prospectively used. The median survival time was 5 months. Although it is difficult to compare phase II studies from an efficacy standpoint, these results suggest that use of prophylactic filgrastim and ciprofloxacin allows improved drug delivery and may lessen hematologic toxicity and possibly infectious complications. Our study was undertaken, in part, because of diverse and extensive preclinical evidence of synergism between the taxanes, docetaxel or paclitaxel, and vinorelbine in a variety of common solid tumors. Recent studies have suggested that the mechanisms of action of docetaxel and paclitaxel are not limited to microtubule stabilization but include Raf-1 phosphorylation, p34CDC2 activation, antiangiogenic effects, and phosphorylation of the proto-oncogene bcl-2 (overexpressed in approximately 20% of NSCLC).2,19,20 Intriguingly, both docetaxel and vinorelbine seem to lead to phosphorylation of bcl-2 on serine residues, leading to inactivation of this protein and facilitating the unopposed action of the proapoptotic protein bax. Furthermore, overexpression of bax has been associated with prolonged intracellular retention of paclitaxel and improved outcome in ovarian cancer.21 This link between an apoptotic pathway relevant in a variety of common cancers and a possible molecular target of action of the taxanes merits further investigation. In an ongoing correlative study, we are performing immunohistochemical analysis of all available pathologic specimens (n = 23) for bcl-2, bax, and p53 expression. These measurements may allow for identification of a profile of a patient most likely (or unlikely) to benefit from this therapy. The degree of activity and survival observed in this trial with vinorelbine and docetaxel equals or exceeds that seen with two-drug cisplatin-containing combinations tested at our institution.10,22 Because the occurrence of certain late toxicities can limit use in some cases, future clinical trials will target settings requiring briefer, fixed periods of treatment, such as in induction or postoperative therapy. These results also support a clinical trial comparing the docetaxel/vinorelbine combination with a platinum-containing regimen. The combination should be considered for study in other cancers where both agents are active including breast, ovarian, head and neck, and bladder cancers.
Supported in part by Rhone-Poulenc Rorer, Inc, Collegeville, PA. V.A.M. is the recipient of an American Cancer Society Clinical Oncology Career Development Award.
Presented in part at the Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15-18, 1999.
1. Haldar S, Basu A, Croce C: Bcl2 is the guardian of microtubule integrity. Cancer Res 57:229-233, 1997 2. Miller VA, Ng K, Grant SC, et al: New chemotherapeutic agents in NSCLC, in Roth JA, Cox JD, Hong WK (eds): Lung Cancer (ed 2). Malden, MA,Blackwell Science, Inc, 1998, pp 217-234 3. Miller VA, Kris MG: Vinorelbine for the treatment of advanced non-small cell lung cancer. Med Lett Drugs Ther 37:72-73, 1995[Medline] 4. Bissery MC, Vrignaud P, Bayssas M, et al: Preclinical in vivo activity of docetaxel-containing combinations. Clin Oncol 14:489, 1995 (abstr 1599) 5. Aoe K, Ueoka H, Kiura K, et al: Synergistic effect of docetaxel (DCT) and vinorelbine (VNB) against in vitro growth of a human small-cell lung cancer cell line. Proc Am Assoc Cancer Res 37:375, 1996 (abstr 2560)
6.
Knick V, Eberwein D, Miller CG: Vinorelbine tartrate and paclitaxel combinations: Enhanced activity against in vivo P388 murine leukemia cells. Cancer Inst 87:1072-1077, 1995 7. Botta M, Arboscello E, Lerza R, et al: Effects of docetaxel on the in vitro growth of human myeloid progenitors. Res 19:1855-1858, 1999 8. Aoe K, Kiura K, Ueoka H, et al: Effect of docetaxel with cisplatin or vinorelbine on lung cancer cell lines. Anticancer Res 19:291-300, 1999[Medline] 9. Miller V, Grant S, Ng K, et al: Phase I trial of docetaxel (DTX) and vinorelbine (VNR) with filgrastim in patients with advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 17:471a, 1998, (abstr 1813) 10. 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[Medline] 11. Eagan RT, Fleming TR, Schoonover V: Evaluation of response criteria in advanced lung cancer. Cancer 44:1125-1128, 1979 [Medline]
12.
Jett JR, Su JQ, Krook JE, et al: Measurable or assessable disease in lung cancer trials: Does it matter? J Clin Oncol 12:2677-2681, 1994 13. Fleming TR: One-sample multiple testing procedure for phase II clinical trials. Biometrics 38:143-151, 1982[Medline] 14. Miller VA, Rigas JR, Francis PA, et al: Phase II trial of a 75-mg/m2 dose of docetaxel with prednisone premedication for patients with advanced non-small cell lung cancer. Cancer 75:968-972, 1995[Medline]
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Vander Els NJ, Miller V: Successful treatment of gemcitabine toxicity with a brief course of oral corticosteroid therapy. Chest 114:1779-1781, 1998
16.
Ramanathan RK, Belani CP, Reddy VV: Transient pulmonary infiltrates: A hypersensitivity reaction to paclitaxel. Ann Intern Med 124:278, 1996 (letter) 17. Monnier A, Riviere A, Douillard JY, et al: Phase II study of docetaxel (Taxotere) and vinorelbine in chemotherapy naive patients with advanced non–small-cell lung carcinoma (NSCLC). Proc Am Soc Clin Oncol. 15:378, 1996 (abstr 1129) 18. Kourousis C, Androulakis N, Kakolyris S, et al: First-line treatment of advanced nonsmall cell lung carcinoma with docetaxel and vinorelbine. Cancer 83:2083-2090, 1998[Medline]
19.
Blagosklonny MV, Schulte T, Nguyen P, et al: Taxol-induced apoptosis and phosphorylation of Bcl-2 protein involves c-Raf-1 and represents a novel c-Raf-1 signal transduction pathway. Cancer Res 56:1851-1854, 1996
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Klaubner N, Parangi S, Flynn E, et al: Inhibition of angiogenesis and breast cancer in mice by the microtubule inhibitors 2-methoxyestradiol and taxol. Cancer Res 57:81-86, 1997
21.
Strobel T, Kraeft S-K, Chen LB, et al: BAX expression is associated with enhanced intracellular accumulation of paclitaxel: A novel role for BAX during chemotherapy-induced cell death. Cancer Res 58:4776-4781, 1998 22. Kris M, Gralla R, Wertheim M, et al: Trial of the combination of mitomycin, vindesine, and cisplatin in patients with advanced non-small cell lung cancer. Cancer Treat Rep 70:1091-1096, 1986[Medline] Submitted August 3, 1999; accepted November 26, 1999. This article has been cited by other articles:
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
